Bisphenol A (BPA), an estrogenic and endocrine disrupting agent, is widely used in manufacturing of polycarbonate plastics and epoxy resins. BPA and other endocrine disrupting chemicals (EDCs) act via multiple mechanisms including interference with mitochondrial functions. Mitochondria are the hub of cellular energy pool and hence are the target of many EDCs. We studied perturbation of activities of mitochondrial enzymes by BPA and its possible role in hepatotoxicity in Wistar rats. Rats were exposed to BPA (150 mg/kg, 250 mg/kg, 500 mg/kg per os, for 14 days) and activities of enzymes of mitochondrial electron transport chain (ETC) were measured. Besides, other biochemical parameters such as superoxide generation, protein oxidation, and lipid peroxidation (LPO) were also measured. Our results indicated a significant decrease in the activities of enzymes of mitochondrial ETC complexes, i.e., complex I, II, III, IV, and V along with significant increase in LPO and protein oxidation. Additionally, a significant increase in mitochondrial superoxide generation was also observed. All these findings could be attributed to enhanced oxidative stress, decrease in reduced glutathione level, and decrease in the activity of superoxide dismutase in rat liver mitochondria isolated from BPA-treated rats. BPA treatment also caused a significant increase in serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and lactate dehydrogenase indicating its potential hepatotoxicity. Furthermore, histopathological findings revealed marked edema formation, hepatocellular degeneration, and necrosis of liver tissue in BPA-exposed rats. In conclusion, this study provides an evidence of impaired mitochondrial bioenergetics and liver toxicity after high-dose BPA exposure in rats. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1922-1934, 2016.

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Objective:To determine the drug utilization pattern of antihyperglycemic agents (AHA) in a tertiary care teaching hospital.Materials and Methods:This was a prospective observational study. All the relevant data were collected and drug utilization pattern of AHA was determined. Direct cost associated with the use of antihyperglycemic medicines was calculated and consumption of the antihyperglycemic medicines was measured as defined daily dose (DDD)/100 bed-days. The adverse drug reactions (ADRs) related to anti-diabetic medicines were monitored.Statistical Analysis Used:Chi square test (χ2), mean±standard deviation.Results:During the study period, 350 patients diagnosed as diabetes mellitus (DM) were admitted. Insulin was prescribed as monotherapy to 81% and to 52% patients during hospital stay and discharge, respectively. Increase in utilization of insulin was recorded in majority of the patients due to presence of co-morbid conditions or resistance to oral hypoglycemic drugs. Use of insulin at the time of discharge decreased significantly (P<0.05) by 29%. Among the oral AHA, combination of glimepiride with metformin was more prevalent during hospital stay and at the time of discharge monotherapy of metformin followed by glimepiride was more prevalent. During hospital stay, cost of AHA was found to be Rs. 95.27 ± 119.03. The total antihyperglycemic drug consumption in the medicine ward during study period was 13.42 DDD/100 bed-days. Fifty ADRs were reported and descriptions of ADRs were found to be only hypoglycemia.Conclusion:The study exhibited a significant increase in the utilization of two drug combination therapies and monotherapy of oral AHA and decrease in the utilization of insulin at the time of discharge.

Inflammation is one of the mechanisms involved in the acute kidney injury (AKI) caused by cisplatin (CP)-induced nephrotoxicity. Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl) has powerful antioxidant activity. We investigated its potential nephroprotective effects and the underlying mechanisms that may add further benefits to its clinical usefulness in a CP-induced AKI model. Male Swiss albino mice were divided randomly into four groups: control, CP (20 mg/kg intraperitoneally), tempol (100 mg/kg/day, per os) + CP, and tempol only treatments. Blood samples were collected to analyze renal function parameters. Immunoblotting and immunohistochemical analysis were used to assess the level and localization of inflammatory markers. Tempol afforded protection to animals from CP-induced elevation of inflammatory markers as indicated by reduced expression of nuclear factor-kappa B, cyclooxygenase-2, and tumor necrosis factor-α in kidney tissue. Histological findings and analysis of kidney function markers corroborated with these findings confirming a nephroprotective role for tempol. In conclusion, this study provides important evidence for the promising anti-inflammatory effects of tempol which appears to contribute significantly to its nephroprotective action.

The alkylating anticancer drug, cyclophosphamide (CP), induces a number of toxic effects including haemorrhagic cystitis (HC) in the urinary bladder. Uroplakins are unique urinary transmembrane proteins of urothelium, which may become potential targets of CP metabolites and reactive free radicals. Natural compounds, especially those rich in thiols, have shown protective effects against CP-induced HC. In this study, we studied the modulatory effect of the thiol-rich compound S-allyl cysteine (SAC) on the mRNA level of uroplakin II by real-time polymerase chain reaction and expression of uroplakin II protein by immunoblotting. SAC (150 mg/kg) showed significant (p < 0.001) protective effects against CP (200 mg/kg)-induced alteration in mRNA level and protein expression of uroplakin II. SAC also protected animals from CP-induced HC as assessed by gross morphological examination of urinary bladder. When compared with mercaptoethane sulphonic acid (mesna) (40 mg/kg), a known thiol-rich drug used in clinical application, SAC was found to be more efficacious in affording protection in urinary bladder tissues. Role of uroplakins in CP-induced urinary bladder toxicity has not been well investigated. This study demonstrated that uroplakins may be the potential target of toxic metabolites of CP and natural compounds such as SAC have the capacity to modulate their expression leading to reduced toxicity burden on the urinary bladder epithelium.

Currently, there are limited treatment options available for the monkeypox disease. We used a computational strategy to design a specific antigenic vaccine against pathogens. After using various immunoinformatic tools and filters, cytotoxic T-cell lymphocyte (CTL)-, helper T-cell lymphocyte (HTL)-, and interferon gamma (IFN-γ)-inducing epitopes, which comprised the vaccine, in addition to other parameters, such as antigenic and allergic profiles, were assessed to confirm the safety of the vaccine. However, vaccine interaction and stability with Toll-like receptors (TLRs) were assessed by dynamic simulation methods, and it was found that the constructed vaccine was stable. In addition, C-IMMSIM tools were used to determine the immune-response-triggering capabilities of the vaccine. These immunoinformatic findings reveal that constructed vaccine candidates may be capable of triggering an efficient immune response for monkeypox viral infections. However, experimental evaluation is required to verify the safety and immunogenic profile of constructed vaccines.

These findings highlight a correlation between downregulaion of UPIIIa and enhanced production of inflammatory biomarkers and protective effects of S-allyl cysteine which has been reported to be a potent uroprotective agent. The present study strengthens its role which could be clinically exploited in chemotherapy regimen.

Tebuconazole is a widely used fungicide in agriculture, and it may easily enter in the human food chain. In addition, tebuconzaol skin permeation coefficient (Log Kp) is −5.55 cm/s and it does not violate Lipinski's rule. It may mimic as a ligand for various endocrine and reproductive receptor leading to toxicological response or disease manifestation. We studied interactive potential of tebuconazole with thyroid and sex hormone‐binding globulin. The main methods for this in silico analyses are molecular docking and molecular dynamic (MD) simulation. This paper explores how agriculture fungicide tebuconzaol exposure can be a risk for endocrine and reprotoxicity due to its stable interactive potency with thyroid and sex hormone‐binding globulin (2CEO and 1D2S). Thyroid impairment is one of the most common endocrine issues in human health. In molecular docking analyses, tebuconazole exhibited binding potency of −6.28 kcal/mol with 2CEO compared to its native ligand thyroxin and inhibitor propylthiouracil which had the binding potency of −9.9 and −4.49 kcal/mol, respectively. The binding score of tebuconzaol with 1D2S was found to be −7.54 kcal/mol compared to native ligand dihydrotestosteron and inhibitor aminoglutethimide which exhibited the binding score of −6.84 and −11.41 kcal/mol, respectively. Therefore, each complex was subjected to MD simulation for comparative assessment of physical movement. The root mean square deviation (RMSD), root mean square fluctuation (RMSF), Radius of Gyration and hydrogen bonding exhibited that fluconazole had stable binding pattern with 2CEO and 1D2S which was almost similar to native ligand and its inhibitor. Study revealed that tebuconazole may lead to potent endocrine and reproductive disruptions.