Fazlullah Khan

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.

Smokeless tobacco ( paan and gutkha ) consumption, prevalence, and contribution to oral cancer

Smokeless tobacco consumption, which is widespread throughout the world, leads to oral submucous fibrosis (OSMF), which is a long-lasting and devastating condition of the oral cavity with the potential for malignancy. In this review, we mainly focus on the consumption of smokeless tobacco, such as paan and gutkha, and the role of these substances in the induction of OSMF and ultimately oral cancer. The list of articles to be examined was established using citation discovery tools provided by PubMed, Scopus, and Google Scholar. The continuous chewing of paan and swallowing of gutkha trigger progressive fibrosis in submucosal tissue. Generally, OSMF occurs due to multiple risk factors, especially smokeless tobacco and its components, such as betel quid, areca nuts, and slaked lime, which are used in paan and gutkha. The incidence of oral cancer is higher in women than in men in South Asian countries. Human oral epithelium cells experience carcinogenic and genotoxic effects from the slaked lime present in the betel quid, with or without areca nut. Products such as 3-(methylnitrosamino)-proprionitrile, nitrosamines, and nicotine initiate the production of reactive oxygen species in smokeless tobacco, eventually leading to fibroblast, DNA, and RNA damage with carcinogenic effects in the mouth of tobacco consumers. The metabolic activation of nitrosamine in tobacco by cytochrome P450 enzymes may lead to the formation of N-nitrosonornicotine, a major carcinogen, and micronuclei, which are an indicator of genotoxicity. These effects lead to further DNA damage and, eventually, oral cancer.

Immunotoxicity of mercury: Pathological and toxicological effects

ABSTRACT Mercury (Hg) is toxic and hazardous metal that causes natural disasters in the earths crust. Exposure to Hg occurs via various routes; like oral (fish), inhalation, dental amalgams, and skin from cosmetics. In this review, we have discussed the sources of Hg and its potential for causing toxicity in humans. In addition, we also review its bio-chemical cycling in the environment; its systemic, immunotoxic, genotoxic/carcinogenic, and teratogenic health effects; and the dietary influences; as well as the important considerations in risk assessment and management of Hg poisoning have been discussed in detail. Many harmful outcomes have been reported, which will provide more awareness.

Effect of styrene exposure on plasma parameters, molecular mechanisms and gene expression in rat model islet cells

Styrene is an aromatic hydrocarbon compound present in the environment and have primary exposure through plastic industry. The current study was designed to evaluate styrene-induced toxicity parameters in rat plasma fasting blood glucose (FBG) level, oral glucose tolerance, insulin secretion, oxidative stress, and inflammatory cytokines in cellular and molecular levels. Styrene was dissolved in corn oil and administered at different doses (250, 500, 1000, 1500, 2000mg/kg/day and control) to each rat, for 42days. In treated groups, styrene significantly increased fasting blood glucose, plasma insulin (p<0.001) and glucose tolerance. Glucose tolerance, insulin resistance and hyperglycemia were found to be the main consequences correlating gene expression of islet cells. Styrene caused a significant enhancement of oxidative stress markers (p<0.001) and inflammatory cytokines in a dose and concentration-dependent manner in plasma (p<0.001). Moreover, the activities of caspase-3 and -9 of the islet cells were significantly up-regulated by this compound at 1500 and 2000mg/kg/day styrene administrated groups (p<0.001). The relative fold change of GLUD1 was downregulated (p<0.05) and upregulated at 1500 and 2000mg/kg, respectively (p<0.01). The relative fold changes of GLUT2 were down regulated at 250 and 1000mg/kg and up regulated in 500, 1500 and 2000mg/kg doses of styrene (p<0.01). The expression level of GCK indicated a significant upregulation at 250mg/kg and downregulation of relative fold changes in the remaining doses of styrene, except for no change at 2000mg/kg of styrene for GCK. Targeting genes (GLUD1, GLUT2 and GCK) of the pancreatic islet cells in styrene exposed groups, disrupted gluconeogenesis, glycogenolysis pathways and insulin secretory functions. The present study illustrated that fasting blood glucose, insulin pathway, oxidative balance, inflammatory cytokines, cell viability and responsible genes of glucose metabolism are susceptible to styrene, which consequently lead to other abnormalities in various organs.

Cinnamon, a promising prospect towards Alzheimer’s disease

&NA; Over the last decades, an exponential increase of efforts concerning the treatment of Alzheimers disease (AD) has been practiced. Phytochemicals preparations have a millenary background to combat various pathological conditions. Various cinnamon species and their biologically active ingredients have renewed the interest towards the treatment of patients with mild‐to‐moderate AD through the inhibition of tau protein aggregation and prevention of the formation and accumulation of amyloid‐&bgr; peptides into the neurotoxic oligomeric inclusions, both of which are considered to be the AD trademarks. In this review, we presented comprehensive data on the interactions of a number of cinnamon polyphenols (PPs) with oxidative stress and pro‐inflammatory signaling pathways in the brain. In addition, we discussed the potential association between AD and diabetes mellitus (DM), vis‐à‐vis the effluence of cinnamon PPs. Further, an upcoming prospect of AD epigenetic pathophysiological conditions and cinnamon has been sighted. Data was retrieved from the scientific databases such as PubMed database of the National Library of Medicine, Scopus and Google Scholar without any time limitation. The extract of cinnamon efficiently inhibits tau accumulations, A&bgr; aggregation and toxicity in vivo and in vitro models. Indeed, cinnamon possesses neuroprotective effects interfering multiple oxidative stress and pro‐inflammatory pathways. Besides, cinnamon modulates endothelial functions and attenuates the vascular cell adhesion molecules. Cinnamon PPs may induce AD epigenetic modifications. Cinnamon and in particular, cinnamaldehyde seem to be effective and safe approaches for treatment and prevention of AD onset and/or progression. However, further molecular and translational research studies as well as prolonged clinical trials are required to establish the therapeutic safety and efficacy in different cinnamon spp. Graphical abstract Figure. No caption available.

Molecular mechanisms of action of styrene toxicity in blood plasma and liver

Styrene is an aromatic colorless hydrocarbon available in liquid form and highly volatile. In its pure form, it gives a sweet smell. The primary source of exposure in the environment is from plastic materials, rubber industries, packaging materials, insulations, and fiber glass and carpet industry. Natural sources of styrene include: few metabolites in plants which are transferred through food chain. The current study was designed to evaluate styrene toxicity, including: superoxide dismutase (SOD) and protein carbonyl, oxidative stress, glucose‐6‐phosphatase (G6Pase), glycogen phosphorylase (GP), and phosphoenolpyruvate carboxykinase (PEPCK) activities, adenosine triphosphate (ATP) to adenosine diphosphate (ADP) ratio, and changes in gene expressions such as glutamate dehydrogenase 1 (GLUD1), glucose transporter 2 (GLUT2), and glucokinase (GCK) in the rat liver tissue. For this purpose, styrene was dissolved in corn oil and was administered via gavage, at doses 250, 500, 1000, 1500, 2000, mg/kg/day per mL and control (corn oil) to each rat with one day off in a week, for 42 days. Plasma SOD and protein carbonyl of plasma were significantly up‐regulated in 1000, 1500, and 2000 mg/kg/day styrene administrated groups (P < .001). In addition, styrene caused an increase in lipid peroxidation (LPO) and reactive oxygen species (ROS) in the dose‐dependent manners in liver tissue (P < .001). Furthermore, the ferrous reducing antioxidant power (FRAP) and total thiol molecules (TTM) in styrene‐treated groups were significantly decreased in liver tissue (P < .001) with increasing doses. In treated rats, styrene significantly increased G6Pase activity (P < .001) and down‐regulated GP activity (P < .001) as compared to the control group. The PEPCK activity was significantly raised in a dose‐dependent manner (P < .001). The ATP/ADP ratio of live cells was significantly raised by increasing the dose (P < .001). There was significantly an up‐regulation of GLUD1 and GCK at 2000 mg/kg group (P < .01) and a down‐regulation for GLUT2 at the same dose. While in the rest of group, GLUT2 showed up‐regulation of relative fold change. By targeting genes such as GLUD1, GLUT2, and GCK, disruption of hepatic gluconeogenesis, glycogenolysis, and insulin secretory functions are obvious. The present study illustrates that induction of oxidative stress followed by changes in G6Pase, GP, and PEPCK activities and the genes responsible for glucose metabolism are the mechanisms of styrenes action in the liver.

Comparative occurrence of diabetes in canine, feline, and few wild animals and their association with pancreatic diseases and ketoacidosis with therapeutic approach

Diabetes mellitus (DM) is a chronic metabolic disorder in which blood glucose level raises that can result in severe complications. However, the incidence increased mostly by obesity, pregnancy, persistent corpus luteum, and diestrus phase in humans and animals. This review has focused on addressing the possible understanding and pathogenesis of spontaneous DM in canine, feline, and few wild animals. Furthermore, pancreatic associated disorders, diabetic ketoacidosis, hormonal and drug interaction with diabetes, and herbal remedies associated with DM are elucidated. Bibliographic search for the present review was done using PubMed, Scopus, and Google Scholar for articles on concurrent DM in small and wild animals. Persistent corpus luteal and pseudopregnancy in female dogs generate gestational DM (GDM). GDM can also be caused by extensive use of drugs/hormones such as glucocorticosteroids. Although many similarities are present between diabetic cats and diabetic humans which present islet amyloidosis, there was a progressive loss of β- and α-cells and the normal number of δ-cells. The most prominent similarity is the occurrence of islet amyloidosis in all cases of diabetic cat and over 90% of human non-insulin dependent DM Type-2. Acute pancreatic necrosis (APN) occurs due to predisposing factors such as insulin antagonism, insulin resistance, alteration in glucose tolerance, obesity, hyperadrenocorticism, and persistent usage of glucocorticoids, as these play a vital role in the progression of APN. To manage such conditions, it is important to deal with the etiological agent, risk factors, diagnosis of diabetes, and hormonal and drug interaction along with its termination with suitable therapy (herbal) protocols. It should be noted that the protocols used for the diagnosis and treatment of human DM are not appropriate for animals. Further investigations regarding diabetic conditions of pets and wild animals are required, which will benefit the health status of all animals health worldwide.

Bisphenol A: What lies beneath its induced diabetes and the epigenetic modulation?

ABSTRACT Nowadays, endocrine disrupting chemical pollution has become one of the major concerns due to the potential role of these chemicals in provoking endocrine disorders especially type 2 diabetes. As a widespread endocrine disrupting chemical, Bisphenol A, with modest estrogenic activity can exert its detrimental effects in the different organs involved in type 2 diabetes such as pancreas, liver, adipocyte and skeletal muscles. Obesity, hepatic steatosis, impaired insulin signaling and pancreatic islet function could be the main results of Bisphenol A exposure. Epigenetic dysregulations can be suggested as an important underlying mechanism for Bisphenol A toxicity in the endocrine system. The most studied genes in this respect, which are responsible for glucose homeostasis include Pdx1, Gck, Igf2, Srebf1 and Srebf2. Aberrant DNA methylation, histone demethylation and deacetylation and impaired miRNAs result in epigenetically dysfunctional genes that finally distract the normal glucose regulation. The present study aimed to summarize the general effects of prenatal and postnatal Bisphenol A exposure on glucose metabolism focusing on animal studies and review the recent investigations on Bisphenol A ‐induced epigenetic perturbations that affect the normal glucose and lipid homeostasis and lead to type 2 diabetes.

The role of epigenetic alterations involved in sepsis: An overview

BACKGROUND Sepsis is among the leading causes of death with no specific etiology or treatment. Increase in health burden in terms of cost, morbidity, and mortality is the reason behind the continuous search for different treatment modalities which involve several targets/approach and one of them includes the involvement of epigenetics in sepsis. OBJECTIVE This review was carried out to explain the epigenetic alterations involved in sepsis, as it affects the disease progression, diagnosis, and treatment. METHODS Information used in this review was obtained from different databases including PUBMED, SCOPUS, Web of Science, and EMBASE. Keywords were used as search terms. RESULT In this review, we provided a concise overview of the significant role of epigenetic alterations in sepsis pathophysiology as it relates to disease progression, diagnosis and treatment derived from in vitro, in vivo, and human studies. These mechanisms affected various targets and pathways involved in sepsis modulation, which correlates with morbidity and mortality. Change in DNA methylation pattern, histone modification, and microRNA regulation has been shown in sepsis models to silence or activate pro-inflammatory genes such as TNF-α and interleukins, anti-oxidant enzymes, and many signaling pathways. Drugs that target these pathways have proven effective in sepsis treatment. CONCLUSION Epigenetic processes involve specific enzymes detected in the blood and other body fluids which can potentially serve as diagnostic, therapeutic, as well as prognostic tools in sepsis. Epigenetic mechanisms can provide a highly sensitive and accurate method for sepsis diagnosis using blood and other body fluids.

Toxicity of Biologically Active Peptides and Future Safety As-pects: An Update

INTRODUCTION Peptides are fragments of proteins with significant biological activities. These peptides are encoded in the protein sequence. Initially, such peptides are inactive in their parental form, unless proteolytic enzymes are released. These peptides exhibit various functions and play a therapeutic role in the body. OBJECTIVE Besides the therapeutic and physiological activities of peptides, the main purpose of this study was to highlight the safety aspects of peptides. METHOD We performed an organized toxicity and search of available literature using PubMed, Google Scholar, Medline, EMBASE, Reaxys and Scopus databases. All the relevant citations including research and review articles about the toxicity of biologically active peptides were evaluated and gathered in this study. RESULT Biological peptides are widely used in the daily routine ranging from food production to the cosmetics industry and also they have a beneficial role in the treatment and prevention of different diseases. These peptides are manufactured by both chemical and biotechnological techniques, which show negligible toxicity, however, some naturally occurring peptides and enzymes may induce high toxicity. Depending upon the demand and expected use in the food or pharmaceutical industry, we need different approaches to acertain the safety of these peptides preferentially through in silico methods. CONCLUSION Intestinal wall disruption, erythrocytes and lymphocytes toxicity, free radical production, enzymopathic and immunopathic tissue damage and cytotoxicity due to the consumption of peptides are the main problems in the biological system that lead to various complicated disorders. Therefore, before considering biologically active peptides for food production and for therapeutic purpose, it is first necessary to evaluate the immunogenicity and toxicities of peptides.