Plastic compounds and liver diseases: Whether bisphenol A is the only culprit.

Plastics, while providing modern conveniences, have become an inescapable source of global concern due to their role in environmental pollution. Particularly, the focus on bisphenol A (BPA) reveals its biohazardous nature and association with liver issues, specifically steatosis. However, research indicates that BPA is just one facet of the problem, as other bisphenol analogues, microplastics, nanoplastics and additional plastic derivatives also pose potential risks. Notably, BPA is implicated in every stage of non-alcoholic fatty liver disease (NAFLD) onset and progression, surpassing hepatitis B virus as a primary cause of chronic liver disease worldwide. As plastic contamination tops the environmental contaminants list, urgent action is needed to assess causative factors and mitigate their impact. This review delves into the molecular disruptions linking plastic pollutant exposure to liver diseases, emphasizing the broader connection between plastics and the rising prevalence of NAFLD.

Pharmacokinetic assessment of rifampicin and des-acetyl rifampicin in carbon tetrachloride induced liver injury model in Wistar rats.

OBJECTIVES: Preclinical evidence is needed to assess drug-metabolite behaviour in compromised liver function for developing the best antitubercular treatment (ATT) re-introduction regimen in drug-induced liver injury (DILI). The pharmacokinetic behavior of rifampicin (RMP) and its active metabolite des-acetyl-rifampicin (DARP) in DILI's presence is unknown. To study the pharmacokinetic behavior of RMP and DARP in the presence of carbon tetrachloride (CCl4) plus ATT-DILI in rats. METHODS: Thirty rats used in the experiment were divided equally into six groups. We administered a single 0.5 mL/kg CCl4 intraperitoneal injection in all rats. Groups II, III, IV, and V were started on daily oral RMP alone, RMP plus isoniazid (INH), RMP plus pyrazinamide (PZA), and the three drugs INH, RMP, and PZA together, respectively, for 21-days subsequently. Pharmacokinetic (PK) sampling was performed at 0, 0.5, 1, 3, 6, 12, and 24 h post-dosing on day 20. We monitored LFT at baseline on days-1, 7, and 21 and sacrificed the rats on the last day of the experiment. RESULTS: ATT treatment sustained the CCl4-induced liver injury changes. A significant rise in mean total bilirubin levels was observed in groups administered rifampicin. The triple drug combination group demonstrated 1.43- and 1.84-times higher area-under-the-curve values of RMP (234.56±30.66 vs. 163.55±36.14 µg h/mL) and DARP (16.15±4.50 vs. 8.75±2.79 µg h/mL) compared to RMP alone group. Histological and oxidative stress changes supported underlying liver injury and PK alterations. CONCLUSIONS: RMP metabolism inhibition by PZA, more than isoniazid, was well preserved in the presence of underlying liver injury.

Melamine Exacerbates Neurotoxicity in D-Galactose-Induced Neuronal SH-SY5Y Cells.

Numerous studies have depicted the role of diet and environmental toxins in aging. Melamine (Mel) is a globally known notorious food adulterant, and its toxicity has been shown in several organs including the brain. However, till now, there are no reports regarding Mel neurotoxicity in aging neurons. So, this study examined the in vitro neurotoxicity caused by Mel in the D-galactose (DG)-induced aging model of neuronal SH-SY5Y cells. In the present study, the neuronal SH-SY5Y cells were treated with DG and Mel separately and in combination to assess the neurotoxicity potential using MTT assay and neurite length measurement. Further, the superoxide dismutase (SOD), catalase (CAT), and total antioxidant activities were evaluated followed by the determination of the intracellular reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and caspase3 (Casp3) activity. The cotreatment of Mel and DG in neuronal SH-SY5Y cells showed maximum cell death than the cells treated with DG or Mel individually and untreated control cells. The neurite length shrinkage and ROS production were maximum in the DG and Mel cotreated cells showing exacerbated toxicity of Mel. The activity of SOD, CAT, and total antioxidants was also found to be lowered in the cotreatment group (Mel + DG) than in Mel- or DG-treated and untreated cells. Further, the combined toxicity of Mel and DG also elevated the Casp3 activity more than any other group. This is the first study showing the increased neurotoxic potential of Mel in an aging model of neuronal SH-SY5Y cells which implicates that Mel consumption by the elderly may lead to increased incidences of neurodegeneration like Alzheimer's disease and Parkinson's disease.

Organophosphorus and carbamate pesticides: Molecular toxicology and laboratory testing.

Population and food requirements are increasing daily throughout the world. To fulfil these requirements application of pesticides is also increasing. Organophosphorous (OP) and Organocarbamate (OC) compounds are widely used pesticides. These pesticides are used for suicidal purposes too. Both inhibit Acetylcholinesterase (AChE) and cholinergic symptoms are mainly used for the diagnosis of pesticide poisoning. Although the symptoms of the intoxication of OP and OC are similar, recent research has described different targets for OP and OC pesticides. Researchers believe the distinction of OP/OC poisoning will be beneficial for the management of pesticide exposure. OP compounds produce adducts with several proteins. There is a new generation of OP compounds like glyphosate that do not inhibit AChE. Therefore, it's high time to develop biomarkers that can distinguish OP poisoning from OC poisoning.

Scopoletin a potential phytochemical therapy for antitubercular treatment drug induced liver injury (ATT-DILI) model in Wistar rats.

OBJECTIVES: The hepatoprotective properties of scopoletin have been explored in carbon tetrachloride (CCl4) induced liver injury but not in drug-induced liver injury (DILI) scenarios. Only N-acetyl-cysteine (NAC) has proven efficacy in DILI treatment. Accordingly, we conducted a study to assess the hepatoprotective action of scopoletin in the anti-tubercular treatment (ATT)-DILI model in Wistar rats, if any. METHODS: A total of 36 rats were evaluated, with six in each group. A 36-day ATT at 100 mg/kg dose for isoniazid, 300 mg/kg for rifampicin and 700 mg/kg for pyrazinamide were fed to induce hepatotoxicity in rats. Group I and II-VI received normal saline and ATT, respectively. Oral scopoletin (1,5 and 10 mg/kg) and NAC 150 mg/kg were administered in groups III, IV, V and VI, respectively, once daily for the last 15 days of the experiment. LFT monitoring was performed at baseline, days 21, 28, and 36. Rats were sacrificed for the histopathology examination. RESULTS: Aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP) and bilirubin levels were significantly increased in group II (receiving ATT) compared to normal control on day 28 and day 36 (p<0.05). All three doses of scopoletin and NAC groups led to the resolution of AST, ALT, ALP, and bilirubin changes induced by ATT medications effect beginning by day 28 and persisting on day 36 (p<0.01). An insignificant effect was observed on albumin and total protein levels. The effect was confirmed with antioxidants and histopathology analysis. CONCLUSIONS: The study confirms the hepatoprotective efficacy of scopoletin in a more robust commonly encountered liver injury etiology.

Pharmacokinetic Assessment of Pyrazinamide and Pyrazinoic Acid in Carbon tetrachloride-induced Liver Injury Model in Wistar Rats.

Background: We investigated the pharmacokinetic behavior of pyrazinamide (PZA) and pyrazinoic acid (PA) in the presence of carbon-tetrachloride (CCl4) plus antitubercular treatment (ATT) drug-induced liver injury (DILI) in rats. Methods: Thirty rats utilized in the experiment were separated equally into five groups. Each rat was injected with 0.5 ml/kg CCl4 intra-peritoneal injection on day zero. Group, I rats did receive only CCl4 (single i.p. injection, 0.5 ml/Kg in olive oil in a 1:1 ratio). Groups II, III, IV, and V did receive daily oral PZA, PZA plus isoniazid (INH), rifampicin (RMP) plus pyrazinamide (PZA), and three drugs together, respectively, for 21-days. Pharmacokinetic sampling was performed at 0, 0.5,1,3,6,12 and 24 hours post-dosing on day-20. Liver function test (LFT) was assessed at days 0,1,7, and 21 days after CCl4 and ATT administration, and rats were sacrificed on the last experiment day. Results: ATT treatment maintained the liver function changes initiated by CCl4 administration. An evidential LFT rise was observed in groups administered with pyrazinamide. Co-administration of Isoniazid caused a 2.02 and 1.78 times increase in Area-under-the-curve (AUC) values of PZA and PA, respectively (p < 0.05). Histological and oxidative-stress changes supported the biochemical and pharmacokinetic observations. Conclusion: The enzyme inhibitory capacity of isoniazid is well-preservd in CCl4-induced liver injury.

Pharmacokinetic Assessment of Isoniazid and Acetylisoniazid in Carbon Tetrachloride-Induced Liver Injury Model in Wistar Rats.

Background: N-acetyl transferase 2 (NAT2) polymorphism testing could not see the light of success as a biomarker tool in tuberculosis management. Additionally, the antitubercular treatment (ATT) drug's reintroduction regimen variations exist because of the scarcity of robust preclinical evidence on ATT drug metabolism. Objective: The experiment was planned to understand the pharmacokinetic (PK) behavior of isoniazid and acetylisoniazid (AcINH) in a Wistar rat model of acute liver injury induced by carbon tetrachloride (CCl4) and preclinical drug-induced liver injury (DILI) model induced with CCl4 + anti-Tuberculosis (TB) drugs together. Materials and Methods: Thirty rats were used for the experiment and were divided into five groups. All rats were administered a single 0.5 ml/kg CCl4 intraperitoneal injection on day 0 to induce an animal model of DILI. Group I rats received CCl4 alone. Groups II-V were started on additional gavage feedings of isoniazid (H) alone, H plus rifampicin (R), H plus pyrazinamide (Z), and H, R, and Z together, respectively, daily for 21 days subsequently. Isoniazid and AcINH PK assessment was accomplished on day 20 of continuous once-daily dosing. Liver function test (LFT) monitoring was done at baseline on days 1, 7, and 21. On the last day of experiments, all experimental rats were sacrificed. Results: Three-week ATT administration sustained the CCl4-induced LFT changes. Area under the curve (AUC) values for isoniazid and AcINH were found to be 2.24 and 1.69 times higher in the H + R group compared with the CCl4 + H group, respectively (P < 0.05). Isoniazid and AcINH maximum concentration (Cmax) reached the highest, while isoniazid clearance reached the lowest in the H + R group. AcINH AUC increased by double in the CCl4 + Isoniazid+Rifampicin+Pyrazinamide (HRZ) group compared with the CCl4 + H group (P < 0.05). Biochemical, histological, and antioxidant changes were consistent with the new liver injury model's development. Conclusion: Rifampicin almost doubles up the isoniazid and AcINH exposure, in presence if DILI.

Novel therapeutic mechanism of action of metformin and its nanoformulation in Alzheimer's disease and role of AKT/ERK/GSK pathway.

INTRODUCTION: Brain Insulin-resistance plays a critical role in pathogenesis of Alzheimer's disease (AD). Current study explored the therapeutic mechanism of metformin (insulin sensitizer) and its solid-lipid nanoformulation (SLN) in rat-model of AD. In our study, SLN was prepared using microemulsion method. AD was induced with ICV-Aß whereas the control-group (sham) received ICV-NS. Treatment arms included, disease-control (no treatment), Metformin (50 mg/kg, 100 mg/kg and 150 mg/kg), SLN-metformin 50 mg/kg and memantine 1.8 mg/kg (positive-control). Animals were tested for cognitive performance (EPM, MWM) after 21 days of therapy and sacrificed. Aß (1-42), hyperphosphorylated tau, pAKTser473, GSK-3ß, p-ERK (ELISA), metformin level(HPLC), neuronal injury score(H&E), Bcl2 and Bax(IHC) was evaluated in isolated brain. In our study, metformin-SLN were of spherical shape (size<200 nm) with 94.08% entrapment efficiency. Metformin was detectable in brain. Compared to sham, the disease-control group showed significantly higher (p ≤ 0.05) memory impairment(MWM and EPM), hyperphosphorylated tau, Aß(1-42), neuronal-injury, Bax and lower Bcl-2 expression. Treatment with metformin and nanoformulation significantly reverse these parameters. AKT-ERK-GSK3ß-Hyperphosphorylated tau pathway was found to be involved in the protective efficacy of metformin. To conclude, both metformin and its SLN were found to be effective as therapeutic agents in AD which act through the AKT-ERK-GSK3ß-Hyperphosphorylated tau pathway. We need population based studies to confirm the same.

Spectrofluorimetric-based approach to screen urine contamination in drinking water: A step toward the development of screening method for leptospirosis.

Hygiene hypothesis and sanitization are two important pivots of modern civilization. The drinking water should be free from urine and stool contamination. Coliform test is popular for understanding feces contamination. However, understanding urine contamination in drinking water is a difficult task. On the other hand, urine contamination can cause disease like leptospirosis. It occurs mainly in animals and infects humans through contaminated water, food, and soil and causes serious consequences. Rat urine is the most common source of such disease outbreaks. Further, sophisticated laboratories with high-end technologies may not be present at the site of disease outbreaks. In this context, we have proposed a spectrofluorimetric approach to screen urine contamination in water. The screening method can sense up to 156 nl/ml of rat urine.

Pharmacological Evaluation of Scopoletin in the Carbon Tetrachloride-Induced Hepatotoxicity Model in Wistar Rats.

Background: Several phyto-chemicals have been identified and suggested as potential therapeutic options for hepatotoxicity management. Objective: To assess the hepatoprotective effect of scopoletin, a pure phyto-chemical, in carbon tetrachloride (CCl4)-induced hepatotoxicity model in Wistar rats. Methods: Thirty-six rats in total, six in each group, were utilized in this study. Animals in group 1 received normal saline; those in group 2 received carbon tetrachloride in olive oil (0.5 ml/kg, i.p. in ratio 1:1); those in groups 3, 4, and 5 received oral scopoletin (1 mg/kg, 5 mg/kg, 10 mg/kg dose-wise groups); and those in group 6 received N-acetyl cysteine (NAC) 150 mg/kg. Blood sampling was performed on day -3, day 1, and day 7 of the CCl4 administration. Rats were sacrificed on day 7 of the experiment for histological examination and oxidative stress measurement of the liver. Results: The 5 mg/kg scopoletin group showed a maximum reduction in AST levels [727.33 ± 29.15 in medium dose (MD) group vs 1526.66 ± 60.72 in the experimental control (EC) group (P < 0.001) and ALT levels of 532.66 ± 24.23 in MD group vs 894.83 ± 52.47 in EC (P < 0.01)]. The dose-dependent action was not observed with scopoletin doses. The protective effect of scopoletin was confirmed by MDA and GSH levels (P < 0.05) coupled with histo-pathological findings. In the present study, a reversible model of CCl4-induced hepatotoxicity was observed to get normalized in a week's time. Conclusion: The study confirms the hepatoprotective action of scopoletin in an acute model of hepatic injury with the putative anti-oxidant mechanism.

Molecular docking analysis of melamine with nuclear factor erythroid 2-related factor 2 and succinate dehydrogenase.

Melamine consumption causes oxidative stress by an unknown mechanism. Therefore, it is of interest to analyze the interaction of melamine with two important proteins involved in oxidative stress biology namely, nuclear factor erythroid 2-related factor 2 and succinate dehydrogenase. The molecular docking data shows the melamine binding with these two proteins at critical residues. These interactions can be logically perceived for the causation of melamine induced oxidative stress.

Fluorimetric method for specific detection of human serum albumin in urine using its pseudoesterase property.

Detection of microalbuminuria is an analytical challenge. There are dye-based methods and immunochemical methods. However, these methods are less specific and sensitive respectively. So, people are trying new approaches for microalbuminuria detection. In this context, we have developed a fluorescent spectroscopic method to detect human serum albumin using its pseudoesterase property. Recently, we had discovered that neostigmine does not inhibit Human serum albumin pseudoesterase activity. Using such a phenomenon, we have devised a specific fluorimetric detection method of HSA using 2NA as a substrate for the pseudoesterase activity. The developed method can sense as low as 0.1 µM of HSA in the urine matrix without dye or antibody. We have proposed a scheme of automation of the proposed method.

Acute aluminum phosphide poisoning: The menace of phosphine exposure.

Aluminum phosphide (AlP) is a popular fumigant used widely for the safe storage of food grain. Although A1P is free from toxic residues, it releases phosphine which acts on mitochondrial components of almost all types of pests. Unfortunately A1P is also a common suicidal agent in developing countries with no known antidote. In addition, accidental exposure to phosphine may also occur. AlP poisoning affects cardiac and vascular tissue directly and can result in multiorgan system failure leading to death in severe cases. There is no specific biomarker for diagnosing AlP poisoning and management depends on a high level of clinical suspicion. Although acetylcholinesterase has been suggested as a surrogate biomarker of AlP exposure, there are opposing views. In this review, we analyzed the relevant published material with emphasis on the need to recognize and explore the use of plasma mitochondrial enzyme activity as a potential biomarker for AlP exposure.

Application of Tucatinib and Trastuzumab: Dual Anti HER2 Therapy Against HER2 Positive Breast Cancer.

Synergism in action of tucatinib and trastumab is reported in breast cancer management. However, its molecular basis is yet to be determined. In this context we attempted to provide an explanation at the molecular level by performing in silico experimentation and coupling its result with already available published observations. Our study will provide basis for planning further experimental study for unravelling the truth.