Thymoquinone Induces Nrf2 Mediated Adaptive Homeostasis: Implication for Mercuric Chloride-Induced Nephrotoxicity.

BACKGROUND: the primary function of the kidney is to eliminate metabolic waste products and xenobiotics from the circulation. During this process, the kidney may become vulnerable to toxicity. OBJECTIVE: it was aimed to investigate the impact of thymoquinone (TQ) in mercuric chloride (HgCl2)-induced nephrotoxicity through estimation of various proteins involved in natural defense mechanisms. MATERIAL AND METHODS: HgCl2 (0.4 mg/kg) was administered to all groups (n = 5) except for the normal control. Three treatment groups received TQ (5, 10, and 15 mg/kg) 60 min before HgCl2 administration. The protective effect of TQ was evaluated from renal and liver function biomarkers, urine examination, glomerulus filtration rate (GFR), histopathological features, oxidative stress biomarkers, Hsp-70, apoptosis biomarkers, and gene expression. RESULTS: TQ significantly attenuated hazardous effects of HgCl2 on renal and hepatic tissues. Urine albumin and glucose were considerably low in the treated groups in comparison with the HgCl2 group. TQ treatment also enhanced % GFR in rats. TQ-enhanced superoxide dismutase, catalase, and glutathione levels by enhancing the expression level of nuclear factor erythroid 2-related factor 2 (Nrf2). TQ increased Hsp-70 and Bcl-2 levels and reduced caspase-3 activity. TQ also protected cells against HgCl2-induced cell death and decreased % DNA fragmentation. TQ increased the expression of protective proteins metallothionein I and II and reduced the expression of kidney injury molecule-1 (Kim-1). CONCLUSION: TQ showed protective effects against HgCl2-induced nephrotoxicity through modifications of various constitutive and inducible protein and enzyme levels in renal tissues.

Assessment of knowledge, attitude and practice of Pakistani population about the risk factors, causes, complications and management of diabetes mellitus.

OBJECTIVE: To compare the knowledge, attitude and practice regarding diabetes mellitus among diabetics and non-diabetics. METHODS: The cross-sectional study was conducted at the Government College University, Faisalabad, Pakistan, from December 2017 to April 2018, and comprised subjects recruited randomly from different cities of Punjab, Pakistan. Data was collected using a predesigned structured questionnaire regarding socio-demographic characteristics, general knowledge about diabetes, perception regarding indication, risk factors, diagnosis, and complications, and practices followed for treatment and management of diabetes. RESULTS: Of the 2,000 subjects, 972(48.6%) had family history of diabetes, 1338(66.9%) were living in urban areas, 1068(53.4%) were university graduates, 804(40.2%) were employed and 1152(57.6%) belonged to socio-economically balanced families. Composite knowledge score was significantly associated with age and socio-economic status (p<0.05). A highly significant association was observed regarding family history (p<0.001), level of education (p<0.0001) and occupation (p<0.001) with composite knowledge score. CONCLUSIONS: The knowledge level about diabetes was seen to be average.

Role of Oxidative Stress and Antioxidant Defense Biomarkers in Neurodegenerative Diseases.

Oxidative stress is caused by an imbalance in a redox system. It may involve either excessive production of reactive oxygen species or dysfunction of the antioxidant defense system. Unlike other viscera, the brain is especially highly susceptible to oxidative damage because of it requires a high oxygen level and contains an abundance of peroxida-tion-susceptible lipid cells. Oxidative stress is among the common etiological factors involved in neurodegeneration. To measure The extent of oxidative stress is measured with several indicators or biomarkers that are known to arise from oxidation of major biomolecules, including lipids, proteins, carbohydrates, and nucleic acids. In this review, we will discuss oxidative stress biomarkers associated with neurodegenerative diseases, for instance, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. We will also highlight the biomarkers of antioxidant defense mechanisms that are impaired in these diseases.

Human exposure to bisphenol A through dietary sources and development of diabetes mellitus: a cross-sectional study in Pakistani population.

Bisphenol A (BPA) is considered as xenoestrogen, a crucial component utilized for the manufacturing of plastic products. It has a potential to disrupt the endocrine system and induces endocrine-related metabolic disorders. We aimed to investigate the exposure of BPA in Pakistani population and its association with sociodemographic features, dietary habits, and risk factors of diabetes mellitus (DM). This cross-sectional study was conducted on 400 participants among which 61.75% participants were diabetic and 38.25% were non-diabetic. We developed a structured questionnaire, gathered sociodemographic data, and collected their urine and blood samples for the estimation of BPA and various biomarkers as risk factors of DM, respectively. Pearson correlation coefficient was determined for urinary BPA levels and DM risk factors. Urinary BPA values were adjusted for confounders. Sociodemographic data shown that urinary BPA level was significantly higher (p < 0.05) in obese people (BMI > 27) living in semi-urban and industrial areas. BPA was detectable in 75% of study participants. Urinary BPA level was found to be higher in diabetic participants compared with that of non-diabetics. A significant correlation is observed between BPA exposure and DM risk factors. We found that urinary BPA level was correlated with elevated levels of HbA1c (r = 0.6028), HOMA-IR (r = 0.5356), CRP (r = 0.6946), BUN (r = 0.6077), AST (r = 0.5151), FFA (r = 0.5759), TGs (r = 0.5608), and MDA (r = 0.6908). Hence, our study adds to the growing body of evidence supporting the role of BPA exposure as a risk factor for DM and may be associated with higher glycemic index, increased pro-inflammatory and oxidative stress biomarkers, dyslipidemia, and impaired functioning of the liver and kidney. Heating food in plastic containers and consumption of packed food items are the main sources of BPA exposure which are positively associated with DM.

Bisphenol A-induced metabolic disorders: From exposure to mechanism of action.

Bisphenol A (BPA) is considered as ubiquitous xenooestrogen and an endocrine disrupting chemical which has deleterious effects on endocrine functions. Human populations are continuously exposed to BPA as it is abundant in daily life. It has been found to be associated with wide range of metabolic disorders notably type 2 diabetes mellitus (DM). Numerous epidemiological studies have been conducted to find its role in development of DM. Experimental studies have found that BPA exposure is associated with pathogenesis of DM and also considered as a risk factor for gestational diabetes. Being a lipophilic compound, BPA is preferably accumulated in adipose tissues where it alters the production of adipokines that play important roles in insulin resistance. BPA induces apoptosis by caspase activation after mitochondrial damage and it impairs insulin signaling pathways by altering associated ion channel activity especially potassium channels. Perinatal exposure of BPA makes offspring more susceptible to develop DM in early years. Epigenetic modifications are the key mechanisms for BPA-induced metabolic re-programming, where BPA alters the expression of DNA methyltransferases involved in methylation of various genes. In this way, DNA methyltransferase controls the expression of numerous genes including genes important for insulin secretion and signaling. Furthermore, BPA induces histone modifications and alters miRNA expression. In this article, we have briefly described the sources of BPA exposure to human being and summarized the evidence from epidemiological studies linking DM with BPA exposure. Additionally, we have also highlighted the potential molecular pathways for BPA-induced DM.

Diabetes-associated infections: development of antimicrobial resistance and possible treatment strategies.

Diabetes mellitus is associated with various types of infections notably skin, mucous membrane, soft tissue, urinary tract, respiratory tract and surgical and/or hospital-associated infections. The reason behind this frequent association with infections is an immunocompromised state of diabetic patient because uncontrolled hyperglycemia impairs overall immunity of diabetic patient via involvement of various mechanistic pathways that lead to the diabetic patient as immunocompromised. There are specific microbes that are associated with each type of infection and their presence indicates specific type of infections. For instance, E. coli and Klebsiella are the most common causative pathogens responsible for the development of urinary tract infections. Diabetic-foot infections commonly occur in diabetic patients. In this article, we have mainly focused on the association of diabetes mellitus with various types of bacterial infections and the pattern of resistance against antimicrobial agents that are frequently used for the treatment of diabetes-associated infections. Moreover, we have also summarized the possible treatment strategies against diabetes-associated infections.

Role of cadmium and arsenic as endocrine disruptors in the metabolism of carbohydrates: Inserting the association into perspectives.

Endocrine disrupting chemicals (EDCs) have widespread environmental distribution originated from both natural and anthropogenic sources. From the last few decades, their contamination has been raised dramatically owing to continuous discharge in sewage and untreated industrial effluents. They have rapidly gained a considerable attention due to their critical role in the development of multiple endocrine-related disorders notably diabetes mellitus (DM). Cadmium and arsenic, among the most hazardous EDCs, are not only widely spread in our environment, but they are also found to be associated with wide range of health hazards. After entering into the human body, they are preferably accumulated in the liver, kidney and pancreas where they exhibit deleterious effects on carbohydrate metabolism pathways notably glycolysis, glucogenesis and gluconeogenesis through the modification and impairment of relevant key enzymes activity. Impairment of hepatic glucose homeostasis plays a crucial role in the pathogenesis of DM. Along with compromised function of pancreas and muscles, diminished liver and kidney functions also contribute considerably to increase the blood glucose level. These metals have potential to bring conformational changes in these enzymes and make them inactive. Additionally, these metals also disturb the hormonal balance, such as insulin, glucocorticoids and catecholamines; by damaging pancreas and adrenal gland, respectively. Moreover, these metals also enhance the production of reactive oxygen species and depress the anti-oxidative defense mechanism with subsequent disruption of multiple organs. In this article, we have briefly highlighted the impact of arsenic and cadmium on the metabolism of carbohydrates and the enzymes that are involved in carbohydrate metabolism and glucose homeostasis.

Gut Microbiota and Metabolic Disorders: Advances in Therapeutic Interventions.

Human gut microbiota consist of numerous microorganisms, but the most abundant species are Bacteroides and Firmicutes. Each human possesses a specific gut microbiota, which can be altered by diet, antibiotics, lifestyle, and genetic background. Gut microbiota perform vital functions, but in this article, we aimed to elaborate the effects of modified composition of microbiota on host metabolism. Ligands for G protein coupled receptors (GPCRs) are short-chain fatty acids (SCFAs) located on endocrine glands, epithelial cells, and adipocytes. SCFAs are produced in the distal gut by bacterial fermentation of nondigestible polysaccharides; they induce the various beneficial effects including decrease serum glucose level, insulin resistance, as well as inflammation; and they increase glucagon-like peptide-1 (GLP-1) secretion. Fasting-induced adipose factor (FIAF) is suppressed by gut microbiota and results in the increased storage of fatty acids in the adipose tissues and liver. An increased lipopolysaccharide level due to altered gut microflora cause the initiation of inflammation associated with type 2 diabetes mellitus (T2DM). Intestinal dysbiosis and metabolic endotoxemia are considered key mechanisms that seem to be associated with the development of T2DM and obesity. Therapeutic interventions that can be used for the treatment of diabetes include metformin, dietary modulation, probiotics, prebiotics, fecal microbiota transplantation and bariatric surgery.

Stem Cell Therapy for Diabetes Mellitus: Recent Progress and Hurdles.

Diabetes mellitus (DM) is a devastating metabolic syndrome. Currently, parenteral exogenous insulin is the only therapy available around the world to treat type 1 DM. However, it does not tightly regulate blood glucose levels that ultimately lead to long-term complications. The development of pancreatic transplantation gives some hope in the radical cure of diabetes. A limited number of donors and host immune rejection are two major drawbacks associated with pancreatic transplantation. Stem cells are distinctive cells that can differentiate into any other type of specialized cells. Embryonic stem cells have been studied extensively and proved successful in producing beta cells. The numerous kinds of stem cells, including embryonic stem cells, induced pluripotent stem cells, and adult stem cells, prove to be among the notable candidates to treat DM. However, all stem cell therapies have their own limitations. This review article focuses on the progress and limitations in stem cell research to treat DM.

Endocrine disruption as an adverse effect of non-endocrine targeting pharmaceuticals.

Endocrine disruptors have gained widespread attention owing to their severe adverse health impacts. These produce enormous burden of disease and are associated with high economic cost especially in developed countries. Environmental pollutants causing endocrine disruption include pesticides, industrial wastes, packaging materials, food constituents, plastics, and cosmetic products. Likewise, pharmaceutical drugs have the endocrine disrupting potential through a wide array of mechanisms. Antipsychotic, antiepileptic, antihypertensive, antiviral, antidiabetic, and anticancer drugs are among the foremost non-hormonal endocrine disruptors. Several drugs affect thyroid hormone synthesis via interaction with iodine uptake to the release of T3 and T4 by thyrocytes. Prolonged use of some drugs increase susceptibility to diabetes mellitus either by direct destruction of ß cells or enhanced insulin resistance. Other drugs may cause serious developmental defects in male or female reproductive system. Appropriate understanding of the mechanisms of endocrine disruption associated with non-hormonal drugs will guide future drug development and help us prevent and cure endocrine-related toxicity of pharmaceuticals. Therefore, this review focuses on endocrine disruption by pharmaceutical drugs as their side effect.

Increasing beta cell mass to treat diabetes mellitus.

Finding a radical cure for diabetes has reached paramount importance in medicine due to the widespread prevalence of the disease. A substantial reduction in insulin-secreting beta cells is evident in diabetes. The failure of cyclin-dependent kinases (CDKs) and cyclins to access the nucleus is responsible for quiescence or senescence in human and rodent beta cells. The augmentation of beta cell proliferation is supposed to reverse diabetes. This concept has inspired the discovery of newer drugs that encourage the proliferation of beta cells. Although it is a rational step towards a cure for diabetes, the differences in biochemical pathways in rodents and human beta cells pose difficulty in promoting the proliferation of human beta cells. Primarily, it is mandatory to clearly understand the intracellular pathways involved in the proliferation of beta cells so as to pave the way for therapeutic interventions. There are several intrinsic factors that trigger the proliferation of beta cells. Furthermore, it is also obvious that the early death of beta cells due to oxidative stress-related upregulation of pro-apoptotic genes also predisposes individuals to diabetes mellitus. Polyphenols, exendin 4, histone deacetylase inhibitors, glucagon-like peptide 1, phenyl pyruvic acid glucoside, and several flavonoids reduce the early apoptosis of beta cells partly through their role in the reduction of oxidative stress. A better understanding of intracellular pathways, the identification of specific mitogens, the induction of beta cell proliferation, and the inhibition of apoptosis may help us treat diabetes mellitus through an increase in beta cell mass.