Anupam Bishayee

Hepatoprotective activity of carrot (Daucus carota L.) against carbon tetrachloride intoxication in mouse liver.

The effect of carrot extract on carbon tetrachloride (CCl4)-induced acute liver damage was evaluated. The increased serum enzyme levels (viz., glutamate oxaloacetate transaminase, glutamate pyruvate transaminase, lactate dehydrogenase, alkaline phosphatase, sorbitol and glutamate dehydrogenase) by CCl4-induction were significantly lowered due to pretreatment with the extract. The extract also decreased the elevated serum bilirubin and urea content due to CCl4 administration. Increased activities of hepatic 5-nucleotidase, acid phosphatase, acid ribonuclease and decreased levels of succinic dehydrogenase, glucose-6-phosphatase and cytochrome P-450 produced by CCl4 were reversed by the extract in a dose-responsive way. Results of this study revealed that carrot could afford a significant protective action in the alleviation of CCl4-induced hepatocellular injury.

Vanadium chemoprevention of 7,12-dimethylbenz(a)anthracene-induced rat mammary carcinogenesis: probable involvement of representative hepatic phase I and II xenobiotic metabolizing enzymes.

Vanadium, a non-platinum group metal and dietary micronutrient, is now proving to act as a promising antitumor agent. The present study was conducted to ascertain its antineoplastic potential against an experimental mammary carcinogenesis. Female Sprague-Dawley rats, at 50 days of age, were treated with 7,12-dimethylbenz(a)anthracene (DMBA) (0.5u2009mg/100u2009g body weight) by a single tail vein injection in an oil emulsion. Vanadium (ammonium monovanadate) at the concentration of 0.5u2009ppm was supplemented in drinking water and given ad libitum to the experimental group immediately after the carcinogen treatment and it continued until the termination of the study (24 weeks for histological and biochemical observations and 35 weeks for morphological findings). It was found that vanadium treatment brought about a substantial protection against DMBA-induced mammary carcinogenesis. This was evident from histological findings that showed no sign of hyperplasia or abnormality after vanadium treatment. There was a significant reduction in incidence (Pu2009<u20090.05), total number, multiplicity (Pu2009<u20090.01) and size of palpable mammary tumors and delay in mean latency period of tumor appearance (u2009<u20090.001) following vanadium supplementation compared to DMBA control. From the cumulative results of various hepatic biochemical indices namely, lipid peroxidation, reduced glutathione level, superoxide dismutase activity, cytochrome P450 content and glutathione S-transferase activity, the anticarcinogenic potential of vanadium was well reflected through stabilization of these parameters. Results of the study indicate that the anticarcinogenic activity of vanadium during DMBA-initiated mammary carcinogenesis is mediated through alteration of hepatic antioxidant status as well as modulation of phase I and II drug metabolizing enzymes. On the basis of the observed results, vanadium can be considered as a readily available, promising and novel cancer chemopreventive agent.

Time Course Effects of Vanadium Supplement on Cytosolic Reduced Glutathione Level and Glutathione S-Transferase Activity

The influence of vanadium, an important dietary micronutrient, was evaluated on the cytosolic reduced glutathione (GSH) content and glutathione S-transferase (GST) activity in several rat target tissues. Supplementation of drinking water with vanadium at the level of 0.2 or 0.5 ppm for 4, 8, or 12 wk was found to increase the GSH level with a concomitant elevation in GST activity in the liver followed by small intestine mucosa, large intestine mucosa, and kidney. The results were almost dose-dependent and mostly pronounced with 0.5 ppm vanadium after 12 wk of its continuous supplementation. Neither the GSH level nor GST activity was significantly altered in forestomach and lung following vanadium supplementation throughout the study. The levels of vanadium that were found to increase the content of GSH and activity of GST in the liver, intestine, and kidney did not exert any toxic manifestation was evidenced from water and food consumption as well as the growth responses of the experimental animals. Moreover, these doses of vanadium did not impair either hepatic or renal functions as they did not alter the serum activities of glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), sorbitol dehydrogenase (SDH), as well as serum urea and creatinine levels. All these results clearly indicate that vanadium under the doses employed in our study has a significant inducing role on GSH content with a concurrent elevation in GST activity in the liver and specific extrahepatic tissues without any apparent sign of cytotoxicity. This attribute of vanadium may have a greater importance in terms of biotransformation and detoxification of xenobiotics, including carcinogens. In addition, since the ability to afford an increment in the endogenous GSH-GST pool by anticarcinogenic natural substances has been found to correlate with their activity to inhibit neoplastic transformation, the trace element vanadium may be considered as a novel anticancer agent.

Molecular Targets Underlying the Anticancer Effects of Quercetin: An Update

Quercetin, a medicinally important member of the flavonoid family, is one of the most prominent dietary antioxidants. It is present in a variety of foods—including fruits, vegetables, tea, wine, as well as other dietary supplements—and is responsible for various health benefits. Numerous pharmacological effects of quercetin include protection against diseases, such as osteoporosis, certain forms of malignant tumors, and pulmonary and cardiovascular disorders. Quercetin has the special ability of scavenging highly reactive species, such as hydrogen peroxide, superoxide anion, and hydroxyl radicals. These oxygen radicals are called reactive oxygen species, which can cause oxidative damage to cellular components, such as proteins, lipids, and deoxyribonucleic acid. Various oxygen radicals play important roles in pathophysiological and degenerative processes, such as aging. Subsequently, several studies have been performed to evaluate possible advantageous health effects of quercetin and to collect scientific evidence for these beneficial health claims. These studies also gather data in order to evaluate the exact mechanism(s) of action and toxicological effects of quercetin. The purpose of this review is to present and critically analyze molecular pathways underlying the anticancer effects of quercetin. Current limitations and future directions of research on this bioactive dietary polyphenol are also critically discussed.

Further Evidence for Chemopreventive Potential of β-Carotene Against Experimental Carcinogenesis: Diethylnitrosamine-Initiated and Phenobarbital-Promoted Hepatocarcinogenesis Is Prevented More Effectively by β-Carotene Than by Retinoic Acid

The comparative effectiveness of β-carotene (BC) and retinoic acid (RA) was investigated against two-stage rat liver carcinogenesis initiated by a single injection of diethylnitrosamine (DEN, 200 mg/kg ip) followed by promotion with phenobarbital (PB, 0.05%) in a basal diet. BC (500 mg/kg) or RA (200 mg/kg) was administered per os daily throughout the entire experiment, before the initiation, or during the promotional stage. Treatment with BC throughout the experiment or before initiation significantly reduced the incidence (p < 0.01), multiplicity (p < 0.05), and size of visible subcapsular hepatocyte nodules (HNs) and reduced (p < 0.001 or 0.05) nodular volume as a percentage of liver volume. The results with RA were of lesser extent than those observed with BC. There was a considerable depletion of hepatic BC and total vitamin A (retinol + ester) in HNs and nonnodular surrounding parenchyma (NNSP) of rats subjected to the DEN-PB regimen than their control counterparts. Treatment with BC significantly elevated hepatic BC and total vitamin A contents in HNs and NNSP compared with DEN-PB control, and the elevation was proportional to the duration of BC treatment. Long-term BC or RA treatment elicited a substantial decrement in reduced glutathione content and γ-glutamyltranspeptidase activity and an increment in cytochrome P-450 content and glutathione peroxidase and glutathione S-transferase activities in the HNs and NNSP, which were otherwise reversed in rats that received DEN-PB treatment alone. Our results suggest that BC or RA has the potential to inhibit DEN-induced hepatocarcinogenesis through selective modulation of the antioxidant defense system and xenobiotic detoxification in the liver. It is also apparent that the beneficial effect of BC or RA is primarily exerted on the initiation phase and secondarily during the promotional stage of DEN-initiated rat liver carcinogenesis and that BC affords a better chemopreventive response than RA.

A multi-targeted approach to suppress tumor-promoting inflammation.

Cancers harbor significant genetic heterogeneity and patterns of relapse following many therapies are due to evolved resistance to treatment. While efforts have been made to combine targeted therapies, significant levels of toxicity have stymied efforts to effectively treat cancer with multi-drug combinations using currently approved therapeutics. We discuss the relationship between tumor-promoting inflammation and cancer as part of a larger effort to develop a broad-spectrum therapeutic approach aimed at a wide range of targets to address this heterogeneity. Specifically, macrophage migration inhibitory factor, cyclooxygenase-2, transcription factor nuclear factor-κB, tumor necrosis factor alpha, inducible nitric oxide synthase, protein kinase B, and CXC chemokines are reviewed as important antiinflammatory targets while curcumin, resveratrol, epigallocatechin gallate, genistein, lycopene, and anthocyanins are reviewed as low-cost, low toxicity means by which these targets might all be reached simultaneously. Future translational work will need to assess the resulting synergies of rationally designed antiinflammatory mixtures (employing low-toxicity constituents), and then combine this with similar approaches targeting the most important pathways across the range of cancer hallmark phenotypes.

Neuroinflammation in Alzheimer's Disease: The Preventive and Therapeutic Potential of Polyphenolic Nutraceuticals

Brain inflammation, characterized by increased microglia and astrocyte activation, increases during aging and is a key feature of neurodegenerative diseases, such as Alzheimers disease (AD). In AD, neuronal death and synaptic impairment, induced by amyloid-β (Aβ) peptide, are at least in part mediated by microglia and astrocyte activation. Glial activation results in the sustained production of proinflammatory cytokines and reactive oxygen species, giving rise to a chronic inflammatory process. Astrocytes are the most abundant glial cells in the central nervous system and are involved in the neuroinflammation. Astrocytes can be activated by numerous factors, including free saturated fatty acids, pathogens, lipopolysaccharide, and oxidative stress. Activation of astrocytes produces inflammatory cytokines and the enzyme cyclooxygenase-2, enhancing the production of Aβ. Furthermore, the role of the receptor for advanced glycation end products/nuclear factor-κB (NF-κB) axis in neuroinflammation is in line with the nonenzymatic glycosylation theory of aging, suggesting a central role of the advanced glycation end products in the age-related cognitive and a possible role of nutraceuticals in the prevention of neuroinflammation and AD. However, modulation of P-glycoprotein, rather than antioxidant and anti-inflammatory effects, could be the major mechanism of polyphenolic compounds, including flavonoids. Curcumin, resvertrol, piperine, and other polyphenols have been explored as novel therapeutic and preventive agents for AD. The aim of this review is to critically analyze and discuss the mechanisms involved in neuroinflammation and the possible role of nutraceuticals in the prevention and therapy of AD by targeting neuroinflammation.

Anticarcinogenic biological response of Mikania cordata: reflections in hepatic biotransformation systems

The chemopreventive role of an Indian medicinal plant Mikania cordata (Compositae), which is consumed as vegetable and advocated in folk-medicine, has been evaluated through its effects on Phase 1 and 2 of the hepatic drug-detoxifying enzyme system in rats. Although oral administration of a methanolic extract of this plant root (50, 100 or 150 mg/kg for 4, 8 or 12 weeks) has been found to have very little or no effect on hepatic microsomal cytochrome P-450 and cytochrome b5 contents as well as NADPH cytochrome c reductase activity, it afforded a marked induction of uridine diphosphoglucuronyl transferase activities of liver microsomes. The extract also significantly increased the activities of microsomal uridine diphosphoglucose dehydrogenase, reduced nicotinamide adenine dinucleotide (phosphate): quinine reductase and cytosolic glutathione s-transferases with a concomittant elevation in the contents of reduced glutathione. All these effects were found to be dose-dependent and maintained during 12 weeks of the extract treatment. Results of the study clearly indicate that the intracellular contents of active intermediates of various xenobiotics including chemical carcinogens would be reduced by the specific enhancement of drug-detoxifying enzymes in the liver of rats treated with the plant extract.

Trianthema portulacastrum affords antihepatotoxic activity against carbon tetrachloride-induced chronic liver damage in mice: reflection in subcellular levels

The efficacy of an ethanol extract of Trianthema portulacastrum as a hepatoprotective agent was investigated against carbon tetrachloride (CCl4)‐induced chronic liver injury in mice. The CCl4 was administered per os (p.o.) three times a week for 5 weeks. Daily administration (p.o.) of T. portulacastrum plant extract at 100 or 150u2009mg/kg was started 2 weeks before the commencement of CCl4 treatment and it continued during the entire period of the treatment. The extract dose‐dependently decreased the activities of serum glutamate oxaloacetate transaminase, glutamate pyruvate transaminase, lactate dehydrogenase, alkaline phosphatase, glutamate dehydrogenase and sorbitol dehydrogenase as well as serum levels of bilirubin and urea which were otherwise significantly elevated with the chronic CCl4 regimen alone. There was a substantial increase in the activities of plasma membrane enzymes γ‐glutamyl transpeptidase and 5′‐nucleotidase and lysosomal enzymes acid phosphatase and acid ribonuclease in hepatic tissue following CCl4 treatment. These changes were reversed towards normalization with the extract in a dose‐dependent manner. The extract also restored CCl4‐induced inhibition of hepatic microsomal enzyme glucose‐6‐phosphatase. The activities of mitochondrial succinate dehydrogenase and adenosine 5′‐triphosphatase which were significantly attenuated by CCl4 administration remained unaltered following the extract therapy. Results of this study provide evidence that the extract possesses a marked liver protective action which is comparable to that of silymarin, a standard hepatoprotective drug. The probable mechanism by which this plant exerts cytoprotection has also been discussed.

Prevention of alcohol-carbon tetrachloride-induced signs of early hepatotoxicity in mice by Trianthema portulacastrum L

The antihepatotoxic potential of an ethanolic extract of the whole plant of Trianthema portulacastrum L. (excluding the roots) was evaluated against alcohol-carbon tetrachloride (CCl(4))-induced acute liver damage in mice. The extract at a dose of 50,100 or 150 mg/kg was administered per os once daily for successive three days concomitant with alcohol-CCl(4) treatment. The substantially elevated serum enzymatic activities of glutamate oxaloacetate transaminase, glutamate pyruvate transaminase, lactate dehydrogenase, alkaline phosphatase, sorbitol and glutamate dehydrogenase due to alcohol-CCl(4) treatment were dose-dependently restored towards normalization following the extract therapy. There was a marked inhibition of serum bilirubin und urea levels in the plant extract-treated groups which were otherwise drastically increased in alcohol-CCl(4) control animals. The extract also significantly prevented the elevation of hepatic malondialdehyde formation (evidence of lipid peroxidation) and depletion of reduced glutathione content in liver of mice intoxicated with alcohol-CCl(4) in a dose-responsive fashion. The results of this study clearly indicate that the plant possesses a potent hepatoprotective action against alcohol-CCl(4)-induced hepatocellular injury which corroborates its use in hepatic disorders as well as alcohol-evoked liver ailments in traditional oriental medicine.