Amjid Ahad

Pharmacological potential of tocotrienols: a review

Tocotrienols, members of the vitamin E family, are natural compounds found in a number of vegetable oils, wheat germ, barley, and certain types of nuts and grains. Like tocopherols, tocotrienols are also of four types viz. alpha, beta, gamma and delta. Unlike tocopherols, tocotrienols are unsaturated and possess an isoprenoid side chain. Tocopherols are lipophilic in nature and are found in association with lipoproteins, fat deposits and cellular membranes and protect the polyunsaturated fatty acids from peroxidation reactions. The unsaturated chain of tocotrienol allows an efficient penetration into tissues that have saturated fatty layers such as the brain and liver. Recent mechanistic studies indicate that other forms of vitamin E, such as γ-tocopherol, δ-tocopherol, and γ-tocotrienol, have unique antioxidant and anti-inflammatory properties that are superior to those of α-tocopherol against chronic diseases. These forms scavenge reactive nitrogen species, inhibit cyclooxygenase- and 5-lipoxygenase-catalyzed eicosanoids and suppress proinflammatory signalling, such as NF-κB and STAT. The animal and human studies show tocotrienols may be useful against inflammation-associated diseases. Many of the functions of tocotrienols are related to its antioxidant properties and its varied effects are due to it behaving as a signalling molecule. Tocotrienols exhibit biological activities that are also exhibited by tocopherols, such as neuroprotective, anti-cancer, anti-inflammatory and cholesterol lowering properties. Hence, effort has been made to compile the different functions and properties of tocotrienols in experimental model systems and humans. This article constitutes an in-depth review of the pharmacology, metabolism, toxicology and biosafety aspects of tocotrienols. Tocotrienols are detectable at appreciable levels in the plasma after supplementations. However, there is inadequate data on the plasma concentrations of tocotrienols that are sufficient to demonstrate significant physiological effect and biodistribution studies show their accumulation in vital organs of the body. Considering the wide range of benefits that tocotrienols possesses against some common human ailments and having a promising potential, the experimental analysis accounts for about a small fraction of all vitamin E research. The current state of knowledge deserves further investigation into this lesser known form of vitamin E.

Ellagic acid, an NF-κB inhibitor, ameliorates renal function in experimental diabetic nephropathy.

Diabetic nephropathy (DN) is a serious complication confronted by diabetic patients. Available data indicate that the development of DN is linked to inflammation. In this context, nuclear factor-kappa B (NF-κB) has received much attention. Ellagic acid (2,3,7,8-tetrahydroxy-chromeno[5,4,3-cde]chromene-5,10-dione), found abundantly in plant extracts and fruits, possesses numerous medicinal properties. We investigated the nephroprotective effects of oral treatment of ellagic acid in high fat diet/low dose streptozotocin (HFD/STZ)-induced type 2 diabetic Wistar albino rats. Ellagic acid treatment for 16weeks post induction of diabetes significantly attenuated renal dysfunction and oxidative stress. Ellagic acid significantly inhibited the renal NF-кB activation. Moreover, ellagic acid significantly lowered renal pathology and suppressed transforming growth factor-beta (TGF-β) and fibronectin expressions in renal tissues. Ellagic acid also significantly reduced the serum levels of pro-inflammatory cytokines, interleukin-1beta (IL-1β), IL-6 and tumor necrosis factor-alpha (TNF-α). In cultured rat NRK 52E proximal tubular epithelial cells, ellagic acid treatment inhibited high glucose-induced activation of NF-κB and pro-inflammatory cytokine synthesis. These results suggest that ellagic acid exhibited renal protective effect in diabetic rats partly through antihyperglycemia which was accompanied by attenuation of inflammatory processes via inhibition of NF-κB pathway.

Chrysin, an anti-inflammatory molecule, abrogates renal dysfunction in type 2 diabetic rats

Diabetic nepropathy (DN) is considered as the leading cause of end-stage renal disease (ESRD) worldwide, but the current available treatments are limited. Recent experimental evidences support the role of chronic microinflammation in the development of DN. Therefore, the tumor necrosis factor-alpha (TNF-α) pathway has emerged as a new therapeutic target for the treatment of DN. We investigated the nephroprotective effects of chrysin (5, 7-dihydroxyflavone) in a high fat diet/streptozotocin (HFD/STZ)-induced type 2 diabetic Wistar albino rat model. Chrysin is a potent anti-inflammatory compound that is abundantly found in plant extracts, honey and bee propolis. The treatment with chrysin for 16weeks post induction of diabetes significantly abrogated renal dysfunction and oxidative stress. Chrysin treatment considerably reduced renal TNF-α expression and inhibited the nuclear transcription factor-kappa B (NF-кB) activation. Furthermore, chrysin treatment improved renal pathology and suppressed transforming growth factor-beta (TGF-β), fibronectin and collagen-IV protein expressions in renal tissues. Chrysin also significantly reduced the serum levels of pro-inflammatory cytokines, interleukin-1beta (IL-1β) and IL-6. Moreover, there were no appreciable differences in fasting blood glucose and serum insulin levels between the chrysin treated groups compared to the HFD/STZ-treated group. Hence, our results suggest that chrysin prevents the development of DN in HFD/STZ-induced type 2 diabetic rats through anti-inflammatory effects in the kidney by specifically targeting the TNF-α pathway.

A review of characterization of tocotrienols from plant oils and foods

Tocotrienols, members of the vitamin E family, are natural compounds found in a number of vegetable oils, wheat germ, barley and certain types of nuts and grains. Vegetable oils provide the best sources of these vitamin E forms, particularly palm oil and rice bran oil contain higher amounts of tocotrienols. Other sources of tocotrienols include grape fruit seed oil, oats, hazelnuts, maize, olive oil, buckthorn berry, rye, flax seed oil, poppy seed oil and sunflower oil. Tocotrienols are of four types, viz. alpha (α), beta (β), gamma (γ) and delta (δ). Unlike tocopherols, tocotrienols are unsaturated and possess an isoprenoid side chain. A number of researchers have developed methods for the extraction, analysis, identification and quantification of different types of vitamin E compounds. This article constitutes an in-depth review of the chemistry and extraction of the unsaturated vitamin E derivatives, tocotrienols, from various sources using different methods. This review article lists the different techniques that are used in the characterization and purification of tocotrienols such as soxhlet and solid–liquid extractions, saponification method, chromatography (thin layer, column chromatography, gas chromatography, supercritical fluid, high performance), capillary electrochromatography and mass spectrometry. Some of the methods described were able to identify one form or type while others could analyse all the analogues of tocotrienol molecules. Hence, this article will be helpful in understanding the various methods used in the characterization of this lesser known vitamin E variant.

Prophylactic effect of baicalein against renal dysfunction in type 2 diabetic rats

Despite a tremendous advancement in the management of diabetes mellitus, diabetic nephropathy (DN) is still a significant problem for many patients with diabetes, because of the inefficacy and associated side effects of pharmacological drugs. There is a demand for new therapeutic drugs which on one hand efficiently prevent the development of DN by targeting several metabolic and inflammatory pathways, and on the other hand, are side-effect free. In recent years, many researchers have suggested that inflammation plays an important role in the development of DN, hence, NF-κB has received much attention. We investigated the nephroptotective effects of baicalein (BAC), a flavonoid, in high fat diet/streptozotocin induced type 2 diabetic Wistar rats. BAC (10 mg/kg bw/day and 20 mg/kg bw/day) treatment was given to the diabetic rats by oral gavage for 16 weeks post induction of diabetes. The effect of BAC was compared to a commercial antidiabetic drug rosiglitazone (RZ, 3 mg/kg bw/day). BAC and RZ treatment significantly lowered food intake, body weight and levels of fasting blood glucose, HbA1c and homeostasis model assessment index (HOMA-IR) in diabetic rats. Both, BAC and RZ restored normal renal function and mitigated renal oxidative stress. BAC and RZ also suppressed the activation of NF-κB, decreased expression of iNOS and TGF-β1, and ameliorated the structural changes in renal tissues. Moreover, BAC also normalized the levels of serum pro-inflammatory cytokines and liver function enzymes. However, rosiglitazone treatment produced liver toxicity as was evident from increased serum levels of liver function enzymes; ALP, SGOT and SGPT. Taken together, BAC treatment preserved renal function by anti-hyperglycemic, antioxidant and anti-inflammatory effects. Moreover, BAC was found to be more effective as compared to RZ, suggesting the efficacy of BAC in the treatment of DN.

Glycine propionyl l-carnitine attenuates d-Galactosamine induced fulminant hepatic failure in wistar rats.

Glycine propionyl l-carnitine (GPLC) is a propionyl ester of carnitine that includes an additional glycine component. The present study evaluated hepatoprotective effect of GPLC in d-Galactosamine (d-GalN) induced fulminant hepatic failure. Rats were intraperitonially administered d-GalN (700mg/kgBW). GPLC was given as a pre-treatment (35mg/kgBW/day) for 1month followed by a single dose of d-GalN on the 31st day. d-GalN administration resulted in increased mortality and serum ALT and AST activities. These increases were significantly attenuated by GPLC. d-GalN treatment increased hepatic lipid peroxidation and a decrease in reduced glutathione content was observed. GPLC pre-treatment significantly decreased lipid peroxidation and augmented the level of GSH. d-GalN increased the circulating level of TNF-α and ATM-Kinase and MAP-Kinase expression. GPLC supplementation inhibited the increase in serum TNF-α and ATM-Kinase and MAP-Kinase expression. d-GalN treatment increased the level of Bax and Caspase-3 m-RNA while as a decline was observed in Bcl2 m-RNA. GPLC prevented the increase in Caspase-3 and Bax m-RNA and at the same time augmented the expression of Bcl2 m-RNA. Our findings suggest that GPLC alleviates d-GalN induced liver injury by strengthening antioxidative defense system and reducing apoptotic signalling pathways.

Mutational analysis of prohibitin--a highly conserved gene in Indian female breast cancer cases.

Prohibitin (PHB) is a chaperone protein which is highly conserved evolutionarily. It shows significant homology with the Drosophila cc gene which is considered important for development and differentiation of Drosophila melanogaster. Investigations have revealed an involvement of PHB in cellular proliferation and development, apoptosis, signal transduction, mitochondrial function and regulation of the estrogen and androgen receptors. Therefore, we conducted the present study to analyze mutations in the highly conserved region in Indian female breast cancer patients. Conventional PCR-SSCP and Automated DNA sequencing were performed with a total of 105 breast cancer samples along with adjacent normal tissue. Of the total, 14.2% (15/105) demonstrated a mutation status of prohibitin observed in our study population. We identified a novel missense mutation (Thr>Ser), a novel deletion of T nucleotide in an intron adjacent to intron-exon boundary and a previously determined missense mutation (Val>Ala). A statistically significant correlation was obtained which suggested that prohibitin may be associated with tumor development and/or progression of at least some proportion of breast cancers.

Nephroprotective potential of Quercus infectoria galls against experimentally induced diabetic nephropathy in rats through inhibition of renal oxidative stress and TGF-β

ABSTRACT Diabetic nephropathy (DN) is the leading cause of death in diabetic patients and the current treatment options available have a limited significance. The insect galls of Quercus infectoria are traditionally important in the treatment of numerous diseases including diabetes. Hence, the present study was undertaken to evaluate the effect of Q. infectoria gall extract (QIGE) against experimental DN. Type 2 diabetes was induced by feeding rats with a high-fat diet (HFD) initially for 5 weeks, followed by a single intraperitoneal injection of streptozotocin (STZ, 35 mg/kg bw/day). QIGE was administered to the rats orally at doses of 100 and 200 mg/kg bw/day, respectively. At the end of the experimental period, various glycemic and renal function parameters were evaluated in the serum, urine and kidney tissues. The QIGE treatment significantly (p < .001) reduced the levels of fasting blood glucose, serum lipid profile, glycated hemoglobin (HbA1c) and homeostasis assessment of insulin resistance in treated rats as compared to diabetic control rats. Markers of oxidative stress and the expression of transforming growth factor-β (TGF-β) in the kidneys of diabetic rats were significantly (p < .001) normalized by QIGE administration. QIGE prevents the development of DN via the inhibition of hyperglycemia-induced oxidative stress and renal TGF-β expression and is, therefore, a potential therapeutic agent in the treatment of diabetic complications, especially DN.