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Biomedical subjects

U N Das

Publications and source records attributed to U N Das.

At least 73 records · Page 4Linked to original sources

Hypothesis: cis-unsaturated fatty acids as potential anti-peptic ulcer drugs.

It is now reasonably well established that Helicobacter pylori is the most likely cause for duodenal ulcer. What is not clear is how this infection is related to the excess acid production, why few people with Helicobacter pylori infection have duodenal ulcer and how diet is related to duodenal ulcer. Here it is suggested that a deficiency of cis-unsaturated fatty acids (otherwise called as polyunsaturated fatty acids, PUFAs) especially gamma-linolenic acid, dihomo-gamma-linolenic acid, arachidonic acid and eicosapentaenoic acid may be responsible for duodenal ulcer. Patients with active duodenal ulcer are known to have low concentrations of these PUFAs in their plasma phospholipid fraction and they revert to normal levels after treatment with H2 blockers. In addition, these PUFAs have the ability to inhibit the growth of Helicobacter pylori, suppress acid production and both in experimental animals and humans these PUFAs could heal the ulcer and protect the gastric mucosa from aspirin and steroid-induced damage. Further, PUFAs have other beneficial actions such as capacity to prevent/arrest atherosclerosis, lower plasma cholesterol and triglyceride levels and cytotoxic action on tumour cells. Since PUFAs can be administered over long periods of time and are relatively non-toxic, it is suggested that PUFAs may be exploited as potential anti-ulcer agents.

Anti-Ulcer Agents↗

Oxidant stress, anti-oxidants, nitric oxide and essential fatty acids in peptic ulcer disease.

In patients with duodenal ulcer (DU), the plasma levels of nitrite and lipid peroxides, the anti-oxidant content of red cells and plasma phospholipid fatty acid analysis were performed both before and after healing of the ulcer following treatment with lansoprazole, a proton pump inhibitor. These results showed that during the phase of active DU, the concentrations of antioxidants (superoxide dismutase, SOD, catalase and glutathione peroxidase) in red cells were low where as those of lipid peroxides and nitric oxide were high. Of the fatty acids measured, the concentration of palmitic acid (16:0) was increased during the active ulcer phase whereas those of arachidonic acid, alpha-linolenic acid and docosahexaenoic acid were low. These biochemical abnormalities reverted to normal following healing of the ulcer with lansoprazole. These results coupled with the observation that polyunsaturated fatty acids (PUFAs) can inhibit the growth of Helicobacterpylori and heal the ulcer suggest that free radicals, anti-oxidants, nitric oxide and PUFAs may play a significant role in the pathogenesis of DU. If this is true, it suggests that PUFAs can be exploited as potential anti-peptic ulcer drugs.

Adolescent↗

Can tumour cell drug resistance be reversed by essential fatty acids and their metabolites?

Tumour cell drug resistance is a major problem in cancer chemotherapy. Essential fatty acids have been shown to be cytotoxic to a variety of tumour cells in vitro. But, the effect of these fatty acids on tumour cell drug resistance has not been well characterized. Gamma-linolenic acid (GLA) of the n-6 series and eicosapentaenoic acid (EPA) of the n-3 series potentiated the cytotoxicity of anti-cancer drugs: vincristine, cis-platinum and doxorubicin on human cervical carcinoma (HeLa) cells in vitro. Alpha-linolenic acid (ALA), GLA, EPA and docosahexaenoic acid (DHA) enhanced the uptake of vincristine by HeLa cells. In addition, DHA, EPA, GLA and DGLA were found to be cytotoxic to both vincristine-sensitive (KB-3-1) and -resistant (KB-ChR-8-5) human cervical carcinoma cells in vitro. Pre-incubation of vincristine-resistant cells with sub-optimal doses of fatty acids enhanced the cytotoxic action of vincristine. GLA, DGLA, AA, EPA and DHA enhanced the uptake and inhibited the efflux of vincristine and thus, augmented the intracellular concentration of the anti-cancer drug(s). Fatty acid analysis of KB-3-1 and KB-ChR-8-5 cells showed that the latter contained low amounts of ALA, GLA, 22:5 n-3 and DHA in comparison to the vincristine-sensitive cells. The concentrations of GLA and DHA were increased 10-15 fold in the phospholipid, free fatty acid and ether lipid cellular lipid pools of GLA and DHA treated cells. These results coupled with the observation that various fatty acids can alter the activity of cell membrane bound enzymes such as sodium-potassium-ATPase and 5'-nucleotidase, levels of various anti-oxidants, p53 expression and the concentrations of protein kinase C suggest that essential fatty acids and their metabolites can reverse tumour cell drug-resistance at least in vitro.

5'-Nucleotidase↗

Leptin--the fat controller.

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.

Animals↗

Oxidants, anti-oxidants, essential fatty acids, eicosanoids, cytokines, gene/oncogene expression and apoptosis in systemic lupus erythematosus.

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.

Animals↗

Oxidant stress, anti-oxidants and essential fatty acids in systemic lupus erythematosus.

Eicosapentaenoic acid and docosahexaenoic acid (EPA and DHA respectively) can suppress the production of interleukin-1 (IL-1), IL-2 and TNF (tumor necrosis factor) but not of IL-4 by human lymphocytes in vitro. In addition, the concentrations of EPA and DHA were also found to be low in the plasma phospholipid fraction of patients with SLE. In a limited clinical study performed by us earlier, it was observed that oral supplementation of EPA/DHA to patients with SLE can induce clinical remission without any side-effects. Since oxygen free radicals are known to be involved in the pathobiology of SLE, we estimated the plasma concentrations of lipid peroxides, nitric oxide, and anti-oxidants such as catalase, superoxide dismutase (SOD), glutathione peroxidase and vitamin E in these patients both before and after the induction of remission following EPA/DHA administration. These results showed that the levels of lipid peroxides are elevated and those of nitric oxide, SOD and glutathione peroxidase are decreased in SLE prior to EPA/DHA supplementation. Following EPA/DHA administration the concentrations of lipid peroxides, and those of nitric oxide, SOD and glutathione peroxidase reverted to near normal levels. These results suggest that oxidant stress, nitric oxide, and anti-oxidants play a significant role in SLE and that EPA/DHA can modulate oxidant stress and nitric oxide synthesis and may have a regulator role in the synthesis of anti-oxidant enzymes such as SOD and glutathione peroxidase. From the results of this study, we would like to suggest that measurement of lipid peroxides, nitric oxide and anti-oxidants can be used as markers to predict prognosis in patients with SLE.

Antioxidants↗

Cytotoxic action of alpha-linolenic and eicosapentaenoic acids on myeloma cells in vitro.

Both alpha-linolenic (ALA) and eicosapentaenoic acids (EPA) were toxic to SP 2/0 mouse myeloma cells in vitro. On the other hand, linoleic acid (LA), gamma-linolenic acid (GLA), di-homo-gamma linolenic acid (DGLA), arachidonic acid (AA), docosahexaenoic acid (DHA) and oleic acid (OA) were much less effective in their growth suppressive actions. Both nordihydroguaiaretic acid (NDGA) and Indomethacin (IM) could block the action of the fatty acids indicating a role for prostaglandins (PGs) and leukotrienes (LTs) in the growth suppressive action of ALA and EPA. Superoxide dismutase (SOD) completely blocked, while vitamin E and reduced glutathione (GSH) could prevent to a limited extent the anti-proliferative effects of ALA and EPA. Catalase, mannitol, chlorpromazine (CPZ) and trifluoperazine (TFP) did not block the cytotoxic actions of ALA and EPA. N(G)-mono-methyl L-arginine (N(G)MMA), an analogue of L-arginine, which inhibits nitric oxide synthase, was ineffective in preventing the cytotoxicity induced by ALA and EPA. Fatty acid analysis of the various lipid fractions of SP 2/0 cells treated with ALA and EPA showed significant incorporation of these fatty acids in the cell membrane lipid pools. These results suggest that ALA and EPA induced suppression of SP 2/0 cell proliferation is cyclo-oxygenase (CO), lipoxygenase (LO) and superoxide dependent. Lipid peroxidation has only a limited role in this process. Both calmodulin dependent process and L-arginine derived nitric oxide do not seem to have a role in the cytotoxic action of ALA and EPA in these cells.

Animals↗

Effect of cis-unsaturated fatty acids, prostaglandins, and free radicals on angiotensin-converting enzyme activity in vitro.

Angiotensin-converting enzyme (ACE) is known to play an important role in the pathobiology of human essential hypertension. Similarly, cis-unsaturated fatty acids, prostaglandins, and free radicals are believed to play a role in the control of blood pressure. It was observed that all the cis-unsaturated fatty acids tested can inhibit ACE activity to a significant degree. On the other hand, prostaglandins and free radicals, superoxide anion, hydrogen peroxide, and hydroxyl radical did not show significant inhibitory effects on ACE activity in vitro. But, the nitric oxide donor sodium nitroprusside showed a potent inhibitory action on ACE activity, suggesting that one of the possible mechanism(s) by which nitric oxide can bring about its anti-hypertensive action might be by modulating ACE activity in addition to its direct vasodilator action. These results indicate that there is a close interaction among ACE activity, cis-unsaturated fatty acids, and nitric oxide, which may have relevance to the pathobiology of human essential hypertension.

Adult↗

Effect of cis-unsaturated fatty acids on cellular oxidant stress in macrophage tumor (AK-5) cells in vitro.

Cis-unsaturated fatty acids (c-UFAs) induced decreased survival of macrophage tumor (AK-5) cells in vitro. The cytotoxic action of c-UfAs was associated with an increase in free radical generation and lipid peroxidation process. In addition, exposure of AK-5 cells to various c-UFAs for a short period (1 h) decreased the cellular concentrations of anti-oxidants: superoxide dismutase (SOD), catalase, glutathione peroxidase, glutathione reductase, glutathione and vitamin E. However, prolonged (24 h) exposure of AK-5 cells to c-UFAs enhanced the levels of SOD with little or no change in the concentrations of catalase, glutathione peroxidase and glutathione reductase. These results indicate that c-UFAs can enhance free radical generation and lower the concentrations of various anti-oxidants in the tumor cells which may explain the cytotoxic action of c-UFAs.

Animals↗

Effect of free fatty acids on two-stage skin carcinogenesis in mice.

The effect of n-3 and n-6 free fatty acids on two stage skin carcinogenesis in mice was studied. Stearic, linoleic, arachidonic, and eicosapentaenoic acids inhibited both initiation and promotion stages of skin carcinogenesis. Although no direct correlation between lipid peroxidation and papilloma formation was observed, a trend towards an increase in the formation of lipid peroxides with the inhibitory effect of fatty acids on papilloma development was noted. In general, the fatty acids applied were incorporated mainly into the phospholipid and free fatty acid pools. All the fatty acids tested, except eicosapentaenoic and docosahexaenoic acids, inhibited the binding of benzo[a]pyrene (BP) to DNA. On the other hand, BP and croton oil-induced skin cell proliferation was not influenced by any of the fatty acids used. In conclusion, the results of the present study suggest that inhibition of papilloma formation by free fatty acids is complex and can be attributed to a limited extent only to their ability to inhibit BP binding to DNA, to block cell proliferation and enhance the lipid peroxidation process.

Animals↗

Effect of dietary fat on diethylnitrosamine induced hepatocarcinogenesis in Wistar rats.

In a diethylnitrosamine (DEN) induced hepatoma model, the effect of fish oil, a rich source of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and ground nut oil, a rich source of oleic acid (OA) and linoleic acid (LA), was studied. Both 20% fish oil and ground nut oil inhibited DEN-induced hepatocarcinogenesis in rats. Contrary to general belief, an inverse correlation was observed between the development of neoplastic nodules and the amount of lipid peroxides formed in the high fat (20% fish oil and ground nut oil) diet groups, indicating that the higher the lipid peroxides formed, the lower the incidence of liver tumours in DEN-treated animals. Results of the analysis of liver fatty acid composition of the phospholipid fraction suggested that DEN and fish oil treatment can inhibit the activity of the delta-6 and 5-desaturases. It is concluded from the results of the present study that a 'high fat' diet and lipid peroxidation can modulate DEN-induced hepatocarcinogenesis in rats.

Animals↗

Local application of gamma-linolenic acid in the treatment of human gliomas.

gamma-Linolenic acid (GLA) has been shown to have selective tumoricidal action both in vitro and in vivo. Earlier, in a limited clinical study, we have demonstrated that intra-tumoral administration of GLA can induce regression of human gliomas. In an extension of this study, we evaluated the effect of intra-cerebral injection of GLA on normal dog brain and in 15 patients with malignant gliomas. Histopathological examination revealed that GLA is not cytotoxic to the normal dog brain cells. Administration of 10 mg of GLA via a cerebral reservoir placed in the tumour bed, at the rate of 1 mg/day over a period of 10 days, revealed that GLA is not only safe and non-toxic but can also regress cerebral gliomas as evaluated by computerised tomography and increased survival of the patients by 1.5-2 years. Based on these results and our earlier in vitro study, we suggest that GLA is a safe anti-tumour agent and recommend its use in the management of human gliomas.

Adult↗

Free radical-dependent suppression of growth of mouse myeloma cells by alpha-linolenic and eicosapentaenoic acids in vitro.

Alpha-linolenic acid (ALA) and eicosapentaenoic acid (EPA) exhibited potent cytotoxic action on SP 2/0 mouse myeloma cells in vitro. Both SOD and vitamin E could inhibit the action of ALA and EPA indicating a role for reactive oxygen species and lipid peroxides. In addition, both ALA and EPA enhanced the formation of superoxide anion, hydrogen peroxide and lipid peroxides, and caused a reduction in the levels of antioxidant enzymes: SOD, catalase and glutathione peroxidase and induced significant damage to DNA in SP 2/0 cells. Thus, ALA and EPA inhibit antioxidant defenses of the cell and damage the DNA, which can ultimately lead to tumor cell lysis.

Animals↗

Prostaglandin metabolism during growth and differentiation of the regenerating vertebrate appendage.

House lizards are able to regenerate their tails. This is an ideal model to study the growth and differentiation of an organ. Prostaglandins (PGs) are local hormones having diverse and potent biological activities. In an effort to understand PG metabolism during the growth and differentiation of the regenerating lizard tail, we analysed the fatty acid (FA) composition of phospholipids are free FAs by GC, the activity of two rate-limiting enzymes (phospholipases A and C), the activity of the enzyme responsible for the oxygenation of polyunsaturated fatty acids to PGs (cyclooxygenase) and characterized the endogenous PGs by HPLC. It was observed that on the 20th day, i.e. the tissue differentiation period, there was an increase in phospholipase A activity, together with a sudden fall in the free arachidonic acid (AA) level, an increase in cyclooxygenase activity and the appearance of endogenous PGE2. PGE2 can stimulate cyclic adenosine monophosphate (cAMP) production and it may stimulate a cascade of events associated with tissue differentiation.

Animals↗

Essential fatty acid metabolism in patients with essential hypertension, diabetes mellitus and coronary heart disease.

Mortality and morbidity from coronary heart disease (CHD), diabetes mellitus (DM) and essential hypertension (HTN) are higher in people of South Asian descent than in other groups. There is evidence to believe that essential fatty acids (EFAs) and their metabolites may have a role in the pathobiology of CHD, DM and HTN. Fatty acid analysis of the plasma phospholipid fraction revealed that in CHD the levels of gamma-linolenic acid (GLA), arachidonic acid (AA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are low, in patients with HTN linoleic acid (LA) and AA are low, and in patients with non-insulin dependent diabetes mellitus (NIDDM) and diabetic nephropathy the levels of dihomo-gamma-linolenic acid (DGLA), AA, alpha-linolenic acid (ALA) and DHA are low, all compared to normal controls. These results are interesting since DGLA, AA and EPA form precursors to prostaglandin E1, (PGE1), prostacyclin (PGI2), and PGI3, which are potent platelet anti-aggregators and vasodilators and can prevent thrombosis and atherosclerosis. Further, the levels of lipid peroxides were found to be high in patients with CHD, HTN, NIDDM and diabetic nephropathy. These results suggest that increased formation of lipid peroxides and an alteration in the metabolism of EFAs are closely associated with CHD, HTN and NIDDM in Indians.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Cytotoxic action of cis-unsaturated fatty acids on human cervical carcinoma (HeLa) cells in vitro.

The effect of n-3 and n-6 fatty acids (FAs) on the growth of human cervical carcinoma (HeLa) cells was studied. Of all the FAs tested, docosahexaenoic acid (DHA, 22:6 n-3) and eicosapentaenoic acid (EPA, 20:5 n-3) were found to be the most potent in their cytotoxic action on HeLa cells and the potency of various fatty acids with regard to their cytotoxic action was as follows: DHA > EPA > dihomo-gamma-linolenic acid (DGLA) = gamma-linolenic acid (GLA) > linoleic acid (LA) > arachidonic acid (AA) > alpha-linolenic acid (ALA). The cycloxygenase inhibitor indomethacin, the lipoxygenase inhibitor nordihydroguaretic acid (NDGA), the antioxidants vitamin E, butylated hydroxyanisole (BHA), and butylated hydroxytoluene (BHT), the superoxide anion quencher superoxide dismutase (SOD), the hydroxyl and hydrogen peroxide quenchers mannitol and catalase, respectively, and the calmodulin antagonists trifluoperazine (TFP) and chlorpromazine (CPZ) could all block the cytotoxic action of GLA, which was used as a representative cytotoxic FA, on HeLa cells. On the other hand, copper and iron salts and buthionine sulfoxamine, a glutathione (GSH) depletor, potentiated the cytotoxic action of suboptimal doses of GLA. GLA-induced radical generation and lipid peroxidation in HeLa cells could be blocked by indomethacin, NDGA and calmodulin antagonists. The cytotoxic action of cis-unsaturated fatty acids (c-UFAs) is not dependent on the alteration in the protein kinase C levels since no alteration in the diacylglycerol levels was observed. Hydroxy and hydroperoxy products of GLA were found to be toxic to HeLa cells, whereas prostaglandin (PG)E1, PGF2 alpha, and prostacyclin stimulated cell growth. From these results, it is evident that radicals are the modulators of the cytotoxic action of c-UFAs, that their formation is a calmodulin-dependent process, and that lipoxygenase products may mediate the tumoricidal action of FAs.

Antineoplastic Agents↗