Pritam Sadhukhan

Morin protects gastric mucosa from nonsteroidal anti-inflammatory drug, indomethacin induced inflammatory damage and apoptosis by modulating NF-κB pathway.

BACKGROUND Deregulation in prostaglandin (PG) biosynthesis, severe oxidative stress, inflammation and apoptosis contribute to the pathogenesis of nonsteroidal anti-inflammatory drug (NSAID)-induced gastropathy. Unfortunately, most of the prescribed anti-ulcer drugs generate various side effects. In this scenario, we could consider morin as a safe herbal potential agent against IND-gastropathy and rationalize its action systematically. METHODS Rats were pretreated with morin for 30 min followed by IND (48 mgkg(-1)) administration for 4 h. The anti-ulcerogenic nature of morin was assessed by morphological and histological analysis. Its effects on the inflammatory (MPO, cytokines, adhesion molecules), ulcer-healing (COXs, PGE(2)), and signaling parameters (NF-κB and apoptotic signaling) were assessed by biochemical, RP-HPLC, immunoblots, IHC, RT-PCR, and ELISA at the time points of their maximal changes due to IND administration. RESULTS IND induced NF-κB and apoptotic signaling in rats gastric mucosa. These increased proinflammatory responses, but reduced the antioxidant enzymes and other protective factors. Morin reversed all the adverse effects to prevent IND-induced gastric ulceration in a PGE2 independent manner. Also, it did not affect the absorption and/or primary pharmacological activity of IND. CONCLUSIONS The gastroprotective action of morin is primarily attributed to its potent antioxidant nature that also helps in controlling several IND-induced inflammatory responses. GENERAL SIGNIFICANCE For the first time, the study reveals a mechanistic basis of morin mediated protective action against IND-induced gastropathy. As morin is a naturally abundant safe antioxidant, future detailed pharmacokinetic and pharmacodynamic studies are expected to establish it as a gastroprotective agent.

Mangiferin attenuates oxidative stress induced renal cell damage through activation of PI3K induced Akt and Nrf-2 mediated signaling pathways

Background Mangiferin is a polyphenolic xanthonoid with remarkable antioxidant activity. Oxidative stress plays the key role in tert-butyl hydroperoxide (tBHP) induced renal cell damage. In this scenario, we consider mangiferin, as a safe agent in tBHP induced renal cell death and rationalize its action systematically, in normal human kidney epithelial cells (NKE). Methods NKE cells were exposed to 20 µM mangiferin for 2 h followed by 50 µM tBHP for 18 h. The effect on endogenous ROS production, antioxidant status (antioxidant enzymes and thiols), mitochondrial membrane potential, apoptotic signaling molecules, PI3K mediated signaling cascades and cell cycle progression were examined using various biochemical assays, FACS and immunoblot analyses. Results tBHP exposure damaged the NKE cells and decreased its viability. It also elevated the intracellular ROS and other oxidative stress-related biomarkers within the cells. However, mangiferin dose dependently, exhibited significant protection against this oxidative cellular damage. Mangiferin inhibited tBHP induced activation of different pro-apoptotic signals and thus protected the renal cells against mitochondrial permeabilization. Further, mangiferin enhanced the expression of cell proliferative signaling cascade molecules, Cyclin d1, NFκB and antioxidant molecules HO-1, SOD2, by PI3K/Akt dependent pathway. However, the inhibitor of PI3K abolished mangiferins protective activity. Conclusions Results show Mangiferin maintains the intracellular anti-oxidant status, induces the expression of PI3K and its downstream molecules and shields NKE cells against the tBHP induced cytotoxicity. General significance Mangiferin can be indicated as a therapeutic agent in oxidative stress-mediated renal toxicity. This protective action of mangiferin primarily attributes to its potent antioxidant and antiapoptotic nature.

Genistein: A Phytoestrogen with Multifaceted Therapeutic Properties.

Countless bioactive constituents obtained from different medicinal plants have long been focused by the researchers of the scientific community and pharmaceutical industry. In recent years, extensive in vitro and in vivo research has been carried out with these biomolecules to develop complementary and alternative medicines. Findings revealed that these molecules may act as promising agents for almost all kinds of pathophysiological states. Further, these novel bioactive compounds are mostly not harmful in dietary doses. In this eclectic review, we highlighted the beneficial role of genistein, an isoflavone available mainly in the legumes particularly in soybean. Genistein is a potent phytoestrogen which binds with both alpha and beta estrogen receptors and regulate the divergent intracellular signaling cascades of estrogen. It also has the potential to competitively inhibit different imperative ATP utilizing enzymes. These properties help genistein in regulating various cellular and biochemical functions at different levels of structural organization in the body. Moreover, its very low cytotoxicity and abundance in regular aliment compared to other isoflavones makes it a more promising therapeutic option. Emerging evidence from the literature proves the competence of genistein in combating oxidative stress, cancer, diabetes, obesity, inflammation, osteoporosis, neuropathy and some other disorders. This review aims to unravel the assorted underlying mechanisms behind the multivariate properties of this unique aglycone.

Mangiferin: A xanthonoid with multipotent anti-inflammatory potential.

Over the last era, small molecules sourced from different plants have gained attention for their varied and long‐term medicinal benefits. Their advantageous therapeutic effects in diverse pathological complications lead researchers to give an ever‐increasing emphasis on them and discover their novel therapeutic potentials. Among these, the heat stable, xanthonoid group of organic molecules has gained special importance with distinctive regards to the bioactive molecule mangiferin due to its solubility in water. Mangiferin, a yellow polyphenol having C‐glycosyl xanthone structure, is widely present in different edible sources like mango, and possesses numerous biological activities. Extensive research with this molecule shows its antioxidant, anti‐inflammatory, antidiabetic, anticancer, antimicrobial, analgesic, and immunomodulatory properties. Thus, it provides protection against a wide range of physiological disorders. The C‐glucosyl linkage and polyhydroxy groups in mangiferins structure contribute essentially to its free radical‐scavenging activity. Moreover, its ability in regulating various transcription factors like NF‐κB, Nrf‐2, etc. and modulating the expression of different proinflammatory signaling intermediates like tumor necrosis factor‐α, COX‐2, etc. contribute to its anti‐inflammatory, anticancer, and antidiabetic potentials. In this comprehensive article, information has been provided about the sources, chemical structure, metabolism, and different biological activities of mangiferin with special emphasis on the underlying cellular signal transduction pathways. Insights into an in‐depth assessment of mangiferins anti‐inflammatory therapeutic potential have also been discussed in detail. On an overall perspective, this review aims to stage mangiferins diversified therapeutic applications and its emerging possibility as a promising drug in future based on its anti‐inflammatory property.

Attenuative role of mangiferin in oxidative stress‐mediated liver dysfunction in arsenic‐intoxicated murines

Mangiferin (MAG), a natural xanthone mainly derived from mangoes, possesses great antioxidative potentials. The present study has been carried out to investigate the hepato‐protective role of MAG, against arsenic (As)‐induced oxidative damages in the murine liver. As, a well‐known toxic metalloid, is ubiquitously found in nature and has been reported to affect nearly all the organs of the human body via oxidative impairment. Administration of As in the form of sodium arsenite (NaAsO2) at a dose of 10 mg/kg body weight for 3 months abruptly increased reactive oxygen species (ROS) level, led to oxidative stress and significantly depleted the first line of antioxidant defense system in the body. Moreover, As caused apoptosis in hepatocytes. Treatment with MAG at a dose of 40 mg/kg for body weight for 30 days simultaneously and separately after NaAsO2 administration decreased the ROS production and attenuated the alterations in the activities of all antioxidant indices. MAG also protected liver against the NaAsO2‐induced apoptosis and disintegrated hepatocytes, thus counteracting with As‐induced toxicity. It could significantly inhibit the expression of different proapoptotic caspases and upregulate the expression of survival molecules such as Akt and Nrf2. On inhibiting Akt (by PI3K inhibitor, LY294002) and ERK1/2 (by ERK1/2 inhibitor, PD98059) specifically, caspase 3 got activated abolishing mangiferins protective role on As‐induced hepatotoxicity. So here, we have briefly elucidated the signaling cascades involved in As‐induced apoptotic cell death in the liver and also the detailed cellular mechanism by which MAG provides protection to this organ.

Targeting Oxidative Stress: A Novel Approach in Mitigating Cancer

Reactive Oxygen Species (ROS) plays a vital role in normal cellular homeostasis and development of pathophysiological conditions. Researches round the globe suggest that cancer cell possesses higher amount of intracellular ROS and impaired metabolic activity along with mitochondrial dysfunction. ROS can initiate cancer, but the primary endogenous elevation of oxidants in malignant tissues leave them more susceptible to secondary stresses. Despite the crucial role of ROS in the development of cancer, anticancer therapies are suggested both by scavenging the excessive intracellular ROS and also by inducing ROS generation through exogenous oxidative insult. In this commentary, we have discussed the dual effect of ROS on the development cancer and emergence of novel anti-cancer therapies by modulating the accumulation of ROS.

Perspectives of the Nrf-2 signaling pathway in cancer progression and therapy

The Nuclear factor erythroid2-related factor2 (Nrf2), a master regulator of redox homoeostasis, is a key transcription factor regulating a wide array of genes for antioxidant and detoxification enzymes. It protects organs from various kinds of toxic insults. On the other hand, activation of Nrf2 is also correlated with cancer progression and chemoresistance. Downregulation of Nrf2 activity has attracted an increasing amount of attention as it may provide an alternative cancer therapy. In this review, we examine recent studies on roles of Nrf2 in several pathophysiological conditions emphasising cancer. We discuss elaborately the current knowledge on Nrf2 regulation including KEAP1-dependent and KEAP1-independent cascades. KEAP1/Nrf2 system is a master regulator of cellular response against a variety of environmental stresses. We also highlight several tightly controlled regulations of Nrf2 by numerous proteins, small molecules, toxic metals, etc. In addition, we evaluate the possible therapeutic approaches of increasing chemosensitivity via modulating Nrf2 signaling.

Therapeutic Insights against Oxidative Stress Induced Diabetic Nephropathy: A Review

Diabetes mellitus (DM) is an outcome of an absolute or relative deficiency of insulin which may be due to autoimmune destruction. It is mainly characterised by hyperglycemia, causes auto-oxidation of glucose, glycation of proteins and activation of polyol mechanism. This leads to oxidative stress, defined as an increase in the intracellular level of reactive oxygen species (ROS). Overproduction of ROS contributes to several microvascular and macrovascular complications of DM including diabetic nephropathy (DN). DN is a primary cause of chronic kidney disease and end-stage renal failure in various parts of the world. Minimizing the risk factors associated with DN is insufficient in lowering the vulnerability of this disorder. Henceforth, an increased knowledge on the role of oxidative stress would lead the way to the exploration of a number of molecules having antioxidant property as therapeutic option. These agents could reduce the severity of DN by decreasing the level of ROS and modulating an array of signalling cascade, thereby ameliorating oxidative stress via its antioxidative and immunomodulatory properties. This review provides valuable information concerning the recent advancements in understanding the role of well-known therapeutic agents in alleviating oxidative stress induced renovascular complications in DM. This review also encompasses the role of different natural products on their effect on the T-cell driven immune response in autoimmune diabetic nephropathy.

Ameliorative role of genistein against age-dependent chronic arsenic toxicity in murine brains via the regulation of oxidative stress and inflammatory signaling cascades

Brain is highly prone to oxidative damage due to its huge lipid content and extensive energy requirements. Exogenous insult in brain via oxidative injury can lead to severe pathophysiological conditions. Age-dependent deterioration of normal brain functions is also noteworthy. Genistein, a polyphenolic isoflavonoid, obtained from the soy plant, is well known to protect against several diseased conditions. Here, in this study chronic brain toxicity model was developed using oral administration of arsenic for 90 days in adult and aged murines. We observed that intraperitoneal administration of genistein improved the arsenic induced behavioral abnormalities in the rats. It was also evident from the histopathological studies that the extent of tissue damage due to arsenic exposure was more in aged rats compared to the adults. Evaluation of different stress markers, intracellular ROS level and mitochondrial membrane potential revealed the involvement of oxidative stress and mitochondrial dysfunction in inducing brain damage in arsenic exposed murines. It was observed that genistein can significantly ameliorate the stressed condition in both the animal groups but the protective effect of genistein was more significant in the adult animals. The underlying signalling mechanism behind the cytotoxicity of arsenic was investigated and revealed that genistein exhibited neuroprotection significantly by modulating the JNK3 mediated apoptosis, ERK1/2 mediated autophagy and TNFα associated inflammatory pathways. Overall study infers that genistein has significant ameliorative effect of against age-dependent cytotoxicity of arsenic in murine brains.

Melatonin attenuates arsenic induced nephropathy via the regulation of oxidative stress and inflammatory signaling cascades in mice

Arsenic is a potent inducer of several acute and chronic nephrotoxic disorders. It promotes deleterious phenomenon like oxidative stress, inflammation, cell death and altered glucose uptake leading to distorted kidney homeostasis that end up in chronic kidney disease. This study investigated the possible protective role of melatonin; a natural antioxidant produced by the pineal gland, against arsenic induced nephrotoxicity. Melatonin successfully ameliorated arsenic induced renal toxicity both in in vitro and in vivo models. Elevated BUN, creatinine, urine glucose and protein levels and altered renal histopathological conditions were observed in arsenic intoxicated mice. Significant oxidative stress induced damage of biomolecules along with downregulation in antioxidant enzymes and thiols were also detected in the kidney tissues of arsenic-intoxicated mice. These alterations along with mitochondrial dysfunction ultimately triggered TNFα mediated inflammatory and cell death cascades. Interestingly arsenic also led to disruption of glucose uptake in the kidney. These findings suggest that melatonin protects the kidney against toxic effect of arsenic, presumably through its antioxidant, anti-inflammatory and antidiabetic properties by inhibiting inflammatory outburst, apoptosis, necroptosis and stimulating glucose uptake. As melatonin is a natural antioxidant molecule, detailed pharmacokinetic and pharmacodynamic studies are expected to establish it as an effective nephro-protective agent in future.