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Albumin, the principal transporter of plasma fatty acids, binds to majority of the drugs ingested, traps oxygen radicals and has potent anti-oxidant actions. Albumin binds to its specific binding sites on vascular endothelial cells and thus, prevents endothelial apoptosis. Albumin regulates the enzyme pyruvate dehydrogenase, the flux of glucose and lactate in astrocytes, and enhances the formation of anti-inflammatory lipoxins, resolvins and protectins from docosahexaenoic acid (DHA) and other polyunsaturated fatty acids that, in turn, could limit ischemia-induced neuronal damage. This may explain the beneficial action of DHA-enriched albumin in stroke and other critical diseases.

Insulin is essential for glucose homeostasis. Insulin/glucose-insulin-potassium (GIK) regimen suppresses the production of tumor necrosis factor-alpha (TNF-alpha), interleukins-6 (IL-6), macrophage migration inhibitory factor (MIF) and other pro-inflammatory cytokines and reactive oxygen species (ROS), enhances the synthesis of endothelial nitric oxide (eNO), and anti-inflammatory cytokines interleukins-4 (IL-4) and interleukin-10 (IL-10). In subjects who are critically ill, monocyte HLA-DR expression was significantly decreased with a concomitant increase in plasma IL-10 and IL-4 concentrations. Large increases in the plasma concentrations of TNF-alpha, IL-6, sustained increase in the expression of leukocyte CD11b/CD18, and ROS generation following surgery and infections were found to be associated with increased mortality. By virtue of its actions on pro- and anti-inflammatory cytokines and ROS, insulin may have the ability to alter HLA-DR expression in the critically ill and thus bring about its beneficial actions in sepsis/septic shock, myocardial recovery following acute myocardial infarction, improve prognosis of those who are critically ill, and suppress inflammation.

Metabolics syndrome is common in SE Asian. An hypothesis that aberrant expression of perilipins and 11-beta-hydroxysteroid dehydrogenase-1 (11-beta-HSD-1) enzyme plays a significant role in the development of metabolic syndrome X in Indians is proposed. Thus, methods designed to target perilipins and 11-beta-HSD-1 may form a novel approach in the prevention and management of metabolic syndrome X.

Essential fatty acids (EFAs)--linoleic acid (LA) and alpha-linolenic acid (ALA) are critical for human survival. EFAs are readily available in the diet. But, to derive their full benefit, EFAs need to be metabolized to their respective long-chain metabolites. EFAs not only form precursors to respective prostaglandins (PGs), thromboxanes (TXs), and leukotrienes (LTs), but also give rise to lipoxins (LXs), resolvins, isoprostanes, and hydroxy- and hydroperoxyeicosatetraenoates. Certain PGs, TXs, and LTs have pro-inflammatory actions whereas LXs and resolvins are anti-inflammatory in nature. Furthermore, EFAs and their long-chain metabolites modulate the activities of angiotensin converting and HMG-CoA reductase enzymes, enhance acetylcholine levels in the brain, increase the synthesis of endothelial nitric oxide, augment diuresis, and enhance insulin action. Thus, EFAs and their metabolites may function as endogenous ACE and HMG-CoA reductase inhibitors, nitric oxide enhancers, beta-blockers, diuretics, anti-hypertensive, and anti-atherosclerotic molecules. In addition, EFAs and their long-chain metabolites react with nitric oxide (NO) to yield respective nitroalkene derivatives that exert cell-signaling actions via ligation and activation of peroxisome proliferator-activated receptors (PPARs). Thus, EFAs and their derivatives have varied biological actions that may have relevance to their involvement in several physiological and pathological processes.

Genetics, oxidative stress: superoxide anion (O2*-) and hydrogen peroxide (H2O2), endothelial nitric oxide (eNO), lipid peroxides, anti-oxidants, endothelin, angiotensin converting enzyme (ACE) activity, angiotensinII, transforming growth factor-beta (TGF-beta), insulin, homocysteine, asymmetrical dimethyl arginine, proinflammatory cytokines: interleukin-6 (IL-6), tumor necrosis factor-a (TNF-alpha), C-reactive protein (hs-CRP), and long-chain polyunsaturated fatty acids (LCPUFAs), and activity of NAD(P)H oxidase have a role in human essential hypertension. There is a close interaction between endogenous molecules: eNO, endothelin, cytokines, and nutrients: folic acid, L-arginine, tetrahydrobiopterin (H4B), vitamin B6, vitamin B12, vitamin C, and LCPUFAs. Statins mediate some, if not all, of their actions through LCPUFAs, whereas these fatty acids (especially omega-3 fatty acids) suppress cyclo-oxygenase activity and the synthesis of pro-inflammatory cytokines, and activate parasympathetic nervous system, actions that reduce the risk of major vascular events. Some LCPUFAs form precursors to lipoxins and resolvins that have anti-inflammatory actions. Low-grade systemic inflammation seen in hypertension seems to have its origins in the perinatal period and availability of adequate amounts of LCPUFAs during the critical periods of brain growth prevents the development of hypertension. This indicates that preventive strategies aimed at decreasing the incidence of hypertension and its associated conditions such as atherosclerosis, type 2 diabetes, coronary heart disease (CHD), and cardiac failure in adulthood need to be instituted during the perinatal period if they are to be effective.

Selective COX-2 inhibitors increase the risk of myocardial infarction and stroke. This has been attributed to their ability to inhibit endothelial COX-2 derived prostacyclin (PGI2) but not platelet COX-1 derived thromboxane A2 (TXA2). On the other hand, aspirin blocks both COX-1 and COX-2 enzymes without decreasing PGI2 but blocks TXA2 synthesis that explains its beneficial action in the prevention of coronary heart disease (CHD). The inhibitory action of aspirin on COX-1 and COX-2 enzymes enhances the tissue concentrations of dihomo-gamma-linolenic acid (DGLA), arachidonic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). These fatty acids form precursors to PGE1, PGI2, PGI3, lipoxins (LXs), and resolvins that have anti-inflammatory actions. In contrast, increase in the concentrations of DGLA, AA, EPA, and DHA is much less with specific COX-2 inhibitors since they do not block the formation of eicosanoids through COX-1 pathway. COX-2 inhibitors interfere with the formation of LXs and resolvins that have neuroprotective and cardioprotective actions. EPA and PGI2 have anti-arrhythmic action. EPA, DHA, and AA augment eNO formation that prevents atherosclerosis. This suggests that COX-2 inhibitors increase cardiovascular and stroke risk by interfering with the formation of eNO, PGI2, LXs, and resolvins and implies that combining EFAs with COX-2 inhibitors could prevent these complications.

Angiotensin-II regulates vascular tone, stimulates the release of pro-inflammatory cytokines, activates NF-kappaB, increases oxidant stress, and suppresses nitric oxide synthesis, and thus, it functions as an inflammatory molecule. Since ACE is present in many tissues, this suggests that angiotensin-II may play a significant role in atherosclerosis, congestive cardiac failure, stroke, bipolar disorder, schizophrenia, dementia, Alzheimer's disease, psoriasis, atopic and non-atopic dermatitis, eczema, several acute and chronic inflammatory diseases, and cancer, conditions in which inflammation is an aetiopathogenic factor. Thus, ACE inhibitors and/or angiotensin-II receptor blockers could be of benefit in these conditions. Furthermore, structural analogues of ACE inhibitors and angiotensin-II receptor blockers could be developed that possess anti-inflammatory actions without significant action on the cardiovascular system.

Metabolic syndrome X is common in Indians. But the exact cause for this is not clear. Earlier, I proposed that this could be due to low activities of delta6 and delta5 desaturases and consequent decreased plasma and tissue concentrations of long-chain polyunsaturated fatty acids of omega-6 and omega-3 series since perinatal period. This implies that perinatal to adult life supplementation of long-chain polyunsaturated fatty acids could prevent, arrest or postpone the development of metabolic syndrome X and its complications.

NF-kappaB activation, and elevated concentrations of macrophage migration inhibitory factor (MIF), tumor necrosis factor-alpha (TNF-alpha), interleukin-1(IL-1), IL-6, free radicals, inducible nitric oxide (iNO), and stress hyperglycemia occurs in sepsis and this leads to systemic inflammatory response and myocardial depression seen in sepsis and septic shock. Conversely, insulin suppresses production of MIF, TNF-alpha, IL-1, IL-6, and free radicals, enhances endothelial NO generation, and enhances the production of anti-inflammatory cytokines IL-4, and IL-10, corrects stress hyperglycemia and improves myocardial function. This supports my earlier proposal that insulin (with or without glucose and potassium) therapy to maintain euglycemia suppresses the inflammatory response, improves myocardial function, and thus, is of benefit in acute myocardial infarction, sepsis andseptic shock.

Background: Endothelial cell dysfunction may play a role in the pathobiology of pre-eclampsia and human essential hypertension. Vasodilators and platelet anti-aggregators such as prostacyclin and nitric oxide are produced by endothelial cells. The half-life of prostacyclin and nitric oxide are reduced by superoxide anion, whereas superoxide dismutase antagonizes its action., Objectives: To estimate the plasma concentrations of nitric oxide and lipid peroxides and those of catalase and superoxide dismutase in patients with pre-eclampsia and essential hypertension., Methods: Patients of essential hypertension and pre-eclampsia were selected for the study. Nitric oxide and lipid peroxides were estimated in the plasma and anti-oxidants catalase and superoxide dismutase were estimated in the RBC membranes., Results: The ratio between lipid peroxides and nitric oxide was elevated and the activity of superoxide dismutase reduced in patients with pre-eclampsia and uncontrolled essential hypertension., Conclusion: These results suggest that oxidants and anti-oxidants are altered in human essential hypertension and pre-eclampsia.

Essential fatty acids (EFAs) form an important component of cell membranes, are eicosanoid precursors and are therefore required for both the structure and function of every cell in the body. EFAs can modulate the activity of protein kinase C, T and B cell response, free radical generation and lipid peroxidation, lymphokine secretion and cell proliferation. EFAs also have anti-mutagenic, anti-bacterial, anti-fungal and anti-viral properties. EFAs and their metabolites lower serum cholesterol, triglycerides and blood pressure. EFAs appear to be of benefit in atopic eczema, premenstrual syndrome, psoriasis, auto-immune disorders especially rheumatoid arthritis and systemic lupus erythematosus, prevention of target organ damage in diabetes mellitus, peptic ulcer disease, ulcerative colitis, coronary heart disease and atherosclerosis. EFAs and their metabolites can selectively kill tumor cells both in vitro and in vivo without harming normal cells. In addition, EFAs seem to play a fundamental role in inflammation and immune response. In view of their actions and relative safety, it is anticipated that EFAs may be useful in the management of several diseases.

GLUT-4 receptor, tumor necrosis factor-alpha (TNF-alpha), essential fatty acids (EFAs) and their metabolites and daf-genes seem to play an important and essential role in the maintenance of glucose homeostasis, and in the pathobiology of obesity and non-insulin dependent diabetes mellitus (NIDDM). Daf-genes encode for proteins which are 35% identical to the human insulin receptor, a transforming growth factor-beta (TGF-beta) type signal and can also enhance the expression of superoxide dismutase (SOD). On the other hand, EFAs and their metabolites can increase the cell membrane fluidity and thus, enhance the expression of GLUT-4 and insulin receptors. In addition, EFAs can suppress TNF-alpha production and secretion and thus, are capable of reversing insulin resistance. Melatonin has anti-oxidant actions similar to daf-16, TGF-beta and SOD. Hence, it is likely that there is a close interaction between GLUT-4, TNF-alpha, EFAs, daf-genes, melatonin and leptin that may have relevance to the development of insulin resistance, obesity, NIDDM, complications due to NIDDM, longevity and ageing.

Systemic lupus erythematosus (SLE) is an auto-immune disease in which free radicals, eicosanoids, cytokines and nitric oxide seem to play a major role. An increase in the generation of superoxide anion and excess of interleukin-2 (IL-2), tumour necrosis factor (TNF) and pro-inflammatory eicosanoids and a fall in the production of nitric oxide and anti-oxidants such as superoxide dismutase and glutathione peroxidase seems to occur during the active phase of the disease. Thus, an imbalance in the pro-and anti-inflammatory molecules and a change in the delicate balance between the oxidants and anti-oxidants seems to have a vital role in the pathophysiology of SLE. In addition, a defect in the apoptosis of pro-inflammatory T cells may perpetuate the chronic inflammatory process in SLE. Thus, methods designed to suppress the generation of free radicals. IL-1, IL-2 and TNF and of eicosanoids and augment the concentrations of nitric oxide and anti-oxidants and enhance the apoptotic death of the pro-inflammatory T cells may be benefit in the management of SLE. Recent studies suggest that essential fatty acids and their metabolites, whose levels were found to be low in SLE, may restore the balance between pro- and anti-inflammatory molecules, oxidants and anti-oxidants and induce apoptosis of T cell.

Obesity is a common health disorder in humans and is inherited genetically. Though several theories have been proposed in the past to understand the mechanisms underlying the control of obesity, the recent discovery of leptin (OB) has made the obesity research interesting. OB, a product of ob gene is a 16 KD protein, secreted by the adipocytes. It acts through its receptor (OB-R), which is a product of db gene. ob and OB-R in conjunction with neuropeptide Y, melanocyte stimulating hormone and melanocortin-4 receptor have been found to control adiposity. Though several issues pertaining to ob need to be addressed, it is anticipated that future treatment of obesity may depend on our understanding of the action(s) of leptin and its associated molecules and receptors.

As anti-inflammatory drugs such as acetylsalicylic acid are known to partially restore insulin response to glucose, the possible beneficial effect of colchicine, an anti-gout and anti-inflammatory drug, in non-insulin dependent diabetes mellitus (NIDDM) was studied. Colchicine could significantly reduce blood glucose levels, both fasting and post-prandial when given at a dose of 0.5 mg thrice a day in NIDDM patients. There were no side-effects due to the therapy. This study suggests that colchicine has anti-diabetic properties.

Recent studies have shown that activation of oncogenes, genes concerned with cell growth, and inactivation of anti-oncogenes may be responsible for uncontrolled cell proliferation leading to malignancy. These oncogenes code for products or proteins which are closely similar to growth factors or receptors of growth factors. Alterations in lipid metabolism in the form of excess formation of inositol triphosphate and relocation of protein kinase C, the second messengers of the mitotic process, can initiate cell division. Oncogenes can be activated by chromosomal aberrations induced by chemicals, viruses and drugs. The identification of oncogenes and their products may have relevance to the development of new therapeutic strategies in cancer.

Tumour necrosis factor/cachectin (TNF) is considered a primary mediator in the pathogenesis of injury, infection and inflammation and seems to be essential for host defense and tissue homeostasis. On the other hand, TNF can also cause septic shock, tissue injury and cachexia. There is a close interaction between TNF and other cytokines such as interferon, interleukin-1 and interleukin-2, and prostaglandins. TNF is responsible for the deleterious effects of endotoxaemia, and passive immunization against it substantially mitigates the lethal effect of endotoxin. It is also a potent pyrogen, causes bone resorption, activates neutrophil adherence and degranulation and phagocytosis, and ultimately participates in inflammatory diseases of the skin, gastrointestinal tract, joints, muscle and central nervous system and in neoplastic diseases.

Free radicals are the major mediators of the bactericidal and cytotoxic actions of polymorphonuclear leucocytes, macrophages and monocytes, and can stimulate lymphocytes mitogenically. Hydrogen peroxide induces interferon production by human macrophages and activates NK (natural killer) cells; interferon can in turn enhance free radical generation in the cells. Anti-cancer drugs such as doxorubicin, vincristine and adriamycin; radiation; and haematoporphyrin derivative-induced photosensitization all can augment free radical generation and thus, cause tumour cell lysis. Our recent studies suggest that some polyunsaturated fatty acids such as gamma-linolenic acid, arachidonic acid and eicosapentaenoic acid can selectively kill tumour cells but not normal cells in vitro by virtue of their capacity to augment free radical generation in the tumour cells. Thus, free radicals have both harmful and beneficial actions.

A simple and rapid method of controlling hyperglycaemia is described. This method involves giving soluble insulin/monocomponent insulin every two hours subcutaneously till the blood sugar falls below 200 mg%, by monitoring blood sugar every 2 hours. The time taken and insulin given to control hyperglycaemia thus gives an indication as to the amount of insulin needed by the patient for 24 hours to keep the diabetes under control.