Explain biochemical basis of:

MYXEDEMA IN HYPOTHYROIDISM:

Hypothyroidism in the adults is referred to as myxedema, that is it is used to describe a dermatological change that can occur in hypothyroidism, (from Greek, myxa means mucus and oidema means swelling). because of the characteristic mucinous protein deposit in the subcutaneous tissue. Levels of hyaluronic acid are high in proliferating tissue. The enzyme hyaluronidase which splits hyaluronic acid into smaller oligosaccharides. Thyroid hormones stimulate tadpole tissue differentiation, which is paralleled by a decrease in hyaluronic acid levels and an increase in hyaluronidase concentrations. In myxedematous tissue from subjects with hypothyroidism there is an increase in hyaluronic acid. These observations suggest that thyroid hormones stimulate differentiation tissue through stimulation of hyaluronidase production.

BOW LEGS IN RICKETS:

Rickets is a skeletal disorder that is caused by a lack of Vitamin-D,  may therefore develop if the skin does not receive adequate irradiation. Since vitamin D3 (cholecalciferol) is activally produced in the skin of humans by the action of UV light on a precursor molecule, 7-dehydrocholesterol. Due to absence of vitamin D in rickets bone demineralization occurs. Hence people with rickets have weak and soft bones; stunted growth and in severe cases, skeletal deformities. Due to softening of bones, the bones of legs are not able to take the body weight and hence bend due to the weight causing the shape to be bow like.

HYPOPHOSPHATEMIA IN HYPERPARATHROIDISM:

Hypophosphatemia is defined as a serum phosphate level of less than 2.5 mg/dL and in hyperparathyroidism there is an increased parathyroid hormone (PTH) levels in the blood.
Below normal levels of Ca2+ result in enhanced PTH secretion. PTH acts on the number of tissues, in most cases elevating directly or indirectly, plasma levels of Ca2+ and decreasing circulating concentrations of PO43-.In hyperparathyroidism, increased PTH levels cause a rapid increase in urinary PO43- concentration. Increased renal excretion of PO43- , in response to PTH enhances the ionization of plasma Ca2+ through lowering of the [Ca2+]*[PO43-] solubility product. Hence since PO43- is excreted, its concentration in blood decreases below a normal level leading to hypophosphatemia in response to elevated PTH, due to hyperparathyroidism.

POLYDIPSIA IN DIABETES INSIPIDUS:

Polydipsia is the term given to excessive thirst and is one of the initial symptoms of diabetes. Impairment of the neurohypophysial system to synthesize or release AVP (Arginine Vasopressin) results in a diminished ability of the kidney to conserve water, resulting in diabetes insipidus, there is water loss by excretion, since kidney can't conserve water it leads to polydipsia.

COLD FEET AND PALPITATIONS DURING ACUTE STRESS.

Cold feet and thumping heart i.e., palpitations are caused by stress hormones, such as adrenaline (epinephrine), which are released into bloodstream and by overactivity of nervous impulses to various parts of the body. When your body is in flight or fight mode, all the blood goes to the areas that need it most especially heart (leading to palpitation). To do that, blood is taken out of extremities, like feet and hands, leaving them cold. Epinephrine causes constriction in many networks of minute blood vessels but dilates the blood vessels in the skeletal muscles and in liver. In the heart, it increases the rate and force of contraction, palpitations, thus increasing the output of blood and raising blood pressure.

What is the basis of oral contraceptive action?

The common contraceptive drugs in clinical use for women contain estrogens or progestogens, either singly or in a variety of combinations and contrations. The estrogens are usually synthetic derivatives of ethinyl estradiol. The progestogen are usually 19-nor testosterone or 17-hydroxy-progesterone derivatives such as norethindrone. The combination contraceptive preparations contain an estrogen and a progestogen and are often administered daily for 21 days and stopped for 7 days, during which time withdrawal uterine bleeding occurs.
Through a combined negative feedback to the hypothalamus, LH and FSH secretion are suppressed. There is an absence of the LH/FSH surge, and the failure of a follicular phase rise in FSH secretion results in lack of ovarian follicular development.

Progesterone administered alone have complex effects that relate to the dosage. Besides suppression of gonadotropin secretion and inhibition of follicular development, cervical mucus composition is modified, which may prevent sperm entry into the uterus cavity. In addition, endometrial histology may be altered and thus interfere with implantations of the ovum should fertilization occur.

Some contraceptives steroids regimes consist of estrogens administered alone for a number of days (usually 15) followed by a progesterone for several days (5). These sequential contraceptive preparations stimulate to some degree the normal sequence of ovarian steroid secretion. A dose of a progestin, e.g., "Plan-B" (Duramed Pharmaceuticals), has been used with success as "morning pill", often used as an emergency postcoital contraceptive.

Increased plasma progesterone concentrations are responsible for the lack of ovulation during pregnancy, this inhibitory effect of progesterone is the basis of current oral contraceptives, which contain a synthetic progesterone analog (a progestin).

Super-active agonistic analogs of GnRH have been developed whose stimulatory effect have been discovered to exert paradoxical inhibitory effects on pituitary-gonadal functions in both sexes, probably because they down regulate pituitary responsiveness to GnRH stimulation. The effect of these GnRH analogs may be mediated at the level of the pituitary, to cause a down regulation of GnRH receptors. Antibodies to choriogonadotropin may provide a novel method of contraception.

How does MAPK cascade alter the transcriptional activity of a cell?

MAPK's are mitogen-activated protein kinases. (Mitogens are extracellular signals that induce mitosis and cell division). MAPK cascades mediate hormone signals via pathways that result in phosphorylation of target enzymes by protein kinases. The target of phosphorylation is often another protein kinase, which then phosphorylates a third protein kinase and so on MAPK cascades mediate signaling initiated by a variety of growth factors, such as platelet derived growth factors (PDGF) and epidermal growth factor (EGF). The three families are:  1) MAPK (ERK)  2)MAPKKs (MEK)  3) MAPKKK (Elk).

Regulation of gene expression by insulin through a MAP kinase cascade:

• INSR is auto phosphorylated (INSR-Insulin receptor) which opens up the active site such that enzyme receptor (tyrosine kinase) can phosphorylate other proteins.
• After auto phosphorylation, it binds to its target Insulin Receptor Substrate 1 (IRS-1).
•  A P-Tyr residue (i.e., phosphorylated tyrosine residue) binds to the SH2 domain of the protein Grb 2. (Grb 2 is an adaptor protein; its function is to bring together IRS-1 and the protein Sos). Grb 2 has two domains : an SH2 domain that binds its P-Tyr to IRS 1 and a second SH3 domain that binds to proline rich region of Sos.
• When bound to Grb 2, Sos acts as a guanosine nucleotide- exchange factor (GEF), catalyzing the replacement of bound GDP with GTP on Ras, a G protein. Ras can exist in either the GTP-bound (active) or GDP-bound (inactive) conformation. When GTP binds, Ras can activate a protein kinases- Raf 1, MEK and ERK.
• Raf 1, MEK and ERK form a cascade in which each kinase activates the next by phosphorylation.
• When activated, ERK enters the nucleus and phosphorylates transcription factors like Elk 1.
• Phosphorylated Elk1 joins SRF to stimulate the transcription of genes needed for cell division. 

How do adipose and liver respond to insulin during the absorptive phase?

In response to elevated glucose levels, insulin is released from the pancreatic islets. Insulin interacts with plasmalemmal receptors of a number of different cell types. Most important are the actions of insulin and hepatic cells, muscle cells and adipose tissue cells. In each case, the effect of insulin is to enhance the uptake of glucose into the cells, where it is metabolized and stored as glycogen or used as an energy substrate in synthesis of protein or fats.
Within the liver, insulin activates glycogen synthase, which produces a direct flow of glucose towards glycogen formation. Glucokinase activity is enhanced, which provides a pool of glucose-6-phosphate that is then converted to glucose 1 phosphate and to uridine diphosphoglucose. Conversion of intracellular glucose to glucose-6-phosphate prevents glucose release from hepatocytes.
In fat cells, insulin-stimulated glucose uptake results in enhanced catabolism of the sugar to glycerol. Insulin activation of endothelial cell lipoprotein lipase results in the release of Free fatty acids from chylomicrons. These fatty acids are then transported into fat cells where they combine with glycerol to form triglycerides and are added to the lipid droplets within the fat cells. Lipid synthesis is stimulated by insulin via an activation of citrate lipase, acetyl- CoA carboxylase, fatty acid synthase and glycerol-3-phosphate dehydrogenase.

Explain the lipolytic actions of catecholamines on adipocytes?

The physiologically relevant catecholamines are epinephrine (E), non-epinephrine (NE) and dopamine (DA). These catecholamines regulate fat metabolism (lipolysis). Adipose tissue cells (or adipocytes) possess beta-Adrenergic receptors, and in response to catecholamines of either sympathetic or adrenal origin, lipolysis stimulated.
Epinephrine- induced cAMP production activates a  hormone sensitive lipase, triglyceride lipase  which metabolizes fats into free fatty acids (FFAs) and glycerol. The FFAs released into the blood are then used directly by certain tissues (brain, cardiac muscles etc.) as source of energy or they may be used in liver in the formation of glucose.
Beta-adrenergic receptors- cAMP is the intracellular second messenger in the glycogenolytic response to beta adrenergic stimulation by epinephrine. Cellular responses to beta Adrenergic receptor stimulation are linked to adenylate cyclase activation and cAMP formation.
Although, both glucagon and epinephrine stimulate glycogenolysis, they do so through separate receptors linked to a common adenylate cyclase.
The beta adrenergic receptor also undergoes desensitization due to a rapid attenuation of the stimulated rate of cAMP generation.

How does insulin activate glycogen synthase?

A major physiological role of insulin is formation of glycogen from glucose in a number of tissues. Glycogen formation is controlled by the activity of a glycogen synthase. This enzyme is active in the dephosphorylated state and inactive in the phosphorylated state. Insulin mediates its action by an inhibition of the phosphorylated state of this enzyme. In both muscle and liver, insulin acts to regulate glycogen synthase via PT-3-kinase mediated activation of protein phosphatase 1, a phosphatase that dephosphorylates (and activates) glycogen synthase. Insulin trigger activation of glycogen synthase b by blocking the activity of GSK 3 (Glycogen Synthetase kinases 3) and activating a phosphoprotein phosphatase (PP1 in muscle). The GSK-3 phosphorylates glycogen synthase and making it inactive whereas PP1 dephosphorylates glycogen synthase b making it active.

What is the relation between PI, DAG, Ca2+ and PKG. How do phorbal esters interfere with signaling pathway involving DAG?

Diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3) are the two potent secondary messengers generated by the activated PIP2-specific PLC (i.e., phosphatidyl inositol 4,5 bisphosphate- specific phospholipase C) that cleaves PIP2 to produce these two secondary messengers. Both DAG and IP3 contribute to the activation of protein-kinase C i.e., PKC.
The IP3 binds to the endoplasmic reticulum (ER) on the Ca2+ channels, causing them to open. SERCA pumps ensures that the cytosolic Ca2+ level is less than ER Ca2+ levels, so when these Ca2+ channel opens, Ca2+ rushes out thus increasing cytosolic Ca2+ levels to about 10^-6 M.
This elevated Ca2+ levels leads to the activation of PKC. DAG cooperates with Ca2+ in activating PKC, thus also acting as a secondary messenger. Activation involves the movement of PKC domain away from its location in the substrate- binding region of the enzyme, allowing the enzyme to bind and phosphorylate proteins that contain a PKC consensus sequences, ser or thr residue recognized by PKC.
Now, Phorbal esters acts as analogs of DAG, so they have the ability to stimulate PKC.
Phorbal esters are potent tumor promoters. By activating PKC they activate other intracellular targets, including cascade of protein kinase known as the MAP kinase pathway, leading to transcription factor phosphorylation, changes in the gene expression and stimulate cell proliferation, hence promoting tumor growth.