1.Catabolism of purine nucleotides Purines are metabolised by several enzymes: 1) Guanine * A nuclease frees the nucleotide * A nucleotidase creates guanosine, * Purine nucleoside phosphorylase converts guanosine to guanine, * Guanase converts guanine to xanthine, * Xanthine oxidase (a form of xanthine oxidoreductase) catalyzes the oxidation of xanthine to uric acid 2) Adenine a) A nuclease frees the nucleotide **A nucleotidase creates adenosine, then adenosine deaminase creates inosine ** Alternatively, AMP deaminase creates inosinic acid, then a nucleotidase creates inosine, ** Purine nucleoside phosphorylase acts upon inosine to create hypoxanthine, ** Xanthine oxidoreductase catalyzes the biotransformation of hypoxanthine to xanthine, ** Xanthine oxidoreductase acts upon xanthine to create uric acid

2. Hereditary disorders of uric acid metabolism.

Hyperuricemia is a level of uric acid in the blood that is abnormally high. In humans, the upper end of the normal range is 360 µmol/L (6 mg/dL) for women and 400 µmol/L (6.8 mg/dL) for men.

Can be associated with Increased production of Uric acid (Lesch-Nychan syndrome) and decreased excretion (gout).

Lesh-Nychan syndrome caused by defect in hypoxantine-guanine phosphoribosyl transferaze – enzyme responsible for Purine salvage (decrease of its amount)

Von Gierkes Disease caused by glucose 6 phosphate deficiency that is responsible for purine overproduction.

Gout arthritis due to accumulation of uric acid.

3.Pyrimidine Catabolism - Pyrimidines are ultimately catabolized (degraded) to CO₂, H₂O, and urea. Cytosine can be broken down to uracil which can be further broken down to N-carbamoyl-β-alanine. Thymine is broken down into β-aminoisobutyrate which can be further broken down into intermediates eventually leading into the citric acid cycle. β-aminoisobutyrate acts as a rough indicator for rate of DNA turnover.

4.Biochemical functions of nucleic acids and nucleotides. Formation of chains.

Nucleic acids are biopolymers that consist of nucleotides, each of them consist of:

Nucleoside – derivative of purine/pyrimidine with attached sugar (ribose/deoxyribose) to nitrogen ring.

Phosphoryl group estrified to a sugar ring.

Function: Nucleic acids are long chains f nucleotides of 4 types (deoxyguanylate, deoxyadenylate, deoxycytidylate, thiamidylate) certain sequences of those are forming DNA code that stores the informations about synthesis of proteins.

Synthesis of nucleic acid from nucleotides: Chains of nucleotides can be formed due to esterification and forming phosphodiester. Phosphodiester bonds can link the other monomers (nucleotides).

5.Nucleic acids: structure, properties, stages of investigation, primary structure of polynucleotides, specifity of DNA RNA structure.

Structue: Nucleic acids are long chains of nucleotides of 4 types (deoxyguanylate, deoxyadenylate, deoxycytidylate, thiamidylate)(DNA)

RNA is similar however sugar that is part of nucleoside is ribose, Rna is single stranded, theres Uracil ribonucleotide in RNA except of thymine.

Properties: DNA consist of sequence of deoxyribonucleotides which has ability to code-encrypt information about symthesis of protein its written in the sequence of deoxyribonucleotides.

Primary structure of nucleic acid is sequence of nucleotides. (AATCGGA etc), Polarity of polynucleotides

6.Secondary structure od DNA, role of hydrogen bonds in stabilization of secondary structure, antiparallelism of DNA chains.

Secondary structure of DNA is based on complementary rule it means that nucleotides of 2 strands are allowed to bind only to other specific nucleotides (e.g adenine-thymine, cytosine-uracil).

Hydrogen bonds are essential in maintaining of secondary structure od DNA via them nucleotides are bounded together and double strand structure is maintained. Hydrogen bonding is the chemical mechanism that underlies the base-pairing rules described above. Appropriate geometrical correspondence of hydrogen bond donors and acceptors allows only the "right" pairs to form stably. DNA with high GC-content is more stable than DNA with low GC-content, but contrary to popular belief, the hydrogen bonds do not stabilize the DNA significantly and stabilization is mainly due to stacking interactions.

Chargaff's rules state that DNA from any cell of all organisms should have a 1:1 ratio of pyrimidine and purine bases and, more specifically, that the amount of guanine is equal to cytosine and the amount of adenine is equal to thymine. This pattern is found in both strands of the DNA.

Antiparallelism means that 2 strands of dna are never parallel and they are going in opposite directions. (3'-5’ and 5-3).

7. Tetriary structure of DNA. Physico-chemical properties of DNA : interactions with cationic ligands, hyperchromic effect; denaturation/renaturation of DNA.

Tertiary structure of DNA means its double helix form. Helix makes full twist every (10.5 pair).

Hyperchromic effect of DNA is the increase of optic absorbance of solution.

Denaturatio/renaturation of DNA: Denaturation of DNA occurs under influence of heat it leads to unwind of double helix and form single strand.

Renaturation: Single strands can bind to each other under certain physiological conditions and salt concentration. However they will bind only to complementary strands.

8.Structure, properties and biological functions of RNA. Structure: Each nucleotide in RNA contains a ribose sugar, with carbons numbered 1' through 5'. A base is attached to the 1' position, in general, adenine (A), cytosine (C), guanine (G), or uracil (U). Adenine and guanine are purines, cytosine, and uracil are pyrimidines.

Biological function of RNA depends on its type:

mRNA carries information about a protein sequence to the ribosomes, the protein synthesis factories in the cell. It is coded so that every three nucleotides (a codon) correspond to one amino acid.

Transfer RNA (tRNA) is a small RNA chain of about 80 nucleotides that transfers a specific amino acid to a growing polypeptide chain at the ribosomal site of protein synthesis during translation. It has sites for amino acid attachment and an anticodon region for codon recognition that binds to a specific sequence on the messenger RNA chain through hydrogen bonding.

Ribosomal RNA (rRNA) is the catalytic component of the ribosomes.

Small nuclear ribonucleic acid (snRNA) is a class of small RNA molecules that are found within the nucleus of eukaryotic cells. They are transcribed by RNA polymerase II or RNA polymerase III and are involved in a variety of important processes such as RNA splicing.

9.Organisation of molecular chromatin and ribosomes. In general terms, there are three levels of chromatin organization:

1. DNA wraps around histone proteins forming nucleosomes; the "beads on a string" structure (euchromatin).

2. Multiple histones wrap into a 30 nm fibre consisting of nucleosome arrays in their most compact form (heterochromatin).

3. Higher-level DNA packaging of the 30 nm fibre into the metaphase chromosome (during mitosis and meiosis).

Ribosomes consist of 2 subunits they are made of rRNA and proteins

10.General Scheme of DNA synthesis

Steps of replication:

1. Identification of the origins of replication.

2. Unwinding (denaturation) of dsDNA to provide an ssDNA

template.

3. Formation of the replication fork.

4. Initiation of DNA synthesis and elongation.

5. Formation of replication bubbles with ligation of the newly

synthesized DNA segments

6. Reconstitution of chromatin structure.

Enzymes of replication:

Polymerazes (eukaryotic)

There are at least 15 Eukaryotic DNA polymerases:^[1]

POLA1, POLA2: Pol α (also called RNA primase): forms a complex with a small catalytic (PriS) and a large noncatalytic (PriL) subunit^[2], with the Pri subunits acting as a primase (synthesizing an RNA primer), and then with DNA Pol α elongating that primer with DNA nucleotides. After around 20 nucleotides^[3] elongation is taken over by Pol ε (on the leading strand) and δ (on the lagging strand).

POLB: Pol β: Implicated in repairing DNA, in base excision repair and gap-filling synthesis.

POLG, POLG2: Pol γ: Replicates and repairs mitochondrial DNA and has proofreading 3'->5' exonuclease activity.

POLD1, POLD2, POLD3, POLD4: Pol δ: Highly processive and has proofreading 3'->5' exonuclease activity. Thought to be the main polymerase involved in leading strand synthesis, though there is still debate about its role^[4].

POLE, POLE2, POLE3: Pol ε: Also highly processive and has proofreading 3'->5' exonuclease activity. Highly related to pol δ, and thought to be the main polymerase involved in lagging strand synthesis^[5], though there is again still debate about its role^[4].

Procariotic Polymerazes

 Pol I: implicated in DNA repair; has 5'->3' polymerase activity, and both 3'->5' exonuclease activity (proofreading) and 5'->3' exonuclease activity (RNA primer removal).

 Pol II: involved in repairing damaged DNA; has 3'->5' exonuclease activity.

 Pol III: the main polymerase in bacteria (responsible for elongation); has 3'->5' exonuclease activity (proofreading).

Helicase- enzyme responsible for rupture of double strand and formation of replication fork (leading and lagging strand)

Topoisomerazes – enzymes responsible for unwinding DNA

11. transcription: General scheme of transcription. Coding and noncoding DNA chains. RNA polymerases. Stages and enzymes of RNA synthesis. Markers of transcription: promotor, initiator, termination of transcription.

 -Transcription is the process of creating a complementary RNA copy of a sequence of DNA.During transcription, a DNA sequence is read by RNA polymerase, which produces a complementary, antiparallel RNA strand. As opposed to DNA replication, transcription results in an RNA complement that includes uracil (U) in all instances where thymine (T) would have occurred in a DNA complement.

 -Transcription can be explained easily in 4 or 5 steps, each moving like a wave along the DNA.

1.Helicase unwinds/"unzips" the DNA by breaking the hydrogen bonds between complementary nucleotides.

2.RNA nucleotides are paired with complementary DNA bases.

3.RNA sugar-phosphate backbone forms with assistance from RNA polymerase.

4.Hydrogen bonds of the untwisted RNA+DNA helix break, freeing the newly synthesized RNA strand.

5/If the cell has a nucleus, the RNA is further processed (addition of a 3' poly-A tail and a 5' cap) and exits through to the cytoplasm through the nuclear pore complex.

 -Coding/Non-Coding DNA chains

When referring to DNA transcription, the coding strand is the DNA strand which has the same base sequence as the RNA transcript produced (although with thymine replaced by uracil). It is this strand which contains codons, while the non-coding strand contains anti codons.

 RNA Polymerases I,II,III,IV,V

 -Stages of Transcription(RNA synthesis):

1.Pre-initiation

2.Initiation

3.Promoter Clearance

4.Elongation

5.Termination

12. translation: Stages of Translation: 1.Initiation

The protein factors bind the small ribosomal subunit (also referred to as the 40S subunit), and these initiation factors hold the mRNA in place. START CODON: Methionine. Eukaryotic initiation factors (eIF) are proteins involved in the initiation phase of eukaryotic translation. They function in forming a complex with the 40S ribosomal subunit and Met-tRNAi called the 43S preinitation complex (PIC). 2.Elongation At the end of the initiation step, the mRNA is positioned so that the next codon can be translated during the elongation stage of protein synthesis. The initiator tRNA occupies the P site in the ribosome, and the A site is ready to receive an aminoacyl-tRNA. During chain elongation, each additional amino acid is added to the nascent polypeptide chain in a three-step microcycle. The steps in this microcycle are (1) positioning the correct aminoacyl-tRNA in the A site of the ribosome, (2) forming the peptide bond and (3) shifting the mRNA by one codon relative to the ribosome.

 

Elongation in eukaryotes is carried out with two elongation factors: eEF-1 and eEF-2.

a) The first is eEF-1, and has two subunits, α and βγ. α acts as counterpart to prokaryotic EF-Tu, mediating the entry of the aminoacyl tRNA into a free site of the ribosome. βγ acts as counterpart to prokaryotic EF-Ts, serving as the guanine nucleotide exchange factor for α, catalyzing the release of GDP from α.

b) The second elongation factor is eEF-2, the counterpart to prokaryotic EF-G, catalyzing the translocation of the tRNA and mRNA . 3.Termination Termination of elongation is dependent on eukaryotic release factors.

Eukaryotic translation termination factor 1 (eRF1), also known asTB3-1,or, eRF, which recognizes all three stop codons in place of RF1, RF2, or RF3.

13. hormones: A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism.

Hormones initiate response by affecting receptors on cell membrane ( protein hormones) or intracellular ( steroid hormones)

-For many hormones, including most protein hormones, the receptor is membrane-associated and embedded in the plasma membrane at the surface of the cell(for protein hormones)

-Some protein hormones also interact with intracellular receptors located in the cytoplasm or nucleus by an intracrine mechanism(in steroid hormones

They can do so because they are lipid-soluble. The combined hormone-receptor complex then moves across the nuclear membrane into the nucleus of the cell, where it binds to specific DNA sequences, effectively amplifying or suppressing the action of certain genes, and affecting protein synthesis. However, it has been shown that not all steroid receptors are located intracellularly. some are associated with the plasma membrane.

 

 Hormone-receptor complex concentrations are effectively determined by three factors:

 -The number of hormone molecules available for complex formation

-The number of receptor molecules available for complex formation

-The binding affinity between hormone and receptor.

 

 Classification:  -Peptide hormones consist of chains of amino acids. Small peptide hormones: TRH, Vasopressin

protein hormones: insulin, growth hormone glycoprotein hormones: luteinizing hormone, Follicle stimulating hormone

 -Lipid and phospholipid:derived hormones Steroid hormones: Testosterone, Cortisol

 -Monoamines derived from aromatic amino acids adrenaline, thyroxine

14. Hormones of hypothalamus: Thyrotropin-releasing hormone:  Stimulate thyroid-stimulating hormone (TSH) release from anterior pituitary (primarily). Stimulate prolactin release from anterior pituitary. Dopamine: Inhibit prolactin release from anterior pituitary Growth hormone-releasing hormone : Stimulate Growth hormone (GH) release from anterior pituitary. Somatostatin : Inhibit Growth hormone (GH) release from anterior pituitary. Inhibit thyroid-stimulating hormone (TSH) release from anterior pituitary. Gonadotropin-releasing hormone : Stimulate follicle-stimulating hormone (FSH) release from anterior pituitary. Stimulate luteinizing hormone (LH) release from anterior pituitary. Corticotropin-releasing hormone : Stimulate adrenocorticotropic hormone (ACTH) release from anterior pituitary. Oxytocin :Uterine contraction Lactation (letdown reflex). Vasopressin : Increase in the permeability to water of the cells of distal tubule and collecting duct in the kidney and thus allows water reabsorption and excretion of concentrated urine

15. Mechanism of hormonal action: Most hormones initiate a cellular response by initially combining with either a specific intracellular or cell membrane associated receptor protein. A cell may have several different receptors that recognize the same hormone and activate different signal transduction pathways, or a cell may have several different receptors that recognize different hormones and activate the same biochemical pathway.

 

For many hormones, including most protein hormones, the receptor is membrane-associated and embedded in the plasma membrane at the surface of the cell. The interaction of hormone and receptor typically triggers a cascade of secondary effects within the cytoplasm of the cell, often involving phosphorylation or dephosphorylation of various other cytoplasmic proteins, changes in ion channel permeability, or increased concentrations of intracellular molecules that may act as secondary messengers (e.g., cyclic AMP). Some protein hormones also interact with intracellular receptors located in the cytoplasm or nucleus by an intracrine mechanism.

 

An important consideration, dictating the level at which cellular signal transduction pathways are activated in response to a hormonal signal, is the effective concentration of hormone-receptor complexes that are formed. Hormone-receptor complex concentrations are effectively determined by three factors:

16. Hormones of anterior pituitary gland: Growth hormone (somatotropin), release under influence of hypothalamic GHRH; inhibited by hypothalamic Somatostatin. !! Prolonged GH excess thickens the bones of the jaw, fingers and toes. Resulting heaviness of the jaw and increased size of digits is referred to as acromegaly. Accompanying problems can include sweating, pressure on nerves, muscle weakness, excess sex hormone-binding globulin, insulin resistance or even a rare form of type 2 diabetes, and reduced sexual function.

~The effects of growth hormone deficiency vary depending on the age at which they occur. In children, growth failure and short stature are the major manifestations of GH deficiency, with common causes including genetic conditions and congenital malformations. It can also cause delayed sexual maturity !!

Prolactin release under influence of multiple hypothalamic (PRH). !! Hyperprolactinaemia is associated with hypoestrogenism, anovulatory infertility, oligomenorrhoea, amenorrhoea, unexpected lactation, and loss of libido in women, and erectile dysfunction and loss of libido in  !! Hypoprolactinemia, or serum prolactin deficiency, is associated with ovarian dysfunction in women, and metabolic syndrome, anxiety, arteriogenic erectile dysfunction, premature ejaculation,oligozoospermia, asthenospermia, hypofunction of seminal vesicles, and hypoandrogenism in men. In one study, normal sperm characteristics were restored when prolactin levels were brought up to normal values in hypoprolactinemic me !!

17. Hormones of posterior pituitary gland: Arginine vasopressin (AVP), is a neurohypophysial hormone found in most mammals, including humans. Vasopressin is a peptide hormone that controls the reabsorption of molecules in the tubules of the kidneys by affecting the tissue's permeability. . It plays a key role in homeostasis. One of the most important roles of AVP is to regulate the body's retention of water; it is released when the body is dehydrated and causes the kidneys to conserve water, thus concentrating the urine, and reducing urine volume. In high concentrations, it also raises blood pressure by inducing moderate vasoconstriction. 1) Increase in the permeability to water of the cells of distal tubule and collecting duct in the kidney 2) Increase in the permeability of the inner medullary portion of the collecting duct to urea, allowing increased reabsorption of urea into the medullary interstitium, down the concentration gradient . 3) Vasopressin increases peripheral vascular resistance and thus increases arterial blood pressure.

 Vasopressin is secreted from the posterior pituitary gland in response to reductions in plasma volume, in response to increases in the plasma osmolality, and in response to cholecystokinin secreted by the small intestine.

The vasopressins are peptides consisting of nine amino acids (nonapeptides). . The amino acid sequence of arginine vasopressin is Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly, with the cysteine residues forming a sulfur bridge. Lysine vasopressin has a lysine in place of the arginine.

 

Oxytocin is a mammalian hormone that acts primarily as a neuromodulator in the brain. Also known as alpha-hypophamine (α–hypophamine). Oxytocin is best known for its roles in female reproduction. It is released in large amounts 1) after distension of the cervix and uterus during labor, and 2) after stimulation of the nipples, facilitating birth and breastfeeding. Oxytocin is a peptide of nine amino acids (a nonapeptide). Its systematic name is cysteine-tyrosine-isoleucine-glutamine-asparagine-cysteine-proline-leucine-glycine-amine (cys–tyr–ile–gln–asn–cys–pro–leu–gly- NH2, or (CYIQNCPLG-NH2). The cysteine residues form a disulfide bond. Oxytocin has a molecular mass of 1007 daltons.

Actions: Letdown Reflex, Uterine Contraction, reduction of urination, Modulation of hypothalamic-pituitary-adrenal axis activity, Autism, Increasing trust and reducing fear, Bonding, sexual arousal, maternal behavior

18. Hormones of pancreatic gland: INSULIN:   Actions:   The actions of insulin on the global human metabolism level include: Control of cellular intake of certain substances, most prominently glucose in muscle and adipose tissue (about two-thirds of body cells) Increase of DNA replication and protein synthesis via control of amino acid uptake Modification of the activity of numerous enzymes The actions of insulin (indirect and direct) on cells include: Increased glycogen synthesis – insulin forces storage of glucose in liver (and muscle) cells in the form of glycogen; lowered levels of insulin cause liver cells to convert glycogen to glucose and excrete it into the blood. This is the clinical action of insulin, which is directly useful in reducing high blood glucose levels as in diabetes. Increased lipid synthesis – insulin forces fat cells to take in blood lipids, which are converted to triglycerides; lack of insulin causes the reverse. Increased esterification of fatty acids – forces adipose tissue to make fats (i.e., triglycerides) from fatty acid esters; lack of insulin causes the reverse. Decreased proteolysis – decreasing the breakdown of protein Decreased lipolysis – forces reduction in conversion of fat cell lipid stores into blood fatty acids; lack of insulin causes the reverse. Decreased gluconeogenesis – decreases production of glucose from nonsugar substrates, primarily in the liver (the vast majority of endogenous insulin arriving at the liver never leaves the liver); lack of insulin causes glucose production from assorted substrates in the liver and elsewhere. Decreased autophagy - decreased level of degradation of damaged organelles. Postprandial levels inhibit autophagy completely. Increased amino acid uptake – forces cells to absorb circulating amino acids; lack of insulin inhibits absorption. Increased potassium uptake – forces cells to absorb serum potassium; lack of insulin inhibits absorption. Insulin's increase in cellular potassium uptake lowers potassium levels in blood. This possible occurs via insulin-induced translocation of the Na+/K+-ATPase to the surface of skeletal muscle cells. Arterial muscle tone – forces arterial wall muscle to relax, increasing blood flow, especially in microarteries; lack of insulin reduces flow by allowing these muscles to contract. Increase in the secretion of hydrochloric acid by parietal cells in the stomach Decreased renal sodium excretion.  Insulin is produced in the pancreas and released when any of several stimuli are detected. These stimuli include ingested protein and glucose in the blood produced from digested food.     In β-cells, insulin is synthesized from the proinsulin precursor molecule by the action of proteolytic enzymes, known asprohormone convertases (PC1 and PC2), as well as the exoproteasecarboxypeptidase E. The endogenous production of insulin is regulated in several steps along the synthesis pathway: At transcription from the insulin gene In mRNA stability At the mRNA translation In the posttranslational modifications     Beta cells in the islets of Langerhans release insulin in two phases. The first phase release is rapidly triggered in response to increased blood glucose levels. The second phase is a sustained, slow release of newly formed vesicles triggered independently of sugar.

19. Catecholamines: are "fight-or-flight" hormones released by the adrenal glands in response to stress. They are part of the sympathetic nervous system. They are called catecholamines because they contain a catechol or 3,4-dihydroxyphenyl group. They are derived from the amino acid tyrosine. In the human body, the most abundant catecholamines are epinephrine (adrenaline), norepinephrine (noradrenaline) and dopamine, all of which are produced from phenylalanineand tyrosine. Various stimulant drugs are catecholamine analogs. Catecholamines are water-soluble and are 50% bound to plasma proteins, so they circulate in the bloodstream. Tyrosine is created from phenylalanine by hydroxylation by the enzyme phenylalanine hydroxylase. (Tyrosine is also ingested directly from dietary protein). It is then sent to catecholamine-secreting neurons. Here, several reactions serially convert tyrosine to L-DOPA, to dopamine, to norepinephrine, and eventually to epinephrine.     Dopamine is the first catecholamine synthesized from DOPA. In turn, norepinephrine and epinephrine are derived from further metabolic modification of dopamine. The enzyme dopamine hydroxylase requires copper as a cofactor and DOPA decarboxylase requires PLP. The rate limiting step in catecholamine biosynthesis is hydroxylation of tyrosine.     Catecholamine synthesis is inhibited by alpha-methyl-p-tyrosine (AMPT), which inhibits tyrosine hydroxylase.     Catecholamines cause general physiological changes that prepare the body for physical activity (fight-or-flight response). Some typical effects are increases in heart rate, blood pressure, blood glucoselevels, and a general reaction of the sympathetic nervous system.     Two catecholamines, norepinephrine and dopamine, act as neuromodulators in the central nervous system and as hormones in the blood circulation.

21.Mineralocorticoids are a class of steroid hormones characterised by their similarity to aldosterone and their influence on salt and water balancesThe name mineralocorticoid derives from early observations that these hormones were involved in the retention of sodium, a mineral. The primary endogenous mineralocorticoid is aldosterone, although a number of other endogenous hormones (including progesterone and deoxycorticosterone) have mineralocorticoid function.Aldosterone acts on the kidneys to provide active reabsorption of sodium and an associated passive reabsorption of water, as well as the active secretion of potassium in the principal cells of the cortical collecting tubule and active secretion of protons via proton ATPases in the lumenal membrane of the intercalated cells of the collecting tubule. This in turn results in an increase of blood pressure and blood volume.Aldosterone is produced in the cortex of the adrenal gland and its secretion is mediated principally by angiotensin but also by adrenocorticotrophic hormone (ACTH) and local potassium levelsAddison’s diseaseis a rare, chronic endocrine disorder wherein the adrenal glands produce insufficient steroid hormones Lifelong, continuous treatment with steroid replacement therapy is required, with regular follow-up treatment and monitoring for other health problemsAldosteronism is a syndrome of high blood pressure and low blood potassium levels caused by an excess of aldosteron.  

20. Steroids of suprarenal glands: Glucocorticoids (GC) are a class of steroid hormones that bind to the glucocorticoid receptor (GR), which is present in almost every vertebrate animal cell. The name glucocorticoid derives from their role in the regulation of the metabolism of glucose, GCs are part of the feedback mechanism in the immune system that turns immune activity (inflammation) down. They are therefore used in medicine to treat diseases that are caused by an overactive immune system, such as allergies, asthma, autoimmune diseases and sepsis. Glucocorticoids are distinguished from mineralocorticoids and sex steroids by their specific receptors, target cells, and effects. Cortisol (or hydrocortisone) is the most important human glucocorticoid. It is essential for life, and it regulates or supports a variety of importantncardiovascular, metabolic, immunologic, and homeostatic functions. Glucocorticoid effects may be broadly classified into two major categories: immunological and metabolic. In addition, glucocorticoids play important roles in fetal development.     Up-regulate the expression of anti-inflammatory proteins     Down-regulate the expression of pro-inflammatory proteins Glucocorticoids are also shown to play a role in the development and homeostasis of T lymphocytes.   Metabolic effects: Stimulation of gluconeogenesis, in particular, in the liver: This pathway results in the synthesis of glucose from non-hexosesubstrates such as amino acids and glycerol from triglyceride breakdown, and is particularly important in carnivores and certain herbivores. Enhancing the expression of enzymes involved in gluconeogenesis is probably the best-known metabolic function of glucocorticoids. Mobilization of amino acids from extrahepatic tissues: These serve as substrates for gluconeogenesis. Inhibition of glucose uptake in muscle and adipose tissue: A mechanism to conserve glucose. Stimulation of fat breakdown in adipose tissue: The fatty acids released by lipolysis are used for production of energy in tissues like muscle, and the released glycerol provide another substrate for gluconeogenesis.   Glucocorticoids not only suppress immune response, but also inhibit the two main products of inflammation, prostaglandins and leukotrienes. Glucocorticoids inhibit prostaglandin synthesis at the level of phospholipase A2 as well as at the level of cyclooxygenase/PGE isomerase (COX-1 and COX-2), the. In addition, glucocorticoids also suppress cyclooxygenase expression.   Cushing Syndrome : Hormones that come from outside the body are called exogenous; hormones that come from within the body are called endogenous. The most common cause of Cushing's syndrome is exogenous administration of glucocorticoids prescribed by a health care practitioner to treat other diseases (called iatrogenic Cushing's syndrome). Cushing's syndrome can also be due to the use of medroxyprogesterone Endogenous Cushing's syndrome results from some derangement of the body's own system of secreting cortisol. In pituitary Cushing's, a benign pituitary adenoma secretes ACTH. This is also known as Cushing's disease and is responsible for 70% of endogenous Cushing's syndrome. In adrenal Cushing's, excess cortisol is produced by adrenal gland tumors, hyperplastic adrenal glands, or adrenal glands with nodular adrenal hyperplasia. Finally, tumors outside the normal pituitary-adrenal system can produce ACTH that affects the adrenal glands.

22. Estrogens are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidalEstrogens are synthesized in all vertebrates[1] as well as some insectsLike all steroid hormones, estrogens readily diffuse across the cell membrane. Once inside the cell, they bind to and activate estrogen receptors which in turn modulate the expression of many genes. Estrone ( E1) is one of several natural estrogensEstrone is relevant to health and disease states because of its conversion to estrone sulfate, a long-lived derivative. Estrone sulfate acts as a reservoir that can be converted as needed to the more active estradiol. Estrone is the predominant estrogen in postmenopausal women Estradiol (E2) is the 2nd predominant sex hormone present in females when naturally produced, but becomes estrone when taken orallycomprises 80% of the naturally occuring estrogens in premenopausal women Estradiol has not only a critical impact on reproductive and sexual functioning, but also affects other organs, including the bones. Estriol is one of the three main estrogens produced by the human bodys only produced in significant amounts during pregnancy as it is made by the placenta. Levels of estriol in non-pregnant women do not change much after menopause, and levels are not significantly different from levels in men.  

23. androgens: are produced in the zona reticularis. The most important androgens include:

Testosterone: a hormone with a wide variety of effects, ranging from enhancing muscle mass and stimulation of cell growth to the development of the secondary sex characteristics. Synthesis: Like other steroid hormones, testosterone is derived from cholesterol (see figure to the right).^[64] The first step in the biosynthesis involves the oxidative cleavage of the sidechain of cholesterol by CYP11A, a mitochondrial cytochrome P450 oxidase with the loss of six carbon atoms to give pregnenolone. In the next step, two additional carbon atoms are removed by the CYP17A enzyme in the endoplasmic reticulum to yield a variety of C₁₉ steroids.^[65] In addition, the 3-hydroxyl group is oxidized by 3-β-HSD to produce androstenedione. In the final and rate limiting step, the C-17 keto group androstenedione is reduced by17-β hydroxysteroid dehydrogenase to yield testosterone. Regulation: In males, testosterone is primarily synthesized in Leydig cells. The number of Leydig cells in turn is regulated by luteinizing hormone (LH) and follicle stimulating hormone (FSH).

Dihydrotestosterone (DHT): a metabolite of testosterone, and a more potent androgen than testosterone in that it binds more strongly to androgen receptors.

24. Thyroid hormones: thyroxine (T₄) and triiodothyronine (T₃), are tyrosine-based hormones produced by the thyroid glandprimarily responsible for regulation of metabolism. An important component in the synthesis of thyroid hormones is iodine

Binging in blood: Unlike the water-soluble hormones, the lipophilic steroid and thyroid hormones do not travel dissolved in the aqueous portion of the plasma; rather, they are transported to their target cells attached to

plasma carrier proteins. These hormones must then dissociate from their carrier proteins in the blood in order to pass through the lipid component of the plasma membrane and enter the target cell, within which their receptor proteins are located.

Functions: The thyronines act on nearly every cell in the body. They act to increase the basal metabolic rate, affect protein synthesis, help regulate long bone growth (synergy with growth hormone), neuronal maturation and increase the body's sensitivity to catecholamines (such as adrenaline) by permissiveness. The thyroid hormones are essential to proper development and differentiation of all cells of the human body. These hormones also regulateprotein, fat, and carbohydrate metabolism, affecting how human cells use energetic compounds. They also stimulate vitamin metabolism. Numerous physiological and pathological stimuli influence thyroid hormone synthesis.

Disorders: Both excess and deficiency of thyroxine can cause disorders.

• Hyperthyroidism (an example is Graves Disease) is the clinical syndrome caused by an excess of circulating free thyroxine, free triiodothyronine, or both. It is a common disorder that affects approximately 2% of women and 0.2% of men. Thyrotoxicosis is often used interchangeably with hyperthyroidism, but there are subtle differences. Although thyrotoxicosis also refers to an increase in circulating thyroid hormones, it can be caused by the intake of thyroxine tablets or by an over-active thyroid, whereas hyperthyroidism refers solely to an over-active thyroid.

• Hypothyroidism (an example is Hashimoto's thyroiditis) is the case where there is a deficiency of thyroxine, triiodiothyronine, or both.

• Clinical depression can sometimes be caused by hypothyroidism[3]. Some research[4] has shown that T₃ is found in the junctions of synapses, and regulates the amounts and activity of serotonin, norepinephrine, and Gamma-aminobutyric acid (GABA) in the brain.

Preterm births can suffer neurodevelopmental disorders due to lack of maternal thyroid hormones, at a time when their own thyroid is unable to meet their postnatal needs

Thyroid-stimulating hormone (TSH) from the anterior pituitary stimulates the thyroid to secrete thyroxine; however, it also exerts a trophic (growth-stimulating) effect on the thyroid. This trophic effect is evident in people who develop an iodine-deficiency (endemic) goiter, or abnormal growth of the thyroid gland. In the absence of sufficient dietary iodine, the thyroid cannot produce adequate amounts of T4 and T3. The resulting lack of negative feedback inhibition causes abnormally high levels of TSH secretion, which in turn stimulates the abnormal growth of the thyroid.

25. CALCIUM: PTH in bones: It enhances the release of calcium from the large reservoir contained in the bones.^[7] Bone resorption is the normal destruction of bone by osteoclasts, which are indirectly stimulated by PTH. Stimulation is indirect since osteoclasts do not have a receptor for PTH; rather, PTH binds to osteoblasts, the cells responsible for creating bone. Binding stimulates osteoblasts to increase their expression of RANKL and inhibits their expression of Osteoprotegerin(OPG). OPG binds to RANKL and blocks it from interacting with RANK, a receptor for RANKL. The binding of RANKL to RANK (facilitated by the decreased amount of OPG) stimulates these osteoclast precursors to fuse, forming new osteoclasts which ultimately enhances bone resorption. CT a) Bone mineral metabolism: - Protect against calcium loss from skeleton during periods of calcium mobilization, such as pregnancy and, especially, lactation b) Serum calcium level regulation - Prevent postprandial hypercalcemia resulting from absorption of Ca²⁺ from foods during a meal - Vitamin D regulation

26. Rickets is a softening of bones in children due to deficiency or impaired metabolism of vitamin D, phosphorus or calcium, potentially leading to fractures and deformity. Rickets is among the most frequent childhood diseases in many developing countries. The predominant cause is a vitamin D deficiency, but lack of adequate calcium in the diet may also lead to rickets (cases of severe diarrhea and vomiting may be the cause of the deficiency). Although it can occur in adults, the majority of cases occur in children suffering from severe malnutrition, usually resulting from famine or starvation during the early stages of childhood. Osteomalacia is the term used to describe a similar condition occurring in adults, generally due to a deficiency of vitamin D.

Osteoporosis is a disease of bones that leads to an increased risk of fracture.^[1] In osteoporosis the bone mineral density (BMD) is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered. The disease may be classified as primary type 1, primary type 2, or secondary.

Hypothyroidism is the underproduction of the thyroid hormones T₃ and T₄. Hypothyroid disorders may occur as a result of congenital thyroid abnormalities (see congenital hypothyroidism), autoimmune disorders such as Hashimoto's thyroiditis, iodine deficiency (more likely in poorer countries) or the removal of the thyroid following surgery to treat severe hyperthyroidism and/or thyroid cancer. Typical symptoms are abnormal weight gain, tiredness, baldness, cold intolerance, and bradycardia. Hypothyroidism is treated with hormone replacement therapy, such as levothyroxine, which is typically required for the rest of the patient's life. Thyroid hormone treatment is given under the care of a physician and may take a few weeks to become effective.

Hyperthyroidism, or overactive thyroid, is the overproduction of the thyroid hormones T₃ and T₄, and is most commonly caused by the development of Graves' disease, an autoimmune disease in which antibodies are produced which stimulate the thyroid to secrete excessive quantities of thyroid hormones. The disease can result in the formation of a toxic goiter as a result of thyroid growth in response to a lack of negative feedback mechanisms. It presents with symptoms such as a thyroid goiter, protruding eyes (exopthalmos), palpitations, excess sweating, diarrhea, weight loss,muscle weakness and unusual sensitivity to heat.

27. eicosanoids are signaling molecules made by oxidation of twenty-carbon essential fatty acids, (EFAs). They exert complex control over many bodily systems, mainly in inflammation or immunity, and as messengers in the central nervous system. The networks of controls that depend upon eicosanoids are among the most complex in the human body.

Eicosanoids derive from either omega-3 (ω-3) or omega-6 (ω-6) EFAs. The ω-6 eicosanoids are generally pro-inflammatory; ω-3's are much less so. The amounts and balance of these fats in a person's diet will affect the body's eicosanoid-controlled functions, with effects on cardiovascular disease, triglycerides, blood pressure, and arthritis. Anti-inflammatory drugs such asaspirin and other NSAIDs act by downregulating eicosanoid synthesis.

There are four families of eicosanoids—the prostaglandins (They are mediators and have a variety of strong physiological effects, such as regulating the contraction and relaxation of smooth muscle tissue.^[1]Prostaglandins are not hormones, but autocrine or paracrine, which are locally acting messenger molecules. They differ from hormones in that they are not produced at a discrete site but in many places throughout the human body), prostacyclins, the thromboxanes (Thromboxane is a vasoconstrictor and a potent hypertensive agent, and it facilitates platelet aggregation.

It is in homeostatic balance in the circulatory system with prostacyclin, a related compound. The mechanism of secretion of thromboxanes from platelets is still unclear.

Leukotrienes act principally on a subfamily of G protein-coupled receptors. They may also act upon peroxisome proliferator-activated receptors. Leukotrienes are involved in asthmatic and allergic reactions and act to sustain inflammatory reactions.For each, there are two or three separate series, derived either from an ω-3 or ω-6 EFA. These series' different activities largely explain the health effects of ω-3 and ω-6 fats

28. The production of saliva is stimulated both by the sympathetic nervous system and the parasympathetic.The saliva stimulated by sympathetic innervation is thicker, and saliva stimulated parasympathetically is more watery.Sympathetic stimulation of saliva is to facilitate respiration, whereas parasympathetic stimulation is to facilitate digestion.Parasympathetic stimulation leads to acetylcholine (ACh) release onto the salivary acinar cells. ACh binds to muscarinic receptors and causes an increased intracellular calcium ion concentration (through the IP3/DAG second messenger system). Increased calcium causes vesicles within the cells to fuse with the apical cell membrane leading to secretion formation. ACh also causes the salivary gland to release kallikrein, an enzyme that converts kininogen to lysyl-bradykinin. Lysyl-bradykinin acts upons blood vessels and capillaries of the salivary gland to generate vasodilation and increased capillary permeability respectively. The resulting increased blood flow to the acinar allows production of more saliva. Lastly, both parasympathetic and sympathetic nervous stimulation can lead to myoepitheilium contraction which causes the expulsion of secretions from the secretory acinus into the ducts and eventually to the oral cavity.Saliva production may also be pharmacologically stimulated by so called sialagogues. It can also be suppressed by so called antisialagogues.

31. Organic composition of saliva: Produced in salivary glands, human saliva is 98% water, but it contains many important substances, including electrolytes, mucus, antibacterial compounds and various enzymes. Mucus in saliva mainly consists of mucopolysaccharides and glycoproteins;

 Antibacterial compounds (thiocyanate, hydrogen peroxide, and secretory immunoglobulin A)

 Epidermal growth factor or EGF

 Various enzymes. There are three major enzymes found in saliva.

       - a-amylase (EC3.2.1.1). Amylase starts the digestion of starch and lipase fat before the food is even swallowed.

It has a pH optima of 7.4.

        -lingual lipase. Lingual lipase has a pH optimum ~4.0 so it is not activated until entering the acidic environment

of the stomach.

        -Antimicrobial enzymes that kill bacteria. Lysozym, Salivary lactoperoxidase, Lactoferrin, Immunoglobulin A

       - Proline-rich proteins (function in enamel formation, Ca2+-binding, microbe killing and lubrication)

        Minor enzymes include salivary acid phosphatases A+B, N-acetylmuramoyl-L-alanine amidase, NAD(P)H dehydrogenase

(quinone), superoxide dismutase, glutathione transferase, class 3 aldehyde dehydrogenase, glucose-6-phosphate isomerase,and tissue kallikrein (function unknown).

    Cells: Possibly as much as 8 million human and 500 million bacterial cells per mL. The presence of bacterial products

(small organic acids, amines, and thiols) causes saliva to sometimes exhibit foul odor.

   Opiorphin, a newly researched pain-killing substance found in human saliva.

29. The digestive functions of saliva include moistening food and helping to create a food bolus, so it can be swallowed easily. Saliva contains the enzyme amylase (also called ptyalin) that breaks up starch into sugar. Thus, digestion of food begins in the mouth. Salivary glands also secrete salivary lipase (a more potent form of lipase) to start fat digestion. Salivary lipase plays a large role in fat digestion in new-borns as their pancreatic lipase still has some time to develop. It also has a protective function, helping to prevent bacterial build-up on the teeth and washing away adhered food particles A common belief is that saliva contained in the mouth has natural disinfectants, which leads people to believe it is beneficial to "lick their wounds". Researchers at the University of Florida at Gainesville have discovered a protein called nerve growth factor (NGF) in the saliva of mice. Wounds doused with NGF healed twice as fast as untreated and unlicked wounds; therefore, saliva can help to heal wounds in some species. NGF has not been found in human saliva; however, researchers find human saliva contains such antibacterial agents as secretory IgA, lactoferrin, lysozyme and peroxidase. It has not been shown that human licking of wounds disinfects them, but licking is likely to help clean the wound by removing larger contaminants such as dirt and may help to directly remove infective bodies by brushing them away. Therefore, licking would be a way of wiping off pathogens, useful if clean water is not available to the animal or person.The mouth of animals is the habitat of many bacteria, some pathogenic. Some diseases, such as herpes, can be transmitted through the mouth. Animal (including human) bites are routinely treated with systemic antibiotics because of the risk of septicemia.Hormonal function-Saliva secretes Gustin hormone which is thought to play a role in the development of taste buds  - Epidermal growth factor or EGF      ·  Various enzymes. There are three major enzymes found in saliva. α-amylase (EC3.2.1.1). Amylase starts the digestion of starch and lipase fat before the food is even swallowed. It has a pH optima of 7.4. lingual lipase. Lingual lipase has a pH optimum ~4.0 so it is not activated until entering the acidic environment of the stomach. Antimicrobial enzymes that kill bacteria. Lysozyme Salivary lactoperoxidase Lactoferrin Immunoglobulin A Proline-rich proteins (function in enamel formation, Ca2+-binding, microbe killing and lubrication) Minor enzymes include salivary acid phosphatases A+B, N-acetylmuramoyl-L-alanine amidase, NAD(P)H dehydrogenase (quinone), superoxide dismutase, glutathione transferase, class 3 aldehyde dehydrogenase, glucose-6-phosphate isomerase, and tissue kallikrein (function unknown). Cells: Possibly as much as 8 million human and 500 million bacterial cells per mL. The presence of bacterial products (small organic acids, amines, and thiols) causes saliva to sometimes exhibit foul odor. Opiorphin, a newly researched pain-killing substance found in human saliva.

32. Inorganic components of saliva: It is a fluid containing:

 

   The saliva can detect the presence of cations: calcium (Ca2 +), magnesium (Mg 2 +), sodium (Na +) and potassium (K +), and the presence of ammonia [13]: 26 (NH 3)neutralizing acidic environment and resulting from the deamination of amino acids (Darginine [8]: 221) from the plaque and gingival fluid.
Among the anions are identified orthophosphate anions (H2PO4-, HPO42-, PO43-) andcarbonate (HCO3-, CO32-) corresponding to the time for buffering properties of saliva(concentration of carbonate also increases with increasing salivary flow, and they arethe main salivary buffer system [8]: 221), chloride anions (Cl-), fluoride (F-), citrate(C6H7O7-,-C6H6O72, C6H5O73-) and  SCN, the latter acting as abactericidal. Water.

 

 

33. Nutritional components:

 

 Personal energy requirement = basic energy requirements + extra energy requirements

 

Basic energy requirements (BER) includes your basal metabolic rate (BMR) and general daily activities

 

    For every Kg of body weight 1.3 Calories is required every hour.

(An athlete weighing 50Kg would require 1.3 × 24hrs × 50Kg = 1560 Calories/day)

 

    For each hours training you require an additional 8.5 Calories for each Kg of body weight.

(For a two hour training session our 50Kg athlete would require 8.5 × 2hrs × 50Kg = 850 Calories)

 

An athlete weighing 50Kg who trains for two hours would require an intake of approximately 2410 Calories

(BER + EER = 1560 + 850)

Energy Fuel

 

the energy we need has to be blended. The blend that we require is as follows:

 

    57% Carbohydrates (sugar, sweets, bread, cakes)

    30% Fats (dairy products, oil)

    13% Protein (eggs, milk, meat, poultry, fish)

 

The energy yield per gram is as follows: Carbohydrate - 4 Calories, Fats - 9 Calories and Protein - 4 Calories.

 

What does a 50 kg athlete require in terms of carbohydrates, fats and protein?

 

    Carbohydrates - 57% of 2410 = 1374 Calories - at 4 Calories/gram = 1374 ÷ 4 = 343 grams

    Fats - 30% of 2410 = 723 Calories - at 9 Calories/gram = 723 ÷ 9 = 80 grams

    Protein - 13% of 2410 = 313 Calories - at 4 Calories/gram = 313 ÷ 4 = 78 grams

 

Our 50kg athlete requires 343 grams of Carbohydrates, 80 grams of Fat and 78 grams of Protein

 

 34. Digestion in stomach Bolus (masticated food) enters the stomach through the oesophagus via the oesophageal sphincter.

 The stomach releases proteases (protein-digesting enzymes such as pepsin) and hydrochloric acid, which kills or

 inhibits bacteria and provides the acidic pH of 2 for the proteases to work. Food is churned by the stomach through muscular contractions of the wall - reducing the volume of the fundus, before looping around the fundus[3] and the

body of stomach as the boluses are converted into chyme (partially digested food). Chyme slowly passes through the

 pyloric sphincter and into the duodenum, where the extraction of nutrients begins. Depending on the quantity and

contents of the meal, the stomach will digest the food into chyme anywhere between 40 minutes and a few hours.

 

 

 35. Hydrochloric acid formation: Gastric acid is one of the main secretions of the stomach. It consists mainly of hydrochloric acid and acidifies the stomach content to a pH of 1 to 2.

 

Chloride (Cl-) and hydrogen (H+) ions are secreted separately in the stomach fundus region at the top of the stomach

by parietal cells of the gastric mucosa into a secretory network called canaliculi before it enters the stomach lumen.

 

Gastric acid acts as a barrier against microorganisms to prevent infections and is important for the digestion of food.

 Its low pH denatures proteins and thereby makes them susceptible to degradation by digestive enzymes such as pepsin.

 The low pH also activates the enzyme precursor pepsinogen into the active enzyme pepsin by self-cleavage. After leaving

 the stomach, the hydrochloric acid of the chyme is neutralized in the duodenum by sodium bicarbonate.

 

The stomach itself is protected from the strong acid by the secretion of a thick, protective mucus layer, and by secretin

 induced buffering with sodium bicarbonate. Heartburn or peptic ulcers can develop when these mechanisms fail. Drugs of

 the antihistaminic and proton pump inhibitor classes can inhibit the production of acid in the stomach, and antacids are

 used to neutralize existing acid

 

36. Digestion of proteins in small intestine:   The small intestine is where most chemical digestion takes place. Most of the digestive enzymes that act in the small intestine are secreted by the pancreas and enter the small intestine via the pancreatic duct. The enzymes enter the small intestine in response to the hormone cholecystokinin, which is produced in the small intestine in response to the presence of nutrients. The hormone secretin also causes bicarbonate to be released into the small intestine from the pancreas in order to neutralize the potentially harmful acid coming from the stomach.

The three major classes of nutrients that undergo digestion are proteins, lipids (fats) and carbohydrates:

 Proteins and peptides are degraded into amino acids. Chemical breakdown begins in the stomach and continues in the

large intestine. Proteolytic enzymes, including trypsin and chymotrypsin, are secreted by the pancreas and cleave proteins into

smaller peptides. Carboxypeptidase, which is a pancreatic brush border enzyme, splits one amino acid at a time. Aminopeptidase and

dipeptidase free the end amino acid products.

 

 

37. Digestion of carbohydrates in small intestine: Pancreatic amylase breaks down some carbohydrates (notably starch) into oligosaccharides. Other carbohydrates pass undigested into the large

intestine and further handling by intestinal bacteria. Brush border enzymes take over from there. The most important

brush border enzymes are dextrinase and glucoamylase which further break down oligosaccharides. Other brush border

enzymes are maltase, sucrase and lactase. Lactase is absent in most adult humans and for them lactose, like most poly-saccharides are not digested in the small intestine. Some carbohydrates, such as cellulose, are not digested at all, despite being made of multiple glucose units.

 

 38. Digestion of lipids: Lipids (fats) are degraded into fatty acids and glycerol. Pancreatic lipase breaks down triglycerides into free fatty  acids and monoglycerides. Pancreatic lipase works with the help of the salts from the bile secreted by the liver and the

gall bladder. Bile salts attach to triglycerides to help emulsify them, which aids access by pancreatic lipase. This

 occurs because the lipase is water-soluble but the fatty triglycerides are hydrophobic and tend to orient towards each

other and away from the watery intestinal surroundings. The bile salts are the "main man" that holds the triglycerides

in the watery surroundings until the lipase can break them into the smaller components that are able to enter the villi

for absorption. Some carbohydrates are degraded into simple sugars, or monosaccharides (e.g., glucogen)

 

39. A vitamins is an organic compound required as a nutrient in tiny amounts by an organism.[1] In other words, an organic

chemical compound (or related set of compounds) is called a vitamin when it cannot be synthesized in sufficient quantities

by an organism, and must be obtained from the diet. Thus, the term is conditional both on the circumstances and on the particular organism. For example, ascorbic acid (vitamin C) is a vitamin for humans, but not for most other animals,and biotin and vitamin D are required in the human diet only in certain circumstances. By convention, the term vitamin

 does not include other essential nutrients such as dietary minerals, essential fatty acids, or essential amino acids

(which are needed in larger amounts than vitamins), nor does it encompass the large number of other nutrients that

 promote health but are otherwise required less often. Thirteen vitamins are presently universally recognized.

Until the mid-1930s, when the first commercial yeast-extract and semi-synthetic vitamin C supplement tablets were sold,

 vitamins were obtained solely through food intake, and changes in diet (which, for example, could occur during a particular growing season) can alter the types and amounts of vitamins ingested. Vitamins have been produced as commodity chemicals and made widely available as inexpensive semisynthetic and synthetic-source multivitamin dietary

supplements, since the middle of the 20th century.

Vitamins are essential for the normal growth and development of a multicellular organism. Using the genetic blueprint

 inherited from its parents, a fetus begins to develop, at the moment of conception, from the nutrients it absorbs.

It requires certain vitamins and minerals to be present at certain times. These nutrients facilitate the chemical reactions that produce among other things, skin, bone, and muscle. If there is serious deficiency in one or more of

these nutrients, a child may develop a deficiency disease. Even minor deficiencies may cause permanent damage

 

 

 40. B1 and B2: Thiamine (B1) is a water-soluble vitamin of the B complex. First named aneurin for the detrimental neurological effects if not present in the diet, it was eventually assigned the generic descriptor name vitamin B1. Its phosphate derivatives are involved in many cellular processes. The best-characterized form is thiamine pyrophosphate (TPP), a coenzyme in the catabolism of sugars and amino acids. In yeast, TPP is also required in the first step of alcoholic fermentation.

Thiamine is a colorless compound with a chemical formula C12H17N4OS. Its structure contains a aminopyrimidine ring and

 a thiazole ring with methyl and hydroxyethyl side chains linked by a methylene bridge. Thiamine is soluble in water,

 methanol, and glycerol and practically insoluble in acetone, ether, chloroform, and benzene. It is stable at acidic

pH, but is unstable in alkaline solutions] Thiamine, which is a N-heterocyclic carbene, can be used in place

of Cyanide as a catalyst for Benzoin condensation. Thiamine is unstable to heat, but stable during frozen storage. It is unstable when exposed to ultraviolet light and gamma irradiation.Thiamine reacts strongly in Maillard-type reactions.

Thiamine derivatives and thiamine-dependent enzymes are present in all cells of the body, thus a thiamine deficiency would seem to adversely affect all of the organ systems. However, the nervous system and the heart are particularly

sensitive to thiamine deficiency, because of their high oxidative metabolism. Beriberi is a neurological and cardiovascular disease. The three major forms of the disorder are dry beriberi, wet beriberi, and infantile beriberi.

 

Riboflavin, B2, is an easily absorbed micronutrient with a key role in maintaining health in humans and animals. It is the central component of the cofactors FAD and FMN, and is therefor required by all flavoproteins. As such, vitamin B2 is required for a wide variety of cellular processes. It plays a key role in energy metabolism, and for the metabolism of fats, ketone bodies, carbohydrates, and proteins.Riboflavin is continuously excreted in the urine of healthy individuals, making deficiency relatively common when dietary intake is insufficient. However, riboflavin deficiency is always accompanied by deficiency of other vitamins.

 

A deficiency of riboflavin can be primary - poor vitamin sources in one's daily diet - or secondary, which may be a

result of conditions that affect absorption in the intestine, the body not being able to use the vitamin, or an increase

 in the excretion of the vitamin from the body.

 

In humans, signs and symptoms of riboflavin deficiency (ariboflavinosis) include cracked and red lips, inflammation of the lining of mouth and tongue,

mouth ulcers, cracks at the corners of the mouth (angular cheilitis), and a sore throat. A deficiency may also cause dry and scaling skin,

fluid in the mucous membranes, and iron-deficiency anemia. The eyes may also become bloodshot, itchy, watery and sensitive to bright light.

41. Properties of vit H (biotin): Biotin is chemically made ​​up of two rings - thiophenoland imidazole and the side chainacid valeraldehyde. Free biotin is a white crystalline substance, soluble in water andalcohol, and sparingly soluble in chloroform, ethyl ether and petroleum ether. Crystallizes inthe form of large needles melting at 230 ° C.
Biotin is very resistant to heat and the action of acids and bases, hence the culinary treatment has a negligible impact on the content of this vitamin. Oxidizing agents inactivatebiotin.
In nature, meets biotin derivatives: oxybiotin (sulfur atom is here replaced by an oxygen atom) and destiobiotin (sulfur atom is replaced with two hydrogen atoms), which have weaker biological properties.

Participance in metabolism wit H is integral part of several enzymes from the group ofcarboxylase, which are important for the Krebs cycle and the biosynthesis of amino acids, sugars,proteins and fatty acids, supporting thyroid function, is involved in the conversion of carbon dioxide, contributes to the proper functioning of the skin and hair, is involvedwith vitamin K in the synthesis of prothrombin (responsiblefor blood clotting).

Sources: Liver, walnuts and peanuts, soy flour, egg yolks, crab, almonds, sardines, mushrooms, brown rice (natural),wholewheat flour, spinach, carrots, tomatoes, yeast, mushrooms, carrots 

Requirement: 200 micrograms per day.

Properties of pantothenic acid (wit B5): molecular formula-C9H17NO5, molar mass-219.23 g mol-1, density-1.266g/cm3, melting point-183.83C, boiling point-551.5C

In the human body is transformed into the active form -acetyl coenzyme A (CoA-SH). This substance is activelyinvolved in the reactions of the Krebs cycle.

Role in the body - essential for the proper metabolism ofproteins, sugars and fats and the synthesis of certain hormones, accelerates wound healing, a prerequisite forthe proper conduct of the release of energy, preventsfatigue and improves cardiovascular, nervous anddigestive, participates in the production of fats, cholesterol , hormones and neurotransmitters, is involvedin tissue regeneration, improves pigmentation andcondition hair.

Sources of vitamin - liver, wheat bran, fish (eg herring,mackerel, trout), mushrooms, whole milk, chicken meat, royal jelly, sunflower seeds, cheese, nuts, eggs,avocados, oranges, potatoes, broccoli, dark rice ,melons, whole grain bread, soy, peanut butter, bananas,Yerba mate.

Requirement:  about 7 mg per day.

Metabolic signifaicence of CoA: Since coenzyme A is, in chemical terms, a thiol, it can react with carboxylic acids to form thioesters, thus functioning as an acyl group carrier. It assists in transferring fatty acids from the cytoplasm to mitochondria. A molecule of coenzyme A carrying an acetyl group is also referred to as acetyl-CoA. When it is not attached to an acyl group, it is usually referred to as 'CoASH' or 'HSCoA'.

Coenzyme A is also the source of the phosphopantetheine group that is added as a prosthetic group to proteins such as acyl carrier protein and formyltetrahydrofolate dehydrogenase.

42. Vitamin B12 (cobalamin) function: Mainly hematopoetic processes, key role in the normal functioning of the brain and nervous system, It is needed for building proteins in the body, red blood cells, and normal function of nervous tissue.

Sources: liver, kidney, yogurt, dairy products, fish, clams, oysters, nonfat dry milk, salmon, sardines. Requirement: adults -about 1-2 mgper day. Symptoms of hypovitaminosis: anemia

Folic acid (witB9, wit M, wit B11,Folate) functions:Folate promotes normal digestion; essential for development of red blood cells. Folic acid regulates growth and functioning of cells,positive influence on the nervous system and brain,determines the mental well-being, so to prevent damage.neural tube defects in a developing unborn child has a positive impact on the weight and development of infants;takes part in the preservation of genetic material, intransmitting hereditary characteristics of cells, regulatetheir distribution, improves the digestive system,contributing to the development of gastric juice, ensure the smooth operation liver, stomach and intestines,stimulates hematopoietic processes, namely the formation of red blood cells, protects the body against cancer (particularly cancer of the uterus). sources: liver, yeast, dark green leafy vegetables, legumes, grains, tomatoes,soybeans, beets, nuts, sunflower seeds, brewer's yeast, egg yolk, bananas, oranges, avocados.
Requirement supplementation at a dose of 0.4 mg. Symptoms of hypovitaminosis: growth inhibition and rebuild of cells in the body, a small amount of red blood cells, neural tube defects in the fetus.

43. Vitamin B6 (pyridoxine ) function: Amino acid metabolism, blood-forming processes, the proper functioning of the nervous system, increases immunity, reduces the side effects of drugs, supports the treatment of kidney, prevents the formation of kidney stones, helps to kill pain and stiffness of wrist and hand,decrease symptoms.of PMS (depression, irritability, breasttenderness, headaches), supports the treatment ofseborrheic dermatitis, hair loss, inflammation of the lips and tongue. Sources: liver, meat, poultry, mackerel, eggs, milk, yeast,vegetables (cabbage, green peas, cauliflower, carrots,spinach, potatoes, beans), cereals (wheat germ),soybeans, peanuts, walnuts, pumpkin seeds, bananas ,and avocado. Requirement: adults - about 2 mg per day. The maximumsafe daily dose: adults - 100 mg. Symptomes of hypovitaminosis: Changes in the bone marrow abnormalities in the nervous system (convulsions), depression, apathy, insomnia, general malaise, reducing the efficiency of mental processes, nerve inflammation, reduced resistance toinfections, skin inflammation, anemia, kidney stones,fatigue, nausea, retching emetic disturbances in the functioning of the heart muscle, increasing the risk of cancer in children - a delayed retardation, bone abnormalities, and epileptic symptoms, irritability

Vitamin B3 (PP, riboflavin) function: The transformation of proteins and carbohydrates, is involved in biochemical changes in the retina

Sources:Eggs, liver, cheese, lean, almonds, mushrooms, game,green parts of vegetables, salmon, trout, mackerel, whole wheat bread, mussels, beans, peas, soybeans, milk,yogurt, kefir, buttermilk, yeast, and walnuts. Requirement: approximately 1.5 mg / day. Symptomes of hypovitaminosis: Changes in skin (seborrhea), changes in the cornea, photophobia, blurred vision, tearing, growth retardation, hair loss, difficulty concentrating, dizziness, insomnia, respiratory disorders, malfunction of the nervous system and mucous membranes, muscular dystrophy

44. Vitamin C (ascorbic acid) function: acts as an antioxidant by protecting the body against oxidative stress. It is also a cofactor in at least eight enzymatic reactions including several collagensynthesis reactions that cause the most severe symptoms of scurvy when they are dysfunctiona. Correct state of the connective tissue, improves immunityand accelerates wound healing. Sources: Potatoes, sauerkraut, wild rose hips, blueberries, raspberries, blackberries, citrus fruits, peppers, brussels sprouts, cabbage, onions, spinach, broccoli, kohlrabi,apples, soybeans, tomatoes, artichokes. Requirement: approximately 60 mg / day. hypovitaminosis: scurvy.

Vitamin P (rutin) function: reduces the permeability of blood vessels, action antioedematous, antioxidant effect. Seals the capillary system of capillaries. Sources: Barberry, elderberry, blackcurrant, red wine, heartsease, capers thorny, peppermint, japanese ginkgo, citrus fruits, coltsfoot, sedum, sorrel, buckwheat, paprika, milk Bactria, tomatoes. requirement: idefinite. Symptoms of hypovitaminosis: tendency to blood extravasations(bruise). Functional interrelations between vitamin C and P. In many cases of skin diseases helps vitamin C (200 to1000 mg) with vitamin P (100 to 500 mg). Treated in this way, such as erythroderma (because the exfoliating theepidermis is eliminated a lot of vitamin C), Addison's disease, bacterial diseases of the skin lesions after-ray,as well as various kinds of hemorrhagic, associated withincreased vascular permeability.

45. Vitamin D (kalcyferol) function: calcium absorption, bone metabolism . vitamin D2 (ergocalciferol) and vitamin D3(cholecalciferol) may be taken in the diet, or can be synthesized from the corresponding provitamin the presence of sunlight. It must be noted, that theD2 vit formed only in plants, a vit D3 - only in animal organisms.
With both compounds the body is able to produce active metabolites (calcitriol), which play an important role in the metabolism of calcium and phosphate. The main effect of vitamin D is its impact on the regulation of calcium and phosphate homeostasis. Two major effector organs associated with this function, which operate on the active metabolites of vitamin D is primarily the intestine and bone, and less kidneys.In the intestine is increase calcium absorption, from bone calcium and phosphate are released (hypocalcaemia)in the kidney interact with teriparatide in reabsorbtion of calcium.

Bone: Vitamin D has a significant impact on bone metabolism -increases the expression of RANKL osteoblast, and this activates RANK on osteoclast precursor, which leads to the formation of mature osteoclast, which by the action of resorption causes the release of calcium from thebones. The developmental period is important in the formation of bones and teeth

Nerves and muscles: regenerates neurons, increases muscle mass and muscle strength.

Immune system: It has immunomodulatory effects and indirect antibacterial properties. Vitamin D activates genes encoding antimicrobial peptides (with the characteristics of naturalantibiotics),β-defensins and katelicydyn . Katelicydyn exhibits biological activity against many bacteria,including tuberculosis bacteria. Katelicydn is produced by immune cells in contact with the cell walls of bacteria, in the presence of 25D form of vitamin D. Anti-inflammatory effects by inhibiting cytokine production. Sources: liver, butter, eggs, milk, meat.
Requirement: Proper level of 20-60 ng / ml (50-150 nM / l),hypervitaminosis: above 150 ng / ml, hypovitaminosis: 8-20 ng / ml deficiency: less than 8 ng / ml. Hypovitaminosis: Rickets in children, osteoporosis inadults. Hypervitaminosis: Demineralization, nausea and vomiting, anorexia,constipation, weakness and fatigability, excessive thirst,increased urination, itching, headaches, mental retardation. Avitaminosis is any disease caused by chronic or long-term vitamin deficiency or caused by a defect in metabolic conversion, such as tryptophan to niacin. They are designated by the same letter as the vitamin.

Conversely hypervitaminosis is the syndrome of symptoms caused by over-retention of fat-soluble vitamins in the body. Avitaminoses include a) vitamin A deficiency causes xerophthalmia or night blindness b) thiamine deficiency causes beriberi, c) niacin deficiency causes pellagra d) B12 deficiency leads to megaloblastic anemia, e) C deficiency leads to scurvy, f) D deficiency causes rickets, g) K deficiency causes impaired coagulation.

46. Vitamin A (retinol) function: Responsible for the proper vision, reduce actinic skin,improves skin tone and protects skin from UV rays, increasing the levels of collagen in the dermis.

Important role in receiving visual stimuli in the retina. The derivative of vitamin A, 11-cis retinal in the rods connects with protein opsyn and form rhodopsin (visualpurple). It is responsible for the integrity of cell membranes, proper functioning of the epithelial tissue cells, such as covering, secretory and sensory, growth regulation of epithelial tissue and other body cells, maintains the correct state of the skin, hair and nails, ensure the normal growth of bones and teeth by regulating the activity of bone tissue, protects epithelium of respiratory against microbes.

Sources: eggs, liver, milk, butter, cheese, blueberries, spinach, fish, dairy products, fatty meat, and, as a provitamin A:carotene, carrots, tomatoes, lettuce, green peas andfruit of wild rose

Requirement: 1000mg per day

Hypovitaminosis: drying of the conjunctiva and corneas, fragile, slow growing nails
dry skin, lack of appetite, night blindness (so-called "night blindness"), blurred vision, growth inhibition, disappearance of epithelia, psoriasis, chert hands and feet, acne, lopecia areata, tendency to diarrhea, malaise

Hypervitaminosis: birth defects in children of mothers with hypervitaminosis during pregnancy, reduced calcification of bones that can lead to osteoporosis,liver enlargement, joint pain, headache.

47. Vitamin E (tokoferol) function: exists in several versions (alpha, beta, gamma, delta),from which the highest activity has alpha-tocopherol. The main antioxidant that protects cells against oxidants, protects red blood cells from premature decomposition, the treatment of male infertility, muscle disorder and ejaculation disorders, atherosclerosis and heart disease. Participates in the delivery ofnutrients to the cells. Strengthens blood vessel walls sources: Almonds, margarine, eggs, walnuts and peanuts,wheat germ, whole wheat flour, milk, sprouts and othergreen leafy vegetables, fruits of wild rose, hazelnut,linden flowers, algae, vegetable oils (soybean, corn, sunflower). requirement is 8-13 mg per day. Hypovitaminosis: Irritability, impaired concentration, impaired functionand skeletal muscle weakness, keratosis and earlyaging of the skin, poorer wound healing, visual impairment, anemia, infertility, increased risk of cardiovascular disease

The mechanism of action of vitamin E: Assists the immune system, prolongs the life of sperm, lowers cholesterol, taken for a week eliminates night cramps calf, it neutralizes free radicals, which make havoc in the skin (it loses flexibility, elasticity and moisture.)

Application in medicine: inhibits premature aging of skin, improves its elasticity and softness. Over the years more and more skin is dry. This is due to less water-binding capacity. Vitamin E increases the ability to maintain proper skin moisture. Improves blood circulation in the skin, reduces the sensitivity to UV radiation. Anti-inflammatory and anti-acne. Accelerates wound healing and reduces scarring. It is often recommended for postmenopaus.

Vitamin F: Exogenous fatty acids (EFAs - essential unsaturated fatty acids, called EFAs – Essential Fatty Acid), a group of fatty acids that can not be synthesized in the animal organism and must be supplied in the diet, in contrast to endogenous fatty acids. Among the unsaturated fatty acid is distinguished by a group of polyunsaturated fatty acids, which contain more than one double bond carbon-carbon in the hydrocarbon chain acid residues. They are an essential element of human diet (called a group.vitamin F), as they are needed to build important compounds , such as prostaglandins. Important essential fatty acids in humans are: linoleic acid, linolenic acid, arachidonic acid

Sources: occur in fats of aquatic animal and vegetable oils. Polyunsaturated fats:
Linoleic-safflower oil, corn oil, sunflower oil, soybean oil, peanut oil, rapeseed oil, olive oil
linolenic-linseed oil, rapeseed oil, soybean oil
Arachidonic-products of animal origin, meat
eicosapentaenoic-algae, salmon, fish oil (cod)
docosahexaenoic acid-oil, mackerel, some algae,flax seeds

Hypovitaminosis: may cause diseases of the skin (dandruff), increases loss of body water,
during pregnancy can lead to underdevelopment of the fetus

Application in medicin: Vitamin F acts immunostimulating for the human body. It lowers cholesterol and blood pressure, a beneficial effect on the absorption of vitamins E, A and D, accelerates regeneration of skin tissue. EFA and phospholipids form the structure of the cell membrane,regulating its fluidity and enzyme activity. It is also known that the components of vitamin F, and especially the most active of them, linoleic acid play an important role in the metabolism of the skin. The skin forms a barrier protecting the body constantly renewsits structure, whose main components are theunsaturated fatty acids. Vitamin F is a team of highlydigestible fats recovering the lipid of the epidermis and the normalization of the physiological protective properties.

48. Vitamin K2 (menachinon) and K3(manadiol) function: K2 is produced by intestinal bacteria, and vitamin K3 is synthesized. It is essential factor for proper blood clotting factor prothrombin, vitamin antihemorrhagical. The main importance of vitamin K is to participate in the processes of post-translational γ-carboxylation of proteins Pivka, and more specifically the glutamic acid residues in these proteins in the γ position. Vitamin Kparticipates in this reaction as a cofactor forγ-carboxylase. Determines that:
maintain normal levels of clotting factors: II, VII, IX, X,and also: osteocalcin, osteopontin, osteonektyna.
synthesis and maintenance of normal levels of naturalcoagulation factors, and calcium-binding proteins inthe kidney, placenta and lungs.
In addition, these vitamins are involved in the process of glycosylation.

Functions in the body: regulate the production of prothrombin, provide blood clotting and bleeding will stop, reduce excessive menstrual bleeding, play a role in the mineralization of calcium and tissue, inhibit the growth of breast, ovarian, colon, stomach,gallbladder, liver and kidney

sources: broccoli, turnip, spinach, cucumber, lettuce, cabbage,alfalfa, kelp, avocado, potatoes, eggs, yogurt, cheese,liver, soybean oil and safflower. Requirement: 2 mg per day Hypovitaminosis: poor blood clotting, ease of formation of internal and external bleeding, problems with wound healing, difficulties in bone mineralization, increased risk of developing cancer, colitis, diarrhea. Mechanism of action: It is generally accepted that the naphthoquinone is the functional group, so that the mechanism of action is similar for all K-vitamins. Substantial differences may be expected, however, with respect to intestinal absorption, transport, tissue distribution, and bio-availability. These differences are caused by the different lipophilicity of the various side chains, and by the different food matrices in which they occur. Application in medicin: generally: condition of bones, osteoporosis, excessive bleeding due to a weaker formation of clots, excessive menstrual bleeding

other application: Vitamin K plays a role in preventing cancer and helping patients who have undergone radiotherapy. Vitamin K may protect the heart, because the delayed deposition
of plaque in the arteries and reduces the concentration of "bad " cholesterol (LDL) levels.

49. Homeostasis coagulation. The principle function of blood is to keep the internal environment of the body tissues constant and in this way to maintain homeostasis. Homeostasis is a term used to describe normal body functions, which include blood pressure, heart rate, body temperature, respiration and blood composition. In order to perform the processes involved in homeostasis, blood must be fluid. A mechanism known as hemostasis keeps the body fluid within the confines of the circulatory system. Normal Hemostasis
Blood normally is a fluid tissue as it circulates through out the body via the blood vessels. When vessels are injured, blood escapes and bleeding continues for a period of time but then slowly subsides. Several biologic systems play a role in stopping the flow of blood from an injured vessel. In addition to the vessels themselves, platelets and clotting factors interact to form a haemostatic clot. The formation of a haemostatic clot is a temporary measure and as the wound heals the clot slowly dissolves.

Mechanism Involved In Hemostasis:
In the case of healthy subjects there exists a equilibrium between the coagulation potential on the one side and fibrinolytic potential + coagulation inhibitors on the other. In the fibrinolytic potential outweighs the coagulation potential or the coagulation factors are diminished then there is a risk of hemorrhage. If the coagulation potential outweighs the fibrinolytic potential or the inhibitors are diminished, there is a risk of thrombosis.
A delicate balance of components on both sides of the scale is required to maintain hemostasis.
1. Blood vessels:
The vascular system is composed of arteries, veins and the microcirculatory system. The blood vessels provide a non-thrombogenic surface allowing the blood to circulate in a closed vascular system. The nonthrombogenic surface is attributed to properties of the vessel walls and activities of platelets.
2. Platelets:
Platelets or thrombocytes are produced in the bone marrow by large cells called megakarycocytes. The normal numbers of platelets circulating are 150,000 to 450,ooo per cubic millimeter blood. To aid in hemostasis, platelets must be present in adequate number and must be functioning normally. 
Platelets have Three major Functions:
a. Support Vascular integrity
Platelets support vascular integrity in two ways,
i. They help the blood vessels to maintain vascular integrity by donating membrane materials to the endothelial cells lining the vessel walls.
ii. Platelets also fill gaps that may occur between endothelial cells because of minimal damage or vasodilatation. By filling the gap a non trombogenic surface is maintained.
If a gap were allowed to remain and became larger, sub endothelial structures which are foreign to platelets and clotting factors would initiate fibrin formation.
b. Adhesion/Aggregation:
Platelets are considered to be first kind of defense in a haemostatic response to an injury. Following injury to a vessel wall, platelets adhere to the injured surface and quickly form a platelet plug. This activity keeps the blood within a closed vascular system. In the formation of the plug, platelets change as they aggregate irreversibly.
Irreversible aggregation causes platelet constituent to be released. Many of the constituent have an immediate effect upon the haemostatic response. One platelet constituent, known as platelet factor 3, becomes available on the surface of the platelets. Platelet factor 3 is a phospholipid and participates with certain clotting factors to produce thrombin with the ultimate formation of fibrin.

50. Blood coagulation cascade mechanism:

The basic mechanisms of coagulation is a proteolitic process extending chained and cascades. These processes occur out and intrinsic. Intrinsic extends inside in the blood not hurted vessels and is slowly, made up after 7minutes.Outrinsic extends in the damaged tissue from the vascular endothelium, and make up quickly after about 7 seconds. In the intrinsic condition to start the process of coagulation is inactive superficial component of blood factor and factor XII

Various substances are required for the proper functioning of the coagulation cascade:

• Calcium and phospholipid (a platelet membrane constituent) are required for the tenase and prothrombinase complexes to function. Calcium mediates the binding of the complexes via the terminal gamma-carboxy residues on FXa and FIXa to the phospholipid surfaces expressed by platelets, as well as procoagulant microparticles or microvesicles shed from them. Calcium is also required at other points in the coagulation cascade.

• Vitamin K is an essential factor to a hepatic gamma-glutamyl carboxylase that adds a carboxylgroup to glutamic acid residues on factors II, VII, IX and X, as well as Protein S, Protein C andProtein Z. In adding the gamma-carboxyl group to glutamate residues on the immature clotting factors Vitamin K is itself oxidized. Another enzyme, Vitamin K epoxide reductase, (VKORC) reduces vitamin K back to its active form. Vitamin K epoxide reductase is pharmacologically important as a target for anticoagulant drugs warfarin and related coumarins such as acenocoumarol,phenprocoumon, and dicumarol. These drugs create a deficiency of reduced vitamin K by blocking VKORC, thereby inhibiting maturation of clotting factors. Other deficiencies of vitamin K (e.g., inmalabsorption), or disease (hepatocellular carcinoma) impairs the function of the enzyme and leads to the formation of PIVKAs (proteins formed in vitamin K absence); this causes partial or non-gamma carboxylation, and affects the coagulation factors' ability to bind to expressed phospholipid.

Vitamin K antagonists (VKA) are a class of anticoagulants. They reduce blood clotting by inhibiting the action of vitamin K. They can cause birth defects (teratogens). All VKAs can be neutralized in action by administration of vitamin K, although for the second generation "super warfarins" intended to kill warfarin resistant rodents, the time of vitamin K administration may need to be prolonged to months in order to combat the long residence time of the poison

Coagulation process consists of three stages: primary hemostasis (platelet plug creation), coagulation (clot formation) and fibrinolysis (clot dissolution). 

Coagulation factors:

I (fibrinogen) Forms clot (fibrin)
II (prothrombin) Its active form (IIa) activates I, V, VII,VIII, XI, XIII, protein C, platelets
Tissue Factor Co-factor of VIIa (formerly known asfactor III)
Calcium Required for coagulation factors to bind toPhospholipid (formerly known as factor IV)
V (proaccelerin, labile factor) Co-factor of X withWhich it forms the prothrombinase complex
VI Unassigned - old name of Factor Va
VII (stable factor, proconvertin) Activates IX, X
VIII (Antihemophilic Factor A) Co-factor of IX withWhich it forms the complex Tenas
IX (Antihemophilic Factor B or Christmas factor)Activates X: Tenas forms complex with factor VIII
X (Stuart-Prower factor) Activates II: formsprothrombinase complex with factor V
XI (plasma thromboplastin antecedent) Activates IX
XII (Hageman factor) Activates Factor XI, VII andprekallikrein
XIII (fibrin-Stabilizing Factor) crosslinks fibrin

51. Anticoagulation system of blood:   Five mechanisms keep platelet activation and the coagulation cascade in check. Abnormalities can lead to an increased tendency toward thrombosis: Protein C is a major physiological anticoagulant. It is a vitamin K-dependent serine protease enzyme that is activated by thrombin into activated protein C (APC). Protein C is activated in a sequence that starts with Protein C and thrombin binding to a cell surface protein thrombomodulin. Thrombomodulin binds these proteins in such a way that it activates Protein C. The activated form, along with protein S and a phospholipid as cofactors, degrades FVa and FVIIIa. Quantitative or qualitative deficiency of either may lead to thrombophilia (a tendency to develop thrombosis). Impaired action of Protein C (activated Protein C resistance), for example by having the "Leiden" variant of Factor V or high levels of FVIII also may lead to a thrombotic tendency. Antithrombin is a serine protease inhibitor (serpin) that degrades the serine proteases: thrombin, FIXa, FXa, FXIa, and FXIIa. It is constantly active, but its adhesion to these factors is increased by the presence of heparan sulfate (a glycosaminoglycan) or the administration of heparins (different heparinoids increase affinity to FXa, thrombin, or both). Quantitative or qualitative deficiency of antithrombin (inborn or acquired, e.g., in proteinuria) leads to thrombophilia. Tissue factor pathway inhibitor (TFPI) limits the action of tissue factor (TF). It also inhibits excessive TF-mediated activation of FIX and FX. Plasmin is generated by proteolytic cleavage of plasminogen, a plasma protein synthesized in the liver. This cleavage is catalyzed by tissue plasminogen activator (t-PA), which is synthesized and secreted by endothelium. Plasmin proteolytically cleaves fibrin into fibrin degradation products that inhibit excessive fibrin formation. Prostacyclin (PGI2) is released by endothelium and activates platelet Gs protein-linked receptors. This, in turn, activates adenylyl cyclase, which synthesizes cAMP. cAMP inhibits platelet activation by decreasing cytosolic levels of calcium and, by doing so, inhibits the release of granules that would lead to activation of additional platelets and the coagulation cascade.

52. Fibrinolysis is the process wherein a fibrin clot is broken down.Its main enzyme plasmin cuts the fibrin mesh at various places, leading to the production of circulating fragments that are cleared by other proteases or by the kidney and liver. Plasmin is produced in an inactive form, plasminogen, in the liver. Although plasminogen cannot cleave fibrin, it still has an affinity for it, and is incorporated into the clot when it is formed. Plasminogen contains secondary structure motifs known as kringles, which bind specifically to lysine and arginineresidues on fibrin(ogen). When converted from plasminogen into plasmin, it functions as a serine protease, cutting C-terminal to these lysine and arginine residues. Fibrin monomers, when polymerized, form protofibrils. These protofibrils contain two strands, anti-parallel, associated non-covalently. Within a single strand, the fibrin monomers are covalently linked through the actions of coagulation factor XIII. Thus, plasmin action on a clot initially creates nicks in the fibrin; further digestion leads to solubilization. Factors of fibrinolysis: Tissue plasminogen activator (t-PA)[3] and urokinase are the agents that convert plasminogen to the active plasmin, thus allowing fibrinolysis to occur. t-PA is released into the blood very slowly by the damaged endothelium of the blood vessels, such that, after several days (when the bleeding has stopped), the clot is broken down. This occurs because plasminogen became entrapped within the clot when it formed; as it is slowly activated, it breaks down the fibrin mesh. t-PA and urokinase are themselves inhibited by plasminogen activator inhibitor-1 and plasminogen activator inhibitor-2(PAI-1 and PAI-2). In contrast, plasmin further stimulates plasmin generation by producing more active forms of both tPA and urokinase. Alpha 2-antiplasmin and alpha 2-macroglobulin inactivate plasmin. Plasmin activity is also reduced by thrombin-activatable fibrinolysis inhibitor (TAFI), which modifies fibrin to make it more resistant to the tPA-mediated plasminogen More details: The removal of the clot is caused by plasmin cleavage of the fibrin monomers into soluble fibrin degradation products. Plasmin is formed by the cleavage of plasminogen between Arg561 and Val562. Plasmin is a two-chain trypsin-like serine protease. Plasminogen activator inhibitor 1 (PAI1) and plasminogen activator inhibitor 2 (PAI2) inhibit cleavage of plasminogen by tissue-type plasminogen activator (tPA) or urokinase plasminogen activator (uPA). The presence of fibrin fibers and fibrin degradation products [(DD)E1 and (DD)E2] exert a two-fold stimulation of tPA and uPA. Plasmin activity is also inhibited by alpha2-antiplasmin. Thrombin activatable fibrinolysis inhibitor (TAFI) is a carboxy-peptidase B-like proenzyme activated by the thrombin-thrombomodulin dimer. TAFI cleaves (DD)E2 to separate DD and E fragments which do not enhance the activation of tPA or uPA and results in a reduced feedback signal. Medicinal fibrinolytic related: Fibrinolytic drugs are given after a heart attack to dissolve the thrombus blocking the coronary artery. Antifibrinolytics, such as aminocaproic acid (ε-aminocaproic acid) and tranexamic acid are used as inhibitors of fibrinolysis. Their application may be beneficial in patients with hyperfibrinolysis because they arrest bleeding rapidly if the other components of the haemostatic system are not severely affected. This may help to avoid the use of blood products such as fresh frozen plasma with its associated risks of infections or anaphylactic reactions.

54. Interferons (IFNs) are proteins made and released by lymphocytes in response to the presence of pathogens—such asviruses, bacteria, or parasites—or tumor cells. They allow communication between cells to trigger the protective defenses of the immune system that eradicate pathogens or tumors. IFNs belong to the large class of glycoproteins known as cytokines. Interferons are named after their ability to "interfere" withviral replication within host cells. IFNs have other functions: they activate immune cells, such as natural killer cells andmacrophages; they increase recognition of infection or tumor cells by up-regulating antigen presentation to T lymphocytes; and they increase the ability of uninfected host cells to resist new infection by virus.

Interleukiny – grupa cytokin, czynników wzrostowych stymulujących podziały limfocytów. Wytwarzane przez makrofagi i limfocyty. Są czynnikiem wywołującym gorączkę. Interleukiny, cytokiny, substancje o charakterze peptydów i białek wytwarzane przez wiele komórek biorących udział w odpowiedzi immunologicznej, a nie mających zdolności wiązania antygenu.

Interlukiny pełnią rolę mediatorów umożliwiających wzajemne oddziaływanie krwinek białych, stymulować ich namnażanie, różnicowanie i aktywność. Interleukiny produkowane przez limfocyty nazywane są limfokinami, natomiast produkowane przez makrofagi (należące dokomórek prezentujących antygen) – monokinami.

Interleukina 1 (IL-1) – silnie działający hormon tkankowy o charakterze polipeptydu, wydzielany przez makrofagi. IL-1 wpływa na limfocyty stymulując je i uwrażliwiając na kontakt z antygenem. Jest odpowiedzialna za podwyższenie temperatury ciała podczas procesów zapalnych (gorączka).

Interleukina 2 (IL-2) – mediator tkankowy o peptydowej budowie, wytwarzany przez limfocyty T helper (Th), stymulujący namnażanie i dojrzewanie limfocytów T. A growth factor is a naturally occurring substance capable of stimulating cellular growth,^[1] proliferation and cellular differentiation. Usually it is a protein or a steroidhormone. Growth factors are important for regulating a variety of cellular processes. Growth factors typically act as signaling molecules between cells. Examples are cytokines and hormones that bind to specific receptors on the surface of their target cells. Ex: Erythropoietin- a glycoprotein hormone that controls erythropoiesis, or red blood cell production. It is a cytokine forerythrocyte (red blood cell) precursors in the bone marrow. Fibroblast growth factors - involved in angiogenesis, wound healing, and embryonic development. The FGFs are heparin-binding proteins and interactions with cell-surface associated heparan sulfate proteoglycans have been shown to be essential for FGF signal transduction. 

Thrombopoietin -is a glycoprotein hormone produced mainly by the liver and the kidney that regulates the production of plateletsby the bone marrow. It stimulates the production and differentiation of megakaryocytes, the bone marrow cells that fragment into large numbers of platelets.

53. Immunoglobulin Structure: Antibodies are heavy globular plasma proteins, called glycoproteins.The variable parts of an antibody are its V regions, and the constant part is its C region.The Ig monomer is a "Y"-shaped molecule that consists of four polypeptide chains; two identical heavy chains and two identical light chainsconnected by disulfide bonds. Each chain is composed of structural domains called immunoglobulin domains. These domains contain about 70-110 amino acids and are classified into different categories Heavy Chain: There are five types of mammalian Ig heavy chain denoted by the Greek letters. Each heavy chain has two regions, the constant region and the variable region. The constant region is identical in all antibodies of the same isotype, but differs in antibodies of different isotypes. Heavy chains γ, α and δ have a constant region composed of three tandem (in a line) Igdomains, and a hinge region for added flexibility; heavy chains μ and ε have a constant region composed of four immunoglobulin domains.The variable region of the heavy chain differs in antibodies produced by different B cells, but is the same for all antibodies produced by a single B cell or B cell clone. The variable region of each heavy chain is approximately 110 amino acids long and is composed of a single Ig domain. Light Chain:  there are two types of immunoglobulin light chain, which are called lambda (λ) and kappa (κ). A light chain has two successive domains: one constant domain and one variable domain. The approximate length of a light chain is 211 to 217 amino acids. Each antibody contains two light chains that are always identical; only one type of light chain, κ or λ, is present per antibody Special part: Some parts of an antibody have unique functions. The arms of the Y, for example, contain the sites that can bind two antigens (in general identical) and, therefore, recognize specific foreign objects. This region of the antibody is called the Fab (fragment, antigen binding) region. It is composed of one constant and one variable domain from each heavy and light chain of the antibody. The base of the Y plays a role in modulating immune cell activity. This region is called the Fc (Fragment, crystallizable) region, and is composed of two heavy chains that contribute two or three constant domains depending on the class of the antibody.[1] Thus, the Fc region ensures that each antibody generates an appropriate immune response for a given antigen, by binding to a specific class of Fc receptors, and other immune molecules, such as complement proteins.   Function: Antibodies contribute to immunity in three ways: they prevent pathogens from entering or damaging cells by binding to them; they stimulate removal of pathogens by macrophages and other cells by coating the pathogen; and they trigger destruction of pathogens by stimulating other immune responses such as the complement pathway. Activation of complement: Antibodies that bind to surface antigens on a bacterium attract the first component of the  complement cascade with their Fc region and initiate activation of the classical complement system. Activation of effector cells To combat pathogens that replicate outside cells, antibodies bind to pathogens to link them together, causing them to agglutinate. Since an antibody has at least two paratopes it can bind more than one antigen by binding identical epitopes carried on the surfaces of these antigens. By coating the pathogen, antibodies stimulate effector functions against the pathogen in cells that recognize their Fc region.The engagement of a particular antibody with the Fc receptor on a particular cell triggers an effector function of that cell; phagocytes will phagocytose, mast cells and neutrophils will degranulate, natural killer cells will release cytokines and cytotoxic molecules; that will ultimately result in destruction of the invading microbe   Different class of Ig's: Immunoglobulin A  (IgA) is an antibody that plays a critical role in mucosal immunity. More IgA is produced in mucosal linings than all other types of antibody combined;IgA has two subclasses (IgA1 and IgA2), IgA is a poor activator of the complement system, and opsonises only weakly. Its heavy chains are of the type α. Immunoglobulin D  (IgD) is an antibody isotype that makes up about 1% of proteins in the plasma membranes of mature B-lymphocytes where it is usually coexpressed with another cell surface antibody. Immunoglobulin E  (IgE) is a class of antibody (or immunoglobulin "isotype") that has been found only in mammals. IgE is a monomeric antibody with 4 Ig-like domains.It plays an important role in allergy, and is especially associated with type 1 hypersensitivity.IgE has also been implicated in immune system responses to most parasitic worms. Immunoglobulin G  (IgG) are involved in predominantly the secondary immune response.The presence of specific IgG, in general, corresponds to maturation of the antibody response.IgG is the only isotype that can pass through the human placenta, thereby providing protection to thefetus in utero. Immunoglobulin M, IgM is the primary antibody against A and B antigens onred blood cells. IgM is by far the physically largest antibody in the human circulatory system. It is the first antibody to appear in response to initial exposure to antigen.

63. Conjugation reactions in hepatocytes. The role of conjugating enzymes is best understood by looking at the interaction between phase I (mostly cytochromes P-450) and phase II (conjugation) enzymes of drug metabolism. A balance between phase I and II enzymes of detoxication largely determines the disposition to drug toxicity. Reactive electrophilic metabolites, generated by phase I enzymes, are often controlled by GSH-tansferases, whereas nucleophilic metabolites such as phenols are controlled by UDP-glucuronosyltransferases (GT) and sulfotransferases. It is more and more recognized that the control of the more stable and more abundant nucleophiles is as important as the control of electrophiles, since the former can be readily converted to electrophiles. For example, phenols and quinols can undergo quinone/quinol redox-cycles with the generation of reactive oxygen species. In the case of benzo(a)pyrene-3,6-quinol toxicity can be prevented by glucuronidation.

55. Hemoglobin is the iron-containingoxygen-transport metalloprotein in the red blood cells of all vertebrates It is composed of 4 polypeptide chains. Each chain contains one heme group, each of which contains one iron ion. The iron is the site of oxygen binding; each iron can bind one O2 molecule thus each hemoglobin molecule is capable of binding a total to four (4) O2 molecules  In the lungs, oxygen diffuses from alveolar air into the blood because the venous blood has a lower partial pressure. The oxygen dissolves in the blood. Only a small amount is carried as a physical solution (0.31 ml per 100 ml). The remainder of the oxygen is carried in chemical combination with the hemoglobin in red blood cells (erthrocytes). Hemoglobin (molecular weight of 68,000) is made from 4 hemes, a porphyrin ring containing iron and globin, a 4 protein chains. Oxygen is bound to the iron for the transport process. Hemoglobin (HHgb) behaves as a weak acid.   If 2 is increased in the blood at the lungs, the equilibrium shifts to the right and H+ ions increase. Oxyhemoglobin can be caused to release oxygen by the addition of H+ ions at the cells. The difference in pH (7.44) of arterial blood and venous blood (pH = 7.35) is sufficient to cause release of oxygen from hemoglobin at the tissue cells.     Variant forms that cause disease: Hemoglobin H (β4) - A variant form of hemoglobin, formed by a tetramer of β chains, which may be present in variants of αthalassemia. Hemoglobin Barts (γ4) - A variant form of hemoglobin, formed by a tetramer of γ chains, which may be present in variants of αthalassemia. Hemoglobin S (α2βS2) - A variant form of hemoglobin found in people with sickle cell disease. There is a variation in the β-chain gene, causing a change in the properties of hemoglobin, which results in sickling of red blood cells. Hemoglobin C (α2βC2) - Another variant due to a variation in the β-chain gene. This variant causes a mild chronic hemolytic anemia. Hemoglobin E (α2βE2) - Another variant due to a variation in the β-chain gene. This variant causes a mild chronic hemolytic anemia. Hemoglobin AS - A heterozygous form causing Sickle cell trait with one adult gene and one sickle cell disease gene Hemoglobin SC disease - Another heterozygous form with one sickle gene and another encoding Hemoglobin C.

56. Buffer System of blood. The bicarbonate buffering system is an important buffer system in the acid-base homeostasis of living things, including humans. As a buffer, it tends to maintain a relatively constantplasma pH and counteract any force that would alter it. In this system, carbon dioxide (CO2) combines with water to form carbonic acid (H2CO3), which in turn rapidly dissociates to form hydrogen ion and bicarbonate (HCO3- ) according to the reaction below. The reaction is catalyzed by the enzyme carbonic anhydrase. Any disturbance of the system will be compensated by a shift in the chemical equilibrium according to Le Chatelier's principle. For example, if the blood gained excess hydrogen ions (a process called acidosis), some of those hydrogen ions would shift to carbon dioxide, minimizing the increased acidity. This buffering system becomes an even more powerful regulator of acid-base homeostasis when it is coupled with the body's capacity for respiratory compensation, in which breathing is altered to modify the amount of CO2 in circulation. In the above example, the body could increase breathing (respiratory alkalosis) to expel the excess CO2, pulling still more hydrogen ions toward the production of carbon dioxide. The process could continue until the excess acid is all exhaled. This process is extremely important in human physiology. It manages the many acid and base imbalances that can be produced by both normal and abnormal physiology. It also affects the handling of carbon dioxide as it is constantly produced as a waste product of cellular respiration when cells make energy.   Acid-base imbalance is an abnormality of the human body's normal balance of acids and bases that causes the plasma pH to deviate out of the normal range (7.35 to 7.45). In the fetus, the normal range differs based on which umbilical vessel is sampled (umbilical vein pH is normally 7.25 to 7.45; umbilical artery pH is normally 7.18 to 7.38).It can exist in varying levels of severity, some life-threatening.There are four basic processes: metabolic acidosis, respiratory acidosis, metabolic alkalosis, and respiratory alkalosis. Metabolic acidosis is a condition that occurs when the body produces too much acid or when the kidneys are not removing enough acid from the body. If unchecked, metabolic acidosis leads to acidemia, i.e., blood pH is low (less than 7.35) due to increased production of hydrogen by the body or the inability of the body to form bicarbonate (HCO3-) in the kidney. Its causes are diverse, and its consequences can be serious, including coma and death. Respiratory acidosis is a medical condition in which decreased respiration (hypoventilation) causes increased blood carbon dioxide and decreased pH. Metabolic alkalosis is a metabolic condition in which the pH of tissue is elevated beyond the normal range ( 7.35-7.45 ). This is usually the result of decreased hydrogen ion concentration, leading to increased bicarbonate, or alternatively a direct result of increased bicarbonate  concentrations.These can be divided into two categories, depending upon urine chloride levels Respiratory alkalosis is a medical condition in which increased respiration (hyperventilation) elevates the blood pH.causes psychiatric causes: anxiety, hysteria and stress CNS causes: stroke, subarachnoid haemorrhage, meningitis drug use: doxapram, aspirin, caffeine and coffee abuse moving into high altitude areas, where the low atmospheric pressure of oxygen stimulates increased ventilation lung disease such as pneumonia, where a hypoxic drive governs breathing more than CO2 levels (the normal determinant) fever, which stimulates the respiratory centre in the brainstem pregnancy high levels of NH4+ leading to brain swelling and decreased blood flow to the brain sexual activity, which may induce excessive breathing due to excitation.

57. Composition of blood: The average adult has a blood volume of roughly 5 liters (1.3 gal), composed of plasma and several kinds of cells (occasionally called corpuscles); these formed elements of the blood are erythrocytes (red blood cells, RBCs), leukocytes (white blood cells), and thrombocytes (platelets). By volume, the red blood cells constitute about 45% of whole blood, the plasma about 54.3%, and white cells about 0.7%.   Cells One microliter of blood contains: 4.7 to 6.1 million (male)erythrocytes: In most mammals, mature red blood cells lack a nucleus and organelles. They contain the blood's hemoglobin and distribute oxygen. The red blood cells (together with endothelial vessel cells and other cells) are also marked by glycoproteins that define the different blood types. The proportion of blood occupied by red blood cells is referred to as the hematocrit, and is normally about 45%. The combined surface area of all red blood cells of the human body would be roughly 2,000 times as great as the body's exterior surface. 4,000–11,000 leukocytes:White blood cells are part of the immune system; they destroy and remove old or aberrant cells and cellular debris, as well as attack infectious agents (pathogens) and foreign substances. The cancer of leukocytes is called leukemia. 200,000–500,000 thrombocytes: also called platelets, are responsible for blood clotting (coagulation). They change fibrinogen into fibrin. This fibrin creates a mesh onto which red blood cells collect and clot, which then stops more blood from leaving the body and also helps to prevent bacteria from entering the body. Plasma About 55% of whole blood is blood plasma, a fluid that is the blood's liquid medium, which by itself is straw-yellow in color. The blood plasma volume totals of 2.7–3.0 liters (2.8–3.2 quarts) in an average human. It is essentially an aqueous solution containing 92% water, 8% blood plasma proteins, and trace amounts of other materials. Plasma circulates dissolved nutrients, such as glucose, amino acids, and fatty acids (dissolved in the blood or bound to plasma proteins), and removes waste products, such as carbon dioxide, urea, and lactic acid. Other important components include: Serum albumin Blood-clotting factors (to facilitate coagulation) Immunoglobulins (antibodies) lipoprotein particles Various other proteins Various electrolytes (mainly sodium and chloride) The term serum refers to plasma from which the clotting proteins have been removed. Most of the proteins remaining are albumin and immunoglobulins.   Blood protein: Blood proteins, also called serum proteins, are proteins found in blood plasma. Serum total protein in blood is 7g/dl. They serve many different functions, including circulatory transport molecules for lipids, hormones, vitamins and metals enzymes, complement components, protease inhibitors, and kinin precursors regulation of acellular activity and functioning and in the immune system. Separating serum proteins by electrophoresis is a valuable diagnostic tool as well as a way to monitor clinical progress. Often mentioned blood proteins: Albumin  -create oncotic pressure and transports other molecules immunoglobulinsn -participate in immune system Fibrinogens- blood coagulation alpha 1-antitrypsin -neutralize trypsin that has leaked from the digestive system Regulatory proteins   Regulation of gene expression   Other types of blood proteins include: Prealbumin Alpha 1 antitrypsin Alpha 1 acid glycoprotein Alpha 1 fetoprotein Haptoglobin Alpha 2 macroglobulin Ceruloplasmin Transferring C3/C4 Beta 2 microglobulin Beta lipoprotein Gamma globulin proteins C-reactive protein (CRP) alpha2-macroglobulin Other globulins, which are of three types- alpha, beta and gamma. Lipoproteins (chylomicrons, VLDL, LDL, HDL) Transferrin Prothrombin MBL or MBP All the plasma proteins are synthesized in liver except gamma globulins.

58. Enzymes of blood plasma: Enzymes Enzymes are the biological catalysts of the body responsible for regulating every chemical process that takes place. The body contains 75,000 different enzyme materials, with each one assigned to a specific chemical process. These materials are made out of protein molecules that are designed to initiate chemical reactions between cells and cell structures. In effect, these materials are present in every area of the body which is why blood samples can provide vital information on the body's enzyme activity. Blood Testing (Enzymodiagnostic) Blood enzyme test results act as a miniature snapshot of the body's chemical processes. Normal test results indicate that the body's organs and system processes are functioning as they should. Major body processes involving heart, liver and kidney function utilize large amounts of enzyme materials. Normal blood test results will show a certain level of each enzyme within a profile. The amount of an enzyme within a blood sample serves as a "marker," meaning it provides an indication of whether or not a condition or disorder is developing within the body. Kidneys There are three main kidney enzymes present within a blood test panel: BUN, creatinine and uric acid. Normal test results for BUN, or blood urea nitrogen, will fall within a range of 7 to 18 deciliters (dL). Normal creatinine levels will range between 0.6 to 1.2 dL. Results for uric acid will show a reading between 3 and 8.2 dL. When readings come back above or below these norms, infection, kidney disease or excess protein in the diet are some of the possible conditions present in the body. Liver Blood testing is one of the most common diagnostic tools used to screen for liver function. If the liver has sustained some sort of damage, its tissue will begin to break down. When this happens the enzymes contained in the tissue will enter the bloodstream. Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) are the primary liver enzymes. Normal test results will show AST and ALP levels between 8 to 20 dL, while ALP readings will come in at 90 to 239 dL Heart Blood enzyme levels are used as a way to determine heart function, as well as any damage the heart may have sustained after a heart attack. As in the case of liver tissue, heart tissue releases enzymes into the bloodstream when damage has occurred. Creative kinase (CK) is an enzyme contained in the heart muscle. Normal test results for CK will fall below 174 dL in men and 140 dL or lower in women. Gamma glutamyl transferase (GGT) is another prominent heart enzyme that also serves as a marker for kidney function. Normal GGT test results will range between 8 and 37 dL for men under 45 years of age and 5 to 24 dL for women under 45 years of age. The range for females who are 45 years or older changes to 6 to 37 dL as hormonal changes begin to effect different processes within the body.

59. Kallicrein-Kinnin System system is plays a role in inflammation, blood pressure control, coagulation and pain. Its important mediators bradykinin and kallidin are vasodilators and act on many cell types. The system consists of a number of large proteins, some small polypeptides and a group of enzymes that activate and deactivate the compounds.   Proteins High-molecular weight kininogen (HMWK) and low-molecular weight kininogen (LMWK) are precursors of the polypeptides. They have no activity of themselves. HMWK is produced by the liver together with prekallikrein (see below). It acts mainly as a cofactor on coagulation and inflammation, and has no intrinsic catalytic activity. LMWK is produced locally by numerous tissues, and secreted together with tissue kallikrein. Polypeptides Bradykinin (BK), which acts on the B2 receptor and slightly on B1, is produced when kallikrein releases it from HMWK. It is a nonapeptide with the amino acid sequence Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg. Kallidin (KD) is released from LMWK by tissue kallikrein. It is a decapeptide. KD has the same amino acid sequence as Bradykinin with the addition of a Lysine at the N-Terminus, thus is sometimes referred to as Lys-Bradykinin. Enzymes Kallikreins (tissue and plasma kallikrein) are serine proteases that liberate kinins (BK and KD) from the kininogens, which are plasma proteins that are converted into vasoactive peptides.Prekallikrein is the precursor of plasma kallikrein. It can only activate kinins after being activated itself by factor XIIa or other stimuli. Carboxypeptidases are present in two forms: N circulates and M is membrane-bound. They remove arginine residues at the carboxy-terminus of BK and KD. Angiotensin converting enzyme (ACE), also termed kininase II, inactivates a number of peptide mediators, including bradykinin. It is better known for activating angiotensin. Neutral endopeptidase also deactivates kinins and other mediators. Pharmacological antagonist of kinine:   Inhibition of ACE with ACE inhibitors leads to decreased conversion of angiotensin I to angiotensin II (a vasoconstrictor) but also to an increase in bradykinin due to decreased degradation. This explains why some patients of ACEi's develop a dry cough, and some react with angioedema, a dangerous swelling of the head and neck region. There are hypotheses that many of the ACE-inhibitors' beneficial effects are due to their influence on the kinin-kallikrein system. This includes their effects in arterial hypertension, inventricular remodeling (after myocardial infarction) and possibly diabetic nephropathy.  

60. Nonorganics components of blood blasma: Inorganic components of blood plasma are the usual electrolyte such as: chlorides,  carbonates,  bicarbonates,  sulfates  phosphates of sodium potassium calcium magnesium iron etc sodium chloride (predominant) Inorganic salts of blood plasma = 1-2% of total volume.
· cations - most of the sodium and potassium ions
· anions - chloride ions are the most numerous and carbonate
The content of inorganic constituents in the tissue fluid is similar to their proportion in the plasma. Of particular importance is the ratio of sodium to potassium, which affectscell excitability, and thus the properties of the cell membrane and cellular metabolism

61. Homeostatic role of the liver. Hepatocytes. Glycemia. Lipid metabolism.bile.

The liver is a vital organ present in vertebrates and some other animals. The liver is necessary for survival; there is currently no way to compensate for the absence of liver function long term, although liver dialysis can be used short term.This organ plays a major role in metabolism and has a number of functions in the body: a) glycogen storage, b) decomposition of red blood cells, c) plasma protein synthesis, d) hormone production, e) detoxification.

A hepatocyte is a cell of the main tissue of the liver. Hepatocytes make up 70-80% of the liver's cytoplasmic mass. These cells are involved in: a) Protein storage, b) Transformation of carbohydrates, c) Synthesis of cholesterol, bile salts and phospholipids.

The enzyme systems of liver are capable of catalyzing the majority of lipid metabolism reactions. Processes like synthesis of higher fatty acids, triglycerides, phospofipids, cholesterol and its esters, the production o keton bodies. Liver is the major side for production of blood plasma VLDL and HDL.

Bile – is a golden yellowish fluid to grinish yellow in colour, secreted by the liver and delivered to small intestine via bille duct. The daily production o bile is about 500 – 700ml (10 ml per kg of body mass).

Bile is a composition of the following materials: water (85%), bile salts (10%), mucus and pigments (3%), fats (1%), inorganic salts (0.7%) and cholesterin (0.3%).

62. detoxyfication function of liver - The liver detoxifies the blood of substances originating from the gut or elsewhere in the body. Part of this function is physical in nature-bacteria and other particulates are trapped in and broken down by the strategically-located Kupffer cells. The remaining reactions are biochemical, and mediated in their first stages by the large number of cytochrome P450 enzymes expressed in hepatocytes. These convert xenobiotics and other toxins to inactive, less lipophilic metabolites. Detoxification reactions are divided into phase I (oxidation, hydroxylation, and other reactions mediated by cytochrome P450s) and phase II (esterification). Ultimately, metabolites are secreted into the bile for elimination via the gastrointestinal tract. In this regard, in addition to disposing of drugs, the liver is responsible for metabolism of essentially all steroid hormones. Liver disease can therefore result in the apparent overactivity of the relevant hormone systems. Cytochrome P-450 - Human CYPs are primarily membrane-associated proteins, located either in the inner membrane of mitochondria or in the endoplasmic reticulum of cells. CYPs metabolize thousands of endogenousand exogenous chemicals. Cytochrome P450 enzymes are present in most tissues of the body, and play important roles in hormone synthesis and breakdown (including estrogenand testosterone synthesis and metabolism), cholesterol synthesis, and vitamin D metabolism. Cytochrome P450 enzymes also function to metabolize potentially toxic compounds, including drugsand products of endogenous metabolism such as bilirubin, principally in the liver.

Microsomal oxidation – is the result of enzyme systems mostly within microsomes of liver. Oxygen acts as an electron acceptor to produce water in final stage; activated oxygen becomes directly incorporated into substrate liable to oxidation. Enzymes in microsomes are divided into: dioxygenases and monooxygenases. Monooxygenases catalyze addition of only one oxygen atom of molecular oxygen to the substrate molecule. The hydrogen atoms which are engaged in reduction of the other oxygen atom to water are supplied by NADPH2. The microsomal enzyme chain contains: cytochrome P-450, flavoprotein with FAD as a coenzyme, protein containing nonheme iron.

64. Role in liver in turnover of bile pigments. Hemoglobin catabolism - When red cells reach the end of their life due to aging or defects, they are broken down, the hemoglobin molecule is broken up and the iron gets recycled. When the porphyrin ring is broken up, the fragments are normally secreted in the bile by the liver. This process also produces one molecule of carbon monoxide for every molecule of heme degraded. This is one of the few natural sources of carbon monoxide production in the human body, and is responsible for the normal blood levels of carbon monoxide even in people breathing pure air. The other major final product of heme degradation is bilirubin. Increased levels of this chemical are detected in the blood if red cells are being destroyed more rapidly than usual. Improperly degraded hemoglobin protein or hemoglobin that has been released from the blood cells too rapidly can clog small blood vessels, especially the delicate blood filtering vessels of the kidneys, causing kidney damage. Transformation of bilirubin: 1) The initial stage in hemoglobin break-down is the scission of one methane bridge to produce verdoglobin. An iron ion and globin are split off from the verdoglobin molecule. This results in formation of biliverdin, which is structurally built of a chain of 4 pyrrole rings linked to one another via methane bridges. Biliverdin when subjected to reduction, converts to bilirubin- indirect (uncojugated). It is insoluble in water and gives an indirect reaction with diazo reagent. 2) In the liver, bilirubin becomes coupled to glucoronic acid. This reaction is catalyzed by the enzyme UDP-glucoronyltransferase. Glucoronic acid enters into the reactrion in an active form, that is, us UDP-glucuronate. Bilirubin glucuronide thus formed is referred to as conjugated bilirubin (b.diglucuronide). t is soluble in water and gives a direct color reaction with diazo reagent.

65) pathobiochemistry of jaundices. Hereditary (enzymatic) jaundices. Jaundice is a yellowish pigmentation of the skin, the conjunctival membranes over the sclerae and other mucous membranes caused by hyperbilirubinemia. This hyperbilirubinemia subsequently causes increased levels of bilirubin in the extracellular fluid. Typically, the concentration of bilirubin in plasma must exceed 1.5 mg/dL^[2](>26µmol/L), three times the usual value of approximately 0.5 mg/dL^[2], for the coloration to be easily visible. Hemolytic j.: catabolytes is intensified in the macrophage system cells. The liver thus rendered incapable of producing bilirubin glucuronides in adequate amount and the unconjugated bilirubin becomes accumulated in blood. Hepatocellular j.: the liver cells undergo degradation, the excretion of conjugated bilirubin int the bile capillaries is disturbed and this bilirubin is excreted directly in the bloodstream, which leads to its increased level in blood. Obstructive j.: the bile excretion is impaired which leads to an increased level of conjugated bilirubin in blood.

66) Porphyrins are a group of organic compounds, many naturally-occuring. One of the best-known porphyrins is heme, the pigment in red blood cells; heme is acofactor of the protein hemoglobin. Porphyrins are heterocyclic macrocycles composed of four modified pyrrole subunits interconnected at their α carbon atoms via methine bridges (=CH-). Porphyrins are aromatic. Biosynthesis: The "committed step" for porphyrin biosynthesis is the formation of D-aminolevulinic acid (dALA) by the reaction of the amino acid glycine with succinyl-CoA from the citric acid cycle. Two molecules of dALA combine to give porphobilinogen (PBG), which contains a pyrrole ring. Four PBGs are then combined through deamination into hydroxymethyl bilane (HMB), which is hydrolysed to form the circular tetrapyrrole uroporphyrinogen III. This molecule undergoes a number of further modifications. Intermediates are used in different species to form particular substances, but, in humans, the main end-product protoporphyrin IX is combined with iron to form heme. Bile pigments are the breakdown products of heme. Heme synthesis: The enzymatic process that produces heme is properly called porphyrin synthesis, as all the intermediates are tetrapyrroles that are chemically classified as porphyrins. The process is highly conserved across biology. In humans, this pathway serves almost exclusively to form heme. In other species, it also produces similar substances such as cobalamin (vitamin B₁₂).

The pathway is initiated by the synthesis of D-Aminolevulinic acid (dALA or δALA) from the amino acid glycine and succinyl-CoA from the citric acid cycle (Krebs cycle). The rate-limiting enzyme responsible for this reaction, ALA synthase, is strictly regulated by intracellular iron levels and heme concentration. A low-iron level, e.g., in iron deficiency, leads to decreased porphyrin synthesis, which prevents accumulation of the toxic intermediates. This mechanism is of therapeutic importance: infusion of heme arginate or hematin can abort attacks of porphyria in patients with an inborn error of metabolism of this process, by reducing transcription of ALA synthase.

67) water: composes produced from nutrient oxidation. 2,5L is excreted by kidneys (1-1,5L), skin vapolarization (0,5-1L), lungs (400mL), and feces (50-200mL). Water of blood composes ~5%. It is the circulating blood volume. 93% is pure water, rest in blood cellular elements. Intacelullar water 35-45% is constantly regulated and must be not changed. Present in: a) bounded to hydrophilic cytoplasm structures c) in cytoplasmic lacunes extracellular 15% the interstitial fluid is close to blood plasma. Trnscellular 1-3% forms digestive juice, cerebrospinal fluid, kidney tubule fluid. Water balance regulation: a) oncotic pressure b) osmotic pressure c) interstitial tissue pH d) hydrodynamic pressure difference between blood and extracellular fluid. E) parcipitation of aldosterone of adrenal cortex, which regulates Na+ reabsorption from primary urine into the blood. *** Excess of sodium cell shrinkage, dry skin, arterial hypertension, thirst, oliguria or anuria. Deficit of sodium cell swelling, edema, polyuria, absence of thirst, a.hypotension, vomiting. Excess of potassium diarrhea, metabolic acidosis. Deficit of potassium vomiting, thirst, met.alkalosis, inability to concentrate urine.

68) Kidneys. pH and acid-base balance: *acidogenesis is secretion oh H+ ions into renal tubules. *ammoniogenesis is formation and secretion of ammonia ion (NH3) into the renal tubules Then, NH3 reacts with H+ to form NH4+. Afterwards it is accompanied by anion Cl-. Neutral salt NH4Cl is formed and excreted in urine. *reabsorption of bicarbonate (NaHCO3) in renal tubules. Consequently, urine examination reflects the acid-base state.

Filtration: A filtrate derived from plasma in the glomerulus must pass through a basement membrane of the glomerular

capillaries and through slits in the processes of the podocytes—the cells that compose the inner layer of the glomerular (Bowman’s) capsule.A. The glomerular ultrafiltrate,formed under the force of blood pressure, has a low protein concentration. Reabsorbtion: I Approximately 65% of the filtered salt and water is reabsorbed across the proximal convoluted tubules. A. Sodium is actively transported, chloride follows passively by electrical attraction, and water

follows the salt out of the proximal tubule. B. Salt transport in the proximal tubules is not under hormonal

regulation.The reabsorption of most of the remaining water occurs as a result of the action of the countercurrent

multiplier system .II A. Sodium is actively extruded from the ascending limb, followed passively by chloride. B. Since the ascending limb is impermeable to water, the remaining filtrate becomes hypotonic. C. Because of this salt transport and because of countercurrent exchange in the vasa recta, the interstitial fluid of the medulla becomes hypertonic. D. The hypertonicity of the medulla is multiplied by a positive feedback mechanism involving the descending limb, which is passively permeable to water and perhaps to salt. III. The collecting duct is permeable to water but not to salt. A. As the collecting ducts pass through the hypertonic renal medulla, water leaves by osmosis and is carried away in surrounding

capillaries. B. The permeability of the collecting ducts to water is stimulated by antidiuretic hormone (ADH).

Renal Plasma Clearance I. Inulin is filtered but neither reabsorbed nor secreted. Its clearance is thus equal

to the glomerular filtration rate. II. Some of the filtered urea is reabsorbed. Its clearance is therefore less than the glomerular filtration rate. III. Since almost all the PAH in blood going through the kidneys is cleared by filtration and secretion, the PAH clearance is a measure of the total renal blood flow. IV. Normally all of the filtered glucose is reabsorbed. Glycosuria occurs when the transport carriers for glucose become saturated as a result of hyperglycemia.

69) Urine: Urine is a transparent solution that can range from colorless to amber but is usually a pale yellow. In the urine of a healthy individual, the color comes primarily from the presence of urobilin. The smell of urine can be affected by the consumption of food. Eating asparagus is known to cause a strong odor in human urine. This is because of the body's breakdown of asparagusic acid. The pH of urine is close to neutral (7) but can normally vary between 4.4 and 8. In persons with hyperuricosuria, acidic urine can contribute to the formation of stones of uric acid in the kidneys, ureters, or bladder. The amount of urine produced depends on numerous factors including level of hydration, activities, environmental factors, weight of individual, and the individual's health. In adult humans the average production is about 1 – 2 L per day. Producing too much or too little urine needs medical attention: Polyuria is a condition of excessive production of urine (> 2.5 L/day), in contrast to oliguria where < 400 mL are produced per day, or anuria with a production of < 100 mL per day. ammoniogenesis is formation and secretion of ammonia ion (NH3) into the renal tubules Then, NH3 reacts with H+ to form NH4+. Afterwards it is accompanied by anion Cl-. Neutral salt NH4Cl is formed and excreted in urine.

70) Composition of physiological urine: Urine is an aqueous solution of greater than 95% water, with the remaining constituents, in order of decreasing concentration urea 9.3 g/L, chloride 1.87 g/L, sodium 1.17 g/L, potassium 0.750 g/L, creatinine 0.670 g/L, calcium 2,5-8,0mmol/day, phosphate 0-38mmol/day, and other dissolved ions, inorganic and organic compounds. Urobilinogen: 0,2-1,0mg/Dl.

71. pathological constituents of urine,

Nitrite (0) -The presence of nitrites in urine indicate the presence of coliform bacteria. This may be a sign of infection, however, the other parameters such as leukocyte esterase, urine white blood cell count, and symptoms such as dysuria, urgency, fevers and chills must be correlated to diagnose an infection.

Sodium (150-300mmol/day) - The sodium levels are frequently ordered during the workup of acute renal failure. The fractional excretion of sodium, abbreviated as FeNa is an important marker in distinguishing pre-renal from post-renal failure.

Potassium (40-90mmol/day) -Urine potassium may be ordered in the workup of hypokalemia. In case of GI loss of potassium, the urine potassium will be low. In case of renal loss of potassium, the urine potassium levels will be high. Decreased levels of urine potassium are also seen in hypoaldosteronism and adrenal insufficiency.

Proteins (0) - The detection of protein in urine, called proteinuria may indicate that the permeability of the glomerulus is abnormally increased. This may be caused by renal infections or it may be caused by other diseases that have secondarily affected the kidneys such as diabetes mellitus, jaundice, or hyperthyroidism.

Glucose -Presence of glucose in the urine is called glucosuria.

Bilirubin - An abnormally high level of blood bilirubin may result from: an increased rate of red blood cell destruction, liver damage, as in hepatitis and cirrhosis, and obstruction of the common bile duct as with gallstones. An increase in blood bilirubin results in jaundice, a condition characterized by a brownish yellow pigmentation of the skin and of the sclera of the eye.

Ketone bodies – ketonuria

White blood cells – infection.

Free cortisol - Values below threshold indicate Addison's disease, while values above indicate Cushing's syndrome. A value smaller than 200 nmol/24h (72 µg/24h^[9]) strongly indicates absence of Cushing's syndrome.

72. Connective tissue is a fibrous tissue. Connective tissue makes up a variety of physical structures including, tendons, blood, cartilage, bone, adipose tissue, and lymphatic tissue. Structurally, connective tissue is formed by three classes of components: cells, fibers, and ground substance. The major constituent of connective tissue is the extracellular matrix. Extracellular matrices consist of different combinations of protein fibers (collagen, reticular, and elastic) and ground substance. Functions: Providing structural suport, Serving as a medium for exchange, Aiding in the defense and protection of the body, Forming a site for storage of fat.

Ground substance is a hydrated, amorphous material that is composed of glycosaminoglycans, long unbranched polymers of repeating disaccharides; proteoglycans, protein cores to which various glycosaminoglycans are covalently linked; and adhesive glycoproteins, large macromolecules responsible for fastening the various components of the extracellular matrix to one another and to integrins and dystroglycans of the cell membrane.

Glycosaminoglycans are of two major types: sulfated, including keratan sulfate, heparan sulfate, heparin, chondroitin sulfates, and dermatan sulfate; and nonsulfated, including hyaluronic acid.

Proteoglycans are covalently linked to hyaluronic acid, forming huge macromolecules called aggrecan aggregates, which are responsible for the gel state of the extracellular matrix.

Fibers of the extracellular matrix are collagen (and reticular) and elastic fibers. Collagen fibers are inelastic and possess great tensile strength. Each fiber is composed of fine subunits, the tropocollagen molecule, composed of three α-chains wrapped around one another in a helical configuration. About 20 different types of collagen fibers are known, which vary in the amino acid sequences of their α-chains. The most common amino acids of collagen are glycine, proline, hydroxyproline, and hydroxylysine.

Elastic fibers are composed of elastin and microfibrils. These fibers are highly elastic and may be stretched to 150% of their resting length without breaking. Their elasticity is due to the protein elastin, and their stability is due to the presence of microfibrils. Elastin is an amorphous material whose main amino acid components are glycine and proline. Additionally, elastin is rich in lysine, the amino acid responsible for the formation of the highly deformable desmosine residues that impart a high degree of elasticity to these fibers.

Cells: a) fixed: Fibroblasts, Adipose cells, Pericytes, Mast cells, Macrophages. B) transient: Plasma cells, Lymphocytes, Neutrophils, Eosinophils, Basophils, Monocytes, Macrophages.

73. Collagen – biosynthesis and degradation - Collagen is a group of naturally occurring proteins found, in nature, exclusively in animals, especially in the flesh and connective tissues of mammals.It is the main component of connective tissue, and is the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content. Collagen, in the form of elongated fibrils, is mostly found in fibrous tissues such as tendon, ligament and skin, and is also abundant in cornea, cartilage, bone, blood vessels, the gut, and intervertebral disc.

Collagen has an unusual amino acid composition and sequence:

• Glycine (Gly) is found at almost every third residue

• Proline (Pro) makes up about 17% of collagen

• Collagen contains two uncommon derivative amino acids not directly inserted during translation. These amino acids are found at specific locations relative to glycine and are modified post-translationally by different enzymes, both of which require vitamin C as a cofactor.

• Hydroxyproline (Hyp), derived from proline.

• Hydroxylysine (Hyl), derived from lysine (Lys). Depending on the type of collagen, varying numbers of hydroxylysines are glycosylated (mostly having disaccharides attached).

• Cortisol stimulates degradation of (skin) collagen into amino acids.

Synthesis

The synthesis of collagen occurs on the RER as individual preprocollagen chains (Fig. 4-7), which are α-chains possessing additional amino acid sequences, known as propeptides, at both the amino and carboxyl ends. As a preprocollagen molecule is being synthesized, it enters the cisterna of the RER, where it is modified. First, the signal sequence directing the molecule to the RER is removed; then some of the proline and lysine residues are hydroxylated (by the enzymes peptidyl proline hydroxylase and peptidyl lysine hydroxylase) in a process known as post-translational modification to form hydroxyproline and hydroxylysine, respectively. Subsequently, selected hydroxylysines are glycosylated by the addition of glucose and galactose.

Three preprocollagen molecules align with each other and assemble to form a tight helical configuration known as a procollagen molecule. It is believed that the precision of their alignment is accomplished by the propeptides. Because these propeptides do not wrap around each other, the procollagen molecule resembles a tightly wound rope with frayed ends. The propeptides apparently have the additional function of keeping the procollagen molecules soluble, thus preventing their spontaneous aggregation into collagen fibers within the cell.

The procollagen molecules leave the RER via transfer vesicles that transport them to the Golgi apparatus, where they are further modified by the addition of oligosaccharides. The modified procollagen molecules are packaged in the trans Golgi network and are immediately ferried out of the cell.

74. Non-colagen proteins Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form in a biologically functional way. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of adjacent amino acid residues. The sequence of amino acids in a protein is defined by the sequence of a gene, which is encoded in the genetic code. In general, the genetic code specifies 20 standard amino acids.

Most proteins consist of linear polymers built from series of up to 20 different L-α-amino acids. All proteinogenic amino acids possess common structural features, including an α-carbon to which an amino group, a carboxyl group, and a variable side chain are bonded. Only proline differs from this basic structure as it contains an unusual ring to the N-end amine group, which forces the CO–NH amide moiety into a fixed conformation. The side chains of the standard amino acids, detailed in the list of standard amino acids, have a great variety of chemical structures and properties; it is the combined effect of all of the amino acid side chains in a protein that ultimately determines its three-dimensional structure and its chemical reactivity.

The amino acids in a polypeptide chain are linked by peptide bonds. Once linked in the protein chain, an individual amino acid is called a residue, and the linked series of carbon, nitrogen, and oxygen atoms are known as the main chain or protein backbone. The peptide bond has two resonance forms that contribute some double-bond character and inhibit rotation around its axis, so that the alpha carbons are roughly coplanar. The other two dihedral angles in the peptide bond determine the local shape assumed by the protein backbone. The end of the protein with a free carboxyl group is known as the C-terminus or carboxy terminus, whereas the end with a free amino group is known as the N-terminus or amino terminus.

The words protein, polypeptide, and peptide are a little ambiguous and can overlap in meaning. Protein is generally used to refer to the complete biological molecule in a stable conformation, whereas peptide is generally reserved for a short amino acid oligomers often lacking a stable three-dimensional structure. However, the boundary between the two is not well defined and usually lies near 20–30 residues. Polypeptide can refer to any single linear chain of amino acids, usually regardless of length, but often implies an absence of a defined conformation.

75. hyaluronic acid  is an anionic, nonsulfated glycosaminoglycan. is a polysaccharide consisting of alternative residues of D-glucuronic acid and N-acetylglucosamine, and unlike other GAGs is not found as a proteoglycan. Hyaluronic acid in the extracellular space confers upon tissues the ability to resist compression by providing a counteracting turgor (swelling) force by absorbing significant amounts of water. Hyaluronic acid is thus found in abundance in the ECM of load-bearing joints. It is also a chief component of the interstitial gel. Hyaluronic acid is found on the inner surface of the cell membrane and is translocated out of the cell during biosynthesis.^[8]

Hyaluronic acid acts as an environmental cue that regulates cell behavior during embryonic development, healing processes, inflammation and tumor development. It interacts with a specific transmembrane receptor, CD44.

Heparan sulfate (HS) is a linear polysaccharide found in all animal tissues. It occurs as a proteoglycan (PG) in which two or three HS chains are attached in close proximity to cell surface or extracellular matrix proteins.^[5][6] It is in this form that HS binds to a variety of protein ligands and regulates a wide variety of biological activities, including developmental processes, angiogenesis, blood coagulation and tumour metastasis.

In the extracellular matrix, especially basement membranes, the multi-domain proteins perlecan, agrin and collagen XVIII are the main proteins to which heparan sulfate is attached.

Chondroitin sulfates contribute to the tensile strength of cartilage, tendons, ligaments and walls of the aorta. They have also been known to affect neuroplasticity.

Keratan sulfates have a variable sulfate content and unlike many other GAGs, do not contain uronic acid. They are present in the cornea, cartilage, bones and the horns of animals.

Glycoaminoglicans - This family of carbohydrates is essential or important for life.

GAGs form an important component of connective tissues. GAG chains may be covalently linked to a protein to form proteoglycans. Water sticks to GAGs; this is where the resistance to pressure comes from. The density of sugar molecules and the net negative charges attract cations, for example, Na+, which, after the sodium binds, attracts water molecules. Some examples of glycosaminoglycan uses in nature include heparin as an anticoagulant, hyaluronan as a component in the synovial fluid lubricant in body joints, and chondroitins, which can be found in connective tissues, cartilage, and tendons.

76. Chemical structure and organization of bone tissue: Osseous tissue, or bone tissue, is the major structural and supportive connective tissue of the body. Osseous tissue forms the rigid part of the bone organs that make up the skeletal system.

Formation: Bone tissue is a mineralized connective tissue. It is formed by cells, called osteoblasts, that deposit a matrix of Type-I collagen and also release calcium, magnesium, and phosphate ions that ultimately combine chemically within the collagenous matrix into a crystalline mineral, known as bone mineral, in the form of hydroxyapatite(Ca10(PO4)6(OH)2) . The combination of hard mineral and flexible collagen makes bone harder and stronger than cartilage without being brittle. Compact bone consists of a repeating structure called a Haversian system, or osteon, which is the primary anatomical and functional unit. Each osteon has concentric layers of mineralized matrix, called concentric lamellae, which are deposited around a central canal, also known as the Haversian canal, each containing a blood and nerve supply.

Types: There are two types of osseous tissue, compact and spongy. Compact bone forms the extremely hard exterior while spongy bone fills the hollow interior. The tissues are biologically identical; the difference is in how the microstructure is arranged.

Functions Osseous tissue performs numerous functions including: a) Directly: **Support for muscles, organs, and soft tissues. **Leverage and movement. **Protection of vital organs. e.g. the heart (Note: some vital organs may not be protected by bones. e.g. the intestines.), **Calcium phosphate storage. B) Indirectly: **Hemopoiesis - formation of blood cells (more correctly this is performed by the bone marrow interspersed within the spongy.

77. inorganic compound of enamel - Enamel Appetites: Apatite is a group of phosphate minerals, usually referring to hydroxyapatite,fluorapatite, chlorapatite and bromapatite, named for high concentrations of OH-, F-,Cl- or Br- ions, respectively, in the crystal. Fluorapatite (or fluoroapatite) is more resistant to acid attack than is hydroxyapatite. For this reason, toothpaste typically contains a source of fluoride anions. Enamel's primary mineral is hydroxylapatite, which is a crystalline calcium phosphate.[4] The large amount of minerals in enamel accounts not only for its strength but also for its brittleness. The hardest tiisue.

78. organic compounds of enamel:

Enamel is the hardest substance in the body. It is translucent, and its coloration is due to the color of the underlying dentin. Enamel consists of 96% calcium hydroxyapatite and 4% organic material and water. The calcified portion of enamel is composed of large crystals coated with a thin layer of organic matrix. The organic constituents of enamel are the keratin-like, high molecular weight glycoproteins, tyrosine-rich enamelins as well as a related protein, tuftleins.

Body_ID: P016015

Enamel is produced by cells known as ameloblasts, which elaborate enamel daily in 4- to 8-μm segments known as rod segments. Successive rod segments adhere to one another, forming keyhole-shaped enamel rods (prisms), which extend over the complete width of the enamel from the dentinoenamel junction to the enamel surface.

organic components: Amelogenin is a protein found in developing tooth enamel, and it belongs to a family of extracellular matrix (ECM) proteins. Developing enamel contains about 30% protein, and 90% of this is amelogenins. Other significant proteins in enamel are ameloblastins,enamelins, and tuftelins.

Tuftelin is an acidic phosphorylated glycoprotein found in tooth enamel- it acts to start the mineralization process of enamel during tooth development.

Enamelin – soluble enamel protein,  modulator for mineral formation and crystal elongation in enamel.

79. Special features of dentin composition; its structure and functional organization.cementum.

DENTIN Its calcified tissue that is harder than bone because of its higher content of calcium salts. By weight it contains: *** 70% mineral hydroxyappetite (Ca10(PO4)6(OH)2 ) *** 20 % mineral materials : a) Glycosoaminoglycans, b) Phosphoproteins, c) Phospholipids *** 10% water. *** It consist of dental tubules, which radiate outward through the dentin from the pulp to the exterior cementum or enamel border.

Cementum is a specialized calcified substance covering the root of a tooth. Cementum is excreted by cells called cementoblasts within the root of the tooth and is thickest at the root apex.

Its composed of: * 65% inorganic material (hydroxyappetite), * 23% organic material (collagen , protein pollysacharides), * 12% water. Its main rol is to anchor the root by attaching it via periodontal ligament.

80. Pulp – The dental pulp is the part in the center of a tooth made up of living connective tissue and cells called odontoblasts.

Each person can have a total of up to 52 pulp organs, 32 in the permanent and 20 in the primary teeth. The total volumes of all the permanent teeth organs is 0.38cc and the mean volume of a single adult human pulp is 0.02cc.

The central region of the coronal and radicular pulp contains large nerve trunks and blood vessels.

This area is lined peripherally by a specialized odontogenic area which has three layers (from innermost to outermost)

1. Cell rich zone (of Rinaggio); innermost pulp layer which contains fibroblasts and undifferentiated mesenchymal cells.

2. Cell free zone (zone of Weil) which is rich in both capillaries and nerve networks. The nerve plexus of Raschkow is located in here

3. Odontoblastic layer; outermost layer which contains odontoblasts and lies next to the predentin and mature dentin

Cells found in the dental pulp include fibroblasts (the principal cell), odontoblasts, defence cells like histiocytes, macrophage, granulocytes, mast cells and plasma cells.

81. Amelogenesis  is the formation of enamel on teeth and occurs during the crown stage of tooth development after dentinogenesis, which is the formation of dentine. Although dentine must be present for enamel to be formed, it is also true that ameloblasts must be present in order for dentinogenesis to continue. A message is sent from the newly differentiated odontoblasts to the inner enamel epithelium (IEE), causing the epithelial cells to further differentiate into active secretory ameloblasts.

Inductive stage Ameloblast differentiation is initiated by the presence of predentin. IDE cells elongate and become preameloblasts.

Initial Secretory stage

A shift in polarity occurs. Preameloblasts elongate and become postmitotic, polarized, secretory ameloblasts. No tomes' process yet. It is at this stage that a signal is sent from the newly differentiated ameloblasts back across the dental-enamel junction (DEJ) to stimulate dentinogenesis.

Secretory ameloblasts Secretory stage ameloblasts are polarized, elongated cells with the cytoplasm full of organelles. Ameloblasts secrete organic matrix: enamel proteins and enzymes.

Secretory stage In the secretory stage, ameloblasts are polarized columnar cells. In the rough endoplasmic reticulum of these cells, enamel proteins are released into the surrounding area and contribute to what is known as the enamel matrix, which is then partially mineralized by the enzyme alkaline phosphatase.

Maturation stage

In the maturation stage, the ameloblasts transport substances used in the formation of enamel.

 Proteins used for the final mineralization process compose most of the transported material. The noteworthy proteins involved are amelogenins, ameloblastins, enamelins, and tuftelins. During this process, amelogenins and ameloblastins are removed after use, leaving enamelins and tuftelin in the enamel. By the end of this stage, the enamel has completed its mineralization.

82. Actin - One of two proteins responsible for contraction of muscle cells and the motility of other cells. It occurs as a monomer, G-actin, a globular protein, and in living cells as a polymer, F-actin, which resembles two strings of beads twisted around each other into thin filaments. The filaments occur in regular structures, alternated and interwoven with thick filaments that contain myosin, the other major muscle protein. The thick and thin filaments slide past each other, under the control of calcium ions, resulting in contraction (shortening) and relaxation (lengthening) of the muscle cells

.Myosine - A contractile protein that forms the thicker of the two types of filaments in muscle fibres. Each myosin molecule is composed of two polypeptide chains twisted together. One end of each is folded into a globular head called the myosin head or myosin cross-bridge. In the presence of calcium ions, the heads with specific sites on the thinner actin filaments interact. The cross-bridges contain ATPase and generate the tension developed by a muscle fibre when it contracts

tropomyosin - A tube-shaped protein found in thin actin filaments of muscle fibres. Tropomyosin has a control function; when calcium ion concentration is low within a muscle fibre, the tropomyosin inhibits muscle contraction by blocking the binding site on actin, thereby preventing myosin cross-bridges from attaching

Troponin complex - is a heteromeric protein playing an important role in the regulation of skeletal and cardiac muscle contraction. Troponin complex consists of three different subunits – troponin T (TnT), troponin I (TnI) and troponin C (TnC). Each subunit is responsible for a part of troponin complex function. TnT is a tropomyosin-binding subunit which regulates the interaction of troponin complex with thin filaments; TnI inhibits ATP-ase activity of acto-myosin; TnC is a Ca2+ - binding subunit, playing the main role in Ca2+ dependent regulation of muscle contraction.

83. .Muscle contraction - The electrochemical process of generating tension within a muscle. You would be forgiven for thinking that when a muscle contracts it shortens. This does happen in some types of contraction (concentric contractions), but muscles can also lengthen during a contraction (eccentric contractions), or stay the same length (isometric contractions). Consequently, many exercise physiologists prefer to use the phrase ‘muscle action’, because this does not imply a change in muscle length.The main feature of muscle contraction is the interaction of actin, myosin and ATP. This fundamental process of contraction is regulated by the tropomyosin-troponin-Ca2+ system. It is accepted, that in the resting muscle tropomyosin (TM) is positioned in the groove of the actin double helix in a way that it sterically blocks the combination of myosin with actin. This is illustrated in Fig. RE1a, which shows a thin filament composed of actin, tropomyosin, and the components of troponin (TN-C, TN-I, TN-T). In the absence of Ca2+ (Relaxed state), TM blocks the crossbridge binding sites on actin. Binding of Ca2+ to TN-C (Activated state) initiates the TM movement, through TN-T, from the center of the actin strand to its side, thereby releasing the steric blocking. In addition, the TN-C-Ca2+ complex removes TN-I from its inhibitory position on actin; thus the combination of the myosin head with actin can take place. Since in the thin filament there is only one TN and one TM molecule per seven G-actin molecules, one has to assume that cooperative interactions play a major role in the regulation of contraction.

84. ATP is resynthesized in muscle by 4 ways: glycolysis, oxidative phosphorylation, creatinine kinase and adenylate kinase. First two are fundament for all tissues. During glycolysis, ATP is formed in two reactions at substrate level: phosphoglycerate kinase reaction and pyruvate kinase reaction. This reactions are anaerobic and that's why muscle can contract for some time in anaerobic condition. Energy of this process forms only 6-7% of total energy of carbohydrates. Positive side of muscle work: high energy efficacy, H2O and CO2 as final products, reserve of power material for this practicaly inexhaustible. During Creatnine Kinasa reaction, creatinine phosphate interacts with ADP forming ATP and creatine: creatine phosphate+ADP<=>Creatine+ATP Adenylate kinase 2ADP-->ATP+AMP

Work of muscle: Myofibril are serounded by sarcoplasmic reticulum( with T-tubules) Action of muscle is generatet by nerv impuls from brain whiche goes to membrane of muscle fibern and T-tubeles than it's spread on all muscle. In sacroplasmic reticulum when impuls arrive the Ca goes to myofibrils (myosin, actine)which causes disclosure of actin and the myosin head is atached this proces called CROSS-BRIDGE

Phosphocreatine can anaerobically donate a phosphate group to ADP to form ATP during the first 2 to 7 seconds following an intense muscular or neuronal effort. On the converse, excess ATP can be used during a period of low effort to convert creatine to phosphocreatine. The reversible phosphorylation of creatine (i.e., both the forward and backward reaction) is catalyzed by several creatine kinases. The presence of creatine kinase (CK-MB, MB for muscle/brain) in plasma is indicative of tissue damage and is used in the diagnosis of myocardial infarction.^[1] The cell's ability to generate phosphocreatine from excess ATP during rest, as well as its use of phosphocreatine for quick regeneration of ATP during - in this case, ATP. Phosphocreatine plays a particularly important role in tissues that have high, fluctuating energy demands such as muscle and brain.

85. Gangliosides is a molecule composed of a glycosphingolipid with one or more sialic acids linked on the sugar chain. Can amount to 6% of the weight of lipids from brain, where they constitute 10 to 12% of the total lipid content (20-25% of the outer layer) of neuronal membranes, for example. Cerebrosides Any one of a class of glycolipids in which a single sugar unit is bound to a sphingolipid. The most common cerebrosides are galactocerebrosides, containing the sugar group galactose; they are found in the plasma membranes of neural tissue and are abundant in the myelin sheaths of neuron. Amino acid neurotransmitters GABA, glutamate, aspirate and taurine were measured in 7 cerebral cortical regions from a group of both Parkinson’s disease and Alzheimer’s disease and from neurologically normal controls. Glutamic acid is accepted as the major excitatory neurotransmitter in the nervous system. It plays a major role in brain development, affecting neuronal migration, neuronal differentiation, axon genesis and neuronal surviva.

86. Acetylcholine Acetylcholine is an ester of acetic acid and choline with chemical formula CH₃COOCH₂CH₂N⁺(CH₃)₃. This structure is reflected in the systematic name, 2-acetoxy-N,N,N-trimethylethanaminium. Its receptors have very high binding constants.The chemical compound acetylcholine (often abbreviated ACh) is a neurotransmitter in both the peripheral nervous system (PNS) and central nervous system (CNS) in many organisms including humans. Acetylcholine is one of many neurotransmitters in the autonomic nervous system (ANS) and the only neurotransmitter used in the motor division of the somatic nervous system. (Sensory neurons use glutamate and various peptides at their synapses.) Acetylcholine is also the principal neurotransmitter in all autonomic ganglia.

Acetylcholine slows the heart rate when functioning as an inhibitory neurotransmitter. However, acetylcholine also behaves as an excitatory neurotransmitter at neuromuscular junctions.

Norepinephrine is a catecholamine and a phenethylamine. The natural stereoisomer is L-(−)-(R)-norepinephrine. The term "norepinephrine" is derived from the chemical prefix nor-, which indicates that norepinephrine is the next lower homolog of epinephrine. The two structures differ only in that epinephrine has a methyl group attached to its nitrogen, while the methyl group is replaced by a hydrogen atom in norepinephrine. The prefix nor- is likely derived as an abbreviation of the word "normal", used to indicate a demethylated compound

. Norepinephrine is synthesized from dopamine by dopamine β-hydroxylase.^[6] It is released from the adrenal medulla into the blood as a hormone, and is also a neurotransmitter in the central nervous system and sympathetic nervous system where it is released from noradrenergic neurons. The actions of norepinephrine are carried out via the binding to adrenergic receptors.

Dopamine has the chemical formula C₆H₃(OH)₂-CH₂-CH₂-NH₂. Its chemical name is "4-(2-aminoethyl)benzene-1,2-diol”. As a medicinal agent, dopamine is synthesized by demethylation of 2-(3,4-dimethoxyphenyl)ethylamine using hydrogen bromide. Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, thissubstituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D₁, D₂, D₃, D₄, and D₅—and their variants. Dopamine is produced in several areas of the brain, including the substantia nigra and the ventral tegmental area.

Serotonin (5-hydroxytryptamine) is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal (GI) tract, platelets, and in the central nervous system (CNS) of animals including humans.

87. A neurotransmitter receptor is a membrane receptor protein. A membrane protein interacts with the lipid bilayer that encloses the cell and a membrane receptor protein interacts with a chemical in the cells external environment, which binds to the cell. Membrane receptor proteins are particularly important in neuronal and glial cells (involved in neuronal transmission, but not technically neurons), because they allow cells to communicate with one another through chemical signals. Neurotransmitter receptors send and receive signals that trigger an electrical signal that runs along the neuron and can be passed along a neural network, by regulating the activity of ion channels ^[1] A neurotransmitter receptor can be paired directly with an ion channel, but most send signals indirectly through guanyl nucleotide-binding proteins or G proteins ^[2]Interactions between neurotransmitters and neurotransmitter receptors are involved in a wide range of differing reactions from the cell receiving the signal, triggering anything from activation to inhibition.