Drug Detoxification Research Articles

Folic acid protects against tuberculosis-drug-induced liver injury in rats and its potential mechanism by metabolomics

Observational study indicated that folic acid (FA) supplementation may protect against tuberculosis-drug-induced liver injury (TBLI). The aim is to investigate the effect and mechanism of FA on TBLI in rats. Liver injury was induced by a daily gavage of isoniazid (INH) and rifampicin (RIF) in the model and FA groups. Rats in the FA group were also treated with 2.5 mg/kg body weight FA. Rats in the control group were not treated. Eight rats were used in each group. The severity of liver injury was measured by the serum levels of hepatic enzymes and histological score. The metabolites in serum and liver tissues were analyzed by HPLC-Q-TOF-MS/MS. FA treatment significantly reduced alanine aminotransferase and liver necrosis. Seventy-nine differential metabolites in the serum and liver tissues were identified among the three groups. N-acylethanolamines, INH and RIF metabolites, phosphatidylcholines, lysophosphatidylcholines, monoglycerides, diglycerides and bile acids were regulated by FA treatment, involving key metabolic pathways, such as N-acylethanolamine metabolism, INH and RIF metabolism, liver regeneration, inflammation alleviation and bile acid metabolism. RT-PCR and western blotting results confirmed the altered N-acylethanolamine metabolism and improved drug metabolism by FA. In conclusion, FA was protective against TBLI, which may be related to the regulation of N-acylethanolamine metabolism and drug detoxification by FA.

Synergizing hexagonal ferrite with transition metals in core-shell-shell nanostructures (SrFe@Dop@M) as dualistic probe for detoxification and electrochemical detection of pharmaceutical drugs

A novel hexagonal ferrite-based core-shell-shell nanostructures (SrFe@Dop@M, M = Cr, Mn, Fe, Co, Ni, Cu and Zn) were designed for dual application of simultaneous electrochemical detection and photocatalytic degradation of pharmaceutical drugs. The phase analysis and topographical investigations of synthesized nanostructures were examined via PXRD, FE-SEM and HR-TEM techniques. XPS was employed to investigate the elemental composition and their corresponding electronic states. The electron transfer rate of synthesized nanostructures was estimated by EIS and CV studies. The comparative photocatalytic evaluation of SrFe, SrFe@Dop and SrFe@Dop@M was performed towards degradation of levofloxacin and sulfamethoxazole. SrFe@Dop@Mn was observed to portray best photocatalytic performance of around 3 times than that of bare SrFe and SrFe@Dop, attributable to its lowest energy band gap value and highest electron transfer rate. The SrFe@Dop@Mn glassy carbon electrode (GCE) was further employed as an electrochemical sensor towards detection of levofloxacin in waste water samples, providing impressive linear range from 55.2 nM to 772.8 nM and limit of detection as low as 0.037 nM. The real sample (tap water, lake water, river water and urine sample) analysis was evaluated to realize the practical applicability of modified sensor.

Regulation of thymidylate synthase: an approach to overcome 5-FU resistance in colorectal cancer.

Thymidylate synthase is the rate-limiting enzyme required for DNA synthesis and overexpression of this enzyme causes resistance to cancer cells. Long treatments with 5-FU cause resistance to Thymidylate synthase targeting drugs. We have also compiled different mechanisms of drug resistance including autophagy and apoptosis, drug detoxification and ABC transporters, drug efflux, signaling pathways (AKT/PI3K, RAS-MAPK, WNT/β catenin, mTOR, NFKB, and Notch1 and FOXM1) and different genes associated with resistance in colorectal cancer. We can overcome 5-FU resistance in cancer cells by regulating thymidylate synthase by natural products (Coptidis rhizoma), HDAC inhibitors, mTOR inhibitors, Folate antagonists, and several other drugs which have been used in combination with TS inhibitors. This review is a compilation of different approaches reported for the regulation of thymidylate synthase to overcome resistance in colorectal cancer cells.

Camellia japonica Root Extract Increases Antioxidant Genes by Induction of NRF2 in HeLa Cells.

Camellia japonica L. (Theaceae) has been used for medicinal and cosmetic purposes in East Asian countries. Most functional components were obtained from the upper parts of the tree, such as leaves, flowers, or seeds. Here, we report a functional effect of the 80% methanolic extract of C. japonica root (CJRE) on antioxidative stress in HeLa cells. The nuclear factor erythroid-derived 2-related factor 2 (NRF2) is a key transcription factor that triggers the induction of oxidative stress-relating genes and drug detoxification. As result, CJRE showed a strong anti-radical scavenging effect in a dose-dependent manner. In addition, the induction of antioxidant response elements (ARE)-luciferase activity was maximized at CJRE 200 µg/mL. Furthermore, CJRE induced the mRNA levels of HO-1 and NQO1 by the nuclear NRF2 accumulation. As a possible mechanism of Nrf2 activation, the phosphorylation of p38 and ERK1/2 signaling might fortify the NRF2 induction as well as its stability. However, the phosphorylation of AKT is rather decreased. Taken together, CJRE may potentiate the antioxidant effects by increasing the NRF2 signaling through MAP kinase signaling and the properties of its radical scavenging activity. Thus, CJRE could apply for other medicinal and cosmetic purposes.

Inflammatory signaling on cytochrome P450-mediated drug metabolism in hepatocytes.

Cytochrome P450 (CYP450) enzymes are membrane-bound blood proteins that are vital to drug detoxification, cell metabolism, and homeostasis. CYP450s belonging to CYP families 1-3 are responsible for nearly 80% of oxidative metabolism and complete elimination of approximately 50% of all common clinical drugs in humans liver hepatocytes. CYP450s can affect the body's response to drugs by altering the reaction, safety, bioavailability, and toxicity. They can also regulate metabolic organs and the body's local action sites to produce drug resistance through altered drug metabolism. Genetic polymorphisms in the CYP gene alone do not explain ethnic and individual differences in drug efficacy in the context of complex diseases. The purpose of this review is to summarize the impact of new inflammatory-response signaling pathways on the activity and expression of CYP drug-metabolizing enzymes. Included is a summary of recent studies that have identified drugs with the potential to regulate drug-metabolizing enzyme activity. Our goal is to inspire the development of clinical drug treatment processes that consider the impact of the inflammatory environment on drug treatment, as well as provide research targets for those studying drug metabolism.

Mechanism and treatment of α-amanitin poisoning.

Amanita poisoning has a high mortality rate. The α-amanitin toxin in Amanita is the main lethal toxin. There is no specific detoxification drug for α-amanitin, and the clinical treatment mainly focuses on symptomatic and supportive therapy. The pathogenesis of α-amanitin mainly includes: α-amanitin can inhibit the activity of RNA polymeraseII in the nucleus, including the inhibition of the largest subunit of RNA polymeraseII, RNApb1, bridge helix, and trigger loop. In addition, α-amanitin acts in vivo through the enterohepatic circulation and transport system. α-Amanitin can cause the cell death. The existing mechanisms of cell damage mainly focus on apoptosis, oxidative stress, and autophagy. In addition to the pathogenic mechanism, α-amanitin also has a role in cancer treatment, which is the focus of current research. The mechanism of action of α-amanitin on the body is still being explored.

Hepato-defensive effect of Cysteine, Ursodeoxycholic acid and Silymarin on histopathological and some biochemical parameters of Wister albino rat intoxicated by CCl4

The liver is an essential organ in the body for detoxification drugs and toxic substances. The present study was designed to investigate the hepatoprotective effects of L-Cysteine, Ursodeoxycholic acid (Ursoflor), and Silymarin against carbon tetrachloride-induced liver injury in rats. Twenty adult male rats were used in this work; they were randomly divided into five groups (4 rats/group). The first group served as the control group and received 0.5 ml of normal saline orally daily; the second group injected intraperitoneally with CCl4 (1.5 ml/kg B.W. twice a week), the third group were treated orally with the silymarin at dose of (200 mg/kg B.W. in normal saline orally + CCl4 daily, the fourth group was treated with Ursoflor drug at dose of (50 mg/kg B.W. in 0.5 normal saline orally+CCl4 daily. While the fifth group was treated with cysteine at dose of (50mg/kg B.W. in normal saline by oral gavage) +CCl4. at the end of this study, the biochemical assessment showed alterations in enzyme activity which indicates the hepatocyte injury due to CCl4 toxicity, The production of ROS indicated by elevated levels in MDA and Peroxynitrite was noticed, which improved partially by the antioxidant effect of L- Cysteine, Ursodeoxycholic acid, and Silymarin, these results further backed by histological examination of the liver showed that CCl4 caused severe injury to the liver including a high number of fat droplets deposition in the cytoplasm of the hepatocyte, clear vascularization appeared and disorganization of the liver cells were determined, on the other hand, Silymarin has showed good protection against these injurious effects of CCl4.

Knockout of NRF2 triggers prostate cancer cells death through ROS modulation and sensitizes to cisplatin.

Prostate cancer (PCa) represents the second most common cancer in men and affects millions worldwide. Chemotherapy is a common treatment for PCa but the development of resistance is often a problem during therapy. NRF2 (nuclear factor erythroid 2-related factor 2) is one of the major transcription factors regulating antioxidant enzymes and is also involved with drug efflux and detoxification. Cancer cells submitted to chemotherapy often promote NRF2 activation to benefit themselves with the cytoprotective response. Here, we found that DU145 and PC3 PCacell lines have different responses regarding NRF2 activation, when subjected to arsenite-induced stress, even in the presence of MG132, a proteasome inhibitor. We also observed that only in PC3 cells treated with arsenite, NRF2 was able to translocate to the nucleus. To better understand the role of NRF2 in promoting chemoresistance, we performed CRISPR knockout of NRF2 (NKO) in DU145 and PC3 cells. The effectiveness of the knockout was confirmed through the downregulation of NRF2 targets (p < 0.0001). PC3 NKO cells exhibited higher levels of reactive oxygen species (ROS) compared to wild-type cells (p < 0.0001), while this alteration was not observed in DU145 NKO cells. Despite no modulation in ROS content, a lower IC50 value (p < 0.05) for cisplatin was observed in DU145 NKO cells, suggesting that the knockout sensitized the cells to the treatment. Besides, the treatment of DU145 NKO with cisplatin led cells to apoptosis as observed by the increased levels of PARP1 cleavage (p < 0.05), possibly triggered by increased DNA damage. Reduced levels of KU70 and phospho-CHK2 (p < 0.05) were also detected. The data presented here support that NRF2 is a mediator of oncogenesis and could be a potential target to sensitize PCacells to chemotherapy, reinforcing the importance of knowing the specific genetic and biochemical characteristics of the cancer cells for a more effective approach against cancer.

The Role of Glutathione Metabolism in Chronic Illness Development and Its Potential Use as a Novel Therapeutic Target.

Glutathione (GSH) is the most abundant thiol antioxidant in the human body and serves many important biochemical functions, including the regulation of vitamins, such as vitamins D, E, and C, and detoxification of drugs and toxins. As a powerful antioxidant, GSH is particularly important as a regulator of mitochondrial metabolism and a free radical scavenger that limits oxidative damage to cellular components. Low GSH levels have been associated with many chronic pro-inflammatory conditions, such as metabolic syndrome, cardiovascular, renal, and hepatic disease, as well as neurodegenerative conditions and autoimmune diseases. Given GSH's known direct protective role in mitochondrial metabolism and its association with chronic diseases of highly metabolically active tissues, this review aims to examine the literature for evidence that low GSH levels may be an important causative factor in the development of chronic illnesses. Because no large prospective human trials have been conducted using direct measurements of GSH, this review focused on the more common biomarker gamma-glutamyl transferase (GGT) which is directly correlated to low GSH levels. Several large prospective studies support this hypothesis by demonstrating that higher GGT levels are correlated with the risk of developing metabolic syndrome and cardiovascular disease in a dose-dependent fashion. Furthermore, as a corollary to this hypothesis, human and animal trials utilizing GSH augmentation using precursor supplementation in chronic conditions, including metabolic syndrome, cardiovascular disease, hepatic disease, renal disease, and neurodegenerative conditions, were also reviewed. While many of these trials were preliminary and small, there is strong evidence that GSH supplementation leads to improved outcomes in all of these chronic conditions. This review seeks to highlight these studies as preliminary evidence demonstrating the contributory role of GSH in chronic disease progression because a simple and cost-effective strategy can be created to screen for, track, and intervene in susceptible patients in the primary care setting at the earliest possible time in the disease process. Such a novel strategy would impact the majority of chronic diseases contributing to the bulk of morbidity and mortality in the Western world, and, thus, even minor benefits across many conditions may substantially impact population-wide health and longevity.

Worldwide Systematic Review of GSTM1 and GSTT1 Null Genotypes by Continent, Ethnicity, and Therapeutic Area.

Glutathione S-transferase Mu 1 (GSTM1) and glutathione S-transferase theta 1 (GSTT1) enzymes are glutathione-S-transferases with broad significance for susceptibility or resistance to multifactorial human diseases, as well as detoxification of environmental chemicals and drugs. Moreover, some individuals may have a complete deletion of GSTM1 and GSTT1 genes, which can contribute to patient-to-patient variability in drug safety and efficacy. GSTM1 and GSTT1 gene deletion frequencies can vary according to ethnicity and continental origin of the studied population with implications for achieving the goal of precision/personalized medicine in clinical practice. We report here a worldwide systematic review of the null genotypes in these two clinically important genes by continents, ethnicities, and therapeutic areas (TAs). Searches were performed in the PubMed database covering the period from 1992 to 2020. Out of the 1925 articles included, most studies analyzed European individuals, corroborating the literature failure for not adequately considering the non-European ethnicities. The frequency of GSTM1 and GSTT1 null genotypes was higher in patients than in healthy volunteers. Conversely, in East Asians, higher frequencies of the null genotypes were observed in healthy volunteers than patients. Oncology was the most intensively studied TA (57% of the articles) in relation to GSTM1 and GSTT1. In all, these results demonstrate that there is an important gap in the literature in terms of failure to consider a broader range of populations, as well as diseases wherein GSTM1 and GSTT1 variations have clinical and biological implications. To achieve precision/personalized medicine on a global/worldwide scale, with equity and inclusiveness, this knowledge/research gap ought to be remedied in studies of GSTM1 and GSTT1 null genotypes. To the best of our knowledge, this is the largest systematic review conducted to date addressing the GSTM1 and GSTT1 null genotypes worldwide. The analyses from the 1925 articles highlighted the current knowledge gaps in different TAs, ethnicities, and populations. Filling these gaps is of importance, given the role these genes play in relation to the metabolism of substances to which we have frequent contact with, the associations observed between their deletion and diseases such as cancer, in addition to the interethnic differences observed for the deletion frequencies of these genes.

Glutathione-Mediated Conjugation of Anticancer Drugs: An Overview of Reaction Mechanisms and Biological Significance for Drug Detoxification and Bioactivation.

The effectiveness of many anticancer drugs depends on the creation of specific metabolites that may alter their therapeutic or toxic properties. One significant route of biotransformation is a conjugation of electrophilic compounds with reduced glutathione, which can be non-enzymatic and/or catalyzed by glutathione-dependent enzymes. Glutathione usually combines with anticancer drugs and/or their metabolites to form more polar and water-soluble glutathione S-conjugates, readily excreted outside the body. In this regard, glutathione plays a role in detoxification, decreasing the likelihood that a xenobiotic will react with cellular targets. However, some drugs once transformed into thioethers are more active or toxic than the parent compound. Thus, glutathione conjugation may also lead to pharmacological or toxicological effects through bioactivation reactions. My purpose here is to provide a broad overview of the mechanisms of glutathione-mediated conjugation of anticancer drugs. Additionally, I discuss the biological importance of glutathione conjugation to anticancer drug detoxification and bioactivation pathways. I also consider the potential role of glutathione in the metabolism of unsymmetrical bisacridines, a novel prosperous class of anticancer compounds developed in our laboratory. The knowledge on glutathione-mediated conjugation of anticancer drugs presented in this review may be noteworthy for improving cancer therapy and preventing drug resistance in cancers.

Bidentate binuclear coordination configuration for peroxymonosulfate catalytic regulation through incorporation of CuFeOx to iron-based metal organic frameworks

The scheme of coordination bridge modification provides a new vision for regulating the catalytic pathway, but how to change the surface coordination of peroxymonosulfate (PMS), thereby affecting the catalytic mechanism of PMS, is still an unknown field. In this, we found that MIL-101(Fe) is expected to control the surface catalytic pathway via the bidentate binuclear coordination configuration, thereby realizing the rapid oxidative detoxification of toxic organic pollutants and CO2 conversion. Introducing Cu on the surface of MIL-101(Fe) to change the surface chemical environment (MIL-101(Fe)/CuFeOx) can shift the catalytic pathway, thereby promoting a 14.5-fold improvement in Bisphenol A (BPA) oxidation kinetics (from 0.00697 min−1 to 0.101 min−1). Characterization, experiments, and density functional theory (DFT) results show that Cu in the vicinity of Fe can tune the electronic structure and properties of Fe-O-Cu, thereby enhancing the electron transfer rate at the active center, facilitating electronic transitions and PMS adsorption. More importantly, shifting the binding configuration of PMS from monodentate mononuclear coordination on a single Fe center to bidentate binuclear coordination on Fe/Cu centers, shorter distance coordination structures and OO pulling of PMS. The effect promoted PMS cleavage to generate more ROS and changed the catalytic pathway from the radical pathway to the 1O2 and high-valent metal species pathway. The free radical/non-radical pathway co-mediated by 1O2, high-valent metal species, ·OH and SO4·− can effectively reduce the biotoxicity of toxic organic pollutants, and can utilize alkali environment captures CO2 as a stable carbonate for environmental use. This study provides a strategy for manipulating the catalytic pathway through coordination configuration and a feasible idea for CO2 conversion in wastewater treatment.

Lineage reprogramming of human adipose mesenchymal stem cells to immune modulatory i-Heps.

Pluripotent stem cell derived-hepatocytes depict fetal -hepatocyte characteristics/maturity and are immunogenic limiting their applications. Attempts have been made to derive hepatocytes from mesenchymal stem cells using developmental cocktails, epigenetic modulators and small molecules. However, achieving a stable terminally differentiated functional state had been a challenge. Inefficient hepatic differentiation could be due to lineage restrictions set during development. Hence a novel lineage reprogramming approach has been utilized to confer competence to adipose-mesenchymal stem cells (ADMSCs) to efficiently respond to hepatogenic cues and achieve a stable functional hepatic state. Lineage reprogramming involved co-transduction of ADMSCs with hepatic endoderm pioneer Transcription factor (TF)-FOXA2, HHEX-a homeobox gene and HNF4α-master TF indispensable for hepatic state maintenance. Lineage priming was evidenced by endogenous HFN4α promoter demethylation and robust responsiveness to minimal hepatic maturation cues. Induced hepatocytes (i-Heps) exhibited mesenchymal-to-epithelial transition and terminal hepatic signatures. Functional characterisation of i-Heps for hepatic drug detoxification systems, xenobiotic uptake/clearance, metabolic status and hepatotropic virus entry validated acquisition of stable hepatic state and junctional maturity Exhaustive analysis of MSC memory in i-Heps indicated loss of MSC-immunophenotype and terminal differentiation to osteogenic/adipogenic lineages. Importantly, i-Heps suppressed phytohemagglutinin-induced T-cell blasts, inhibited allogenic mixed-lymphocyte reactions (MLRs) and secreted immunomodulatory- indoleamine 2,3-dioxygenase in T-cell blast co-cultures akin to native ADMSCs. In a nutshell, the present study identifies a novel cocktail of TFs that reprogram ADMSCs to stable hepatic state. i-Heps exhibit adult hepatocyte functional maturity with robust immune-modulatory abilities rendering suitability for rigorous drug testing, hepatocyte-pathogen interaction studies and transplantation in allogenic settings.

Role and Regulation of Hepatobiliary ATP-Binding Cassette Transporters during Chemical-Induced Liver Injury.

Severity of drug-induced liver injury (DILI) ranges from mild, asymptomatic, and transient elevations in liver function tests to irreversible liver damage, often needing transplantation. Traditionally, DILI is classified mechanistically as high-frequency intrinsic DILI, commonly dose dependent or DILI that rarely occurs and is idiosyncratic in nature. This latter form is not dose dependent and has a pattern of histopathological manifestation that is not always uniform. Currently, a third type of DILI called indirect hepatotoxicity has been described that is associated with the pharmacological action of the drug. Historically, DILI was primarily linked to drug metabolism events; however, the impact of transporter-mediated rates of drug uptake and excretion has gained greater prominence in DILI research. This review provides a comprehensive view of the major findings from studies examining the contribution of hepatic ATP-binding cassette transporters as key contributors to DILI and how changes in their expression and function influence the development, severity, and overall toxicity outcome. SIGNIFICANCE STATEMENT: Drug-induced liver injury (DILI) continues to be a focal point in drug development research. ATP-binding cassette (ABC) transporters have emerged as important determinants of drug detoxification, disposition, and safety. This review article provides a comprehensive analysis of the literature addressing: (a) the role of hepatic ABC transporters in DILI, (b) the influence of genetic mutations in ABC transporters on DILI, and (c) new areas of research emphasis, such as the influence of the gut microbiota and epigenetic regulation, on ABC transporters.

Rapid detoxification of Jatropha curcas cake by fermentation with a combination of three microbial strains and characterization of their metabolic profiles.

Our previous study reported a strain that can detoxify Jatropha curcas L. cake (JCC), but the detoxification duration is long. This study intends to explore the efficient detoxification of JCC through multi-strain collaborative fermentation to accelerate the detoxification process. Mucor circinelloides SCYA25 strain that we previously reported can effectively degrade the toxicity of JCC, and the newly screened Bacillus megaterium SCYA10 and Geotrichum candidum SCYA23 strains were used to detoxify JCC. Different solid-state-fermentation (SSF) parameters were optimized by single-factor tests and response surface methodology. A detoxification rate established by zebrafish toxicity of JCC at 96% was achieved under the following optimized conditions: the combination ratio of B. megaterium SCYA10, G. candidum SCYA23 and M. circinelloides SCYA25 at 2:3:1, a total injection amount of 15.25%, a feed to water ratio of 1:0.68, a fermentation temperature of 30.3°C and fermentation duration of 21.5 days. The protein content of fermented JCC (FJCC) increased, while the concentrations of ether extract, crude fibre and toxins were all degraded considerably. Metabolomics analysis revealed that the fermentation increased the contents of neurotransmitter receptor modulator, emulsifier, aromatic substances and insecticidal compounds, as well as decreasing the contents of oxidative stress and neurotoxic substances. A rat feeding trial showed that the growth performance of the rats provided with the FJCC diet was similar to that of the corn-soybean meal group, and no lesions in the liver and kidney were observed. The co-bio-fermentation process can effectively detoxify JCC and improve its nutritional value, which means it could be served as a protein feed in animal husbandry. The combination of three microbial strains can detoxify JCC in a safe and effective manner to provide a great potential alternative to soybean meal. The research also suggests that metabonomics and bioinformatics are useful tools for revealing the bio-detoxification mechanism.

Quantification of spatial pharmacogene expression heterogeneity in breast tumors.

Chemotherapeutic drug concentrations vary across different regions of tumors and this is thought to be involved in development of chemotherapy resistance. Insufficient drug delivery to some regions of the tumor may be due to spatial differences in expression of genes involved in the disposition, transport, and detoxification of drugs (pharmacogenes). Therefore, in this study, we analyzed the spatial expression of 286 pharmacogenes in six breast cancer tissues using the recently developed Visium spatial transcriptomics platform to (1) determine if these pharmacogenes are expressed heterogeneously across tumor tissue and (2) to determine which pharmacogenes have the most spatial expression heterogeneity. The spatial transcriptomics technology sequences the transcriptome of 55 um diameter barcoded sections (spots) across a tissue sample. We analyzed spatial gene expression profiles of four biobank-sourced breast tumor samples in addition to two breast tumor sample datasets from 10× Genomics. We define heterogeneity as the interquartile range of read counts. Collectively, we identified 8887 spots in tumor regions, 3814 in stroma, 44 in lymphocytes, and 116 in normal regions based on pathologist annotation of the tissues. We showed statistically significant differences in expression of pharmacogenes in tumor regions compared to surrounding non-tumor regions. We also observed that the most heterogeneously expressed genes within tumor regions were involved in reactive oxygen species (ROS)handling and detoxification mechanisms. GPX4, GSTP1, MGST3, SOD1, CYP4Z1, CYB5R3, GSTK1, and NAT1 showed the most heterogeneous expression within tumor regions. The heterogeneous expression of these pharmacogenes may have important implications for cancer therapy due to their ability to impact drug distribution and efficacy throughout the tumor. Our results suggest that chemoresistance caused by expression of GPX4, GSTP1, MGST3, and SOD1 may be intrinsic, not acquired, since the heterogeneity is not specific to chemotherapy-treated samples or cell type. Additionally, we identified candidate chemoresistance pharmacogenes that can be further tested through focused follow-up studies.

Hepatoprotective evaluation of tinospora cordifolia against drug induced hepatotoxicity

Purpose: Detoxification of several drugs and xenobiotics and also the metabolic and physiological processes happens in the liver. The liver is severely damaged by the reactive chemical intermediates by the detoxification process. There are various drugs available in the market and consumption of these drugs may lead to idiosyncratic drug reactions mediated hepatotoxicity. Various drugs are called off from the market because of its hepatotoxicity. Due to these reasons there has been search for the hepatoprotective drugs that has lead to the screening of the herbal drugs. Therapeutic efficiency of the herbal drugs are been evaluated by the pharmaceutical industries and scientific groups. Various herbal drugs present in different ethnopharmacological practices having hepatoprotective activity are used to treat some of the liver diseases. Method: The methanolic extract of TinosporaCardifoliahas hepatoprotective properties was studied in rats by inducing toxicity with Paracetamol. Result: The plant extract possessed significant hepatoprotective activities that was confirmed by observing the lowered levels of AST, ALP, ALT, LDH and bilirubin. Conclusion: The goal of this study is to see if the methanolic extract of TinosporaCardifolia has any hepatoprotective properties in albino wistar rats.

Consumption of Grapes Modulates Gene Expression, Reduces Non-Alcoholic Fatty Liver Disease, and Extends Longevity in Female C57BL/6J Mice Provided with a High-Fat Western-Pattern Diet.

A key objective of this study was to explore the potential of dietary grape consumption to modulate adverse effects caused by a high-fat (western-pattern) diet. Female C57BL/6J mice were purchased at six-weeks-of-age and placed on a standard (semi-synthetic) diet (STD). At 11 weeks-of-age, the mice were continued on the STD or placed on the STD supplemented with 5% standardized grape powder (STD5GP), a high-fat diet (HFD), or an HFD supplemented with 5% standardized grape powder (HFD5GP). After being provided with the respective diets for 13 additional weeks, the mice were euthanized, and liver was collected for biomarker analysis, determination of genetic expression (RNA-Seq), and histopathological examination. All four dietary groups demonstrated unique genetic expression patterns. Using pathway analysis tools (GO, KEGG and Reactome), relative to the STD group, differentially expressed genes of the STD5GP group were significantly enriched in RNA, mitochondria, and protein translation related pathways, as well as drug metabolism, glutathione, detoxification, and oxidative stress associated pathways. The expression of Gstp1 was confirmed to be upregulated by about five-fold (RT-qPCR), and, based on RNA-Seq data, the expression of additional genes associated with the reduction of oxidative stress and detoxification (Gpx4 and 8, Gss, Gpx7, Sod1) were enhanced by dietary grape supplementation. Cluster analysis of genetic expression patterns revealed the greatest divergence between the HFD5GP and HFD groups. In the HFD5GP group, relative to the HFD group, 14 genes responsible for the metabolism, transportation, hydrolysis, and sequestration of fatty acids were upregulated. Conversely, genes responsible for lipid content and cholesterol synthesis (Plin4, Acaa1b, Slc27a1) were downregulated. The two top classifications emerging as enriched in the HFD5GP group vs. the HFD group (KEGG pathway analysis) were Alzheimer’s disease and nonalcoholic fatty liver disease (NAFLD), both of which have been reported in the literature to bear a causal relationship. In the current study, nonalcoholic steatohepatitis was indicated by histological observations that revealed archetype markers of fatty liver induced by the HFD. The adverse response was diminished by grape intervention. In addition to these studies, life-long survival was assessed with C57BL/6J mice. C57BL/6J mice were received at four-weeks-of-age and placed on the STD. At 14-weeks-of-age, the mice were divided into two groups (100 per group) and provided with the HFD or the HFD5GP. Relative to the HFD group, the survival time of the HFD5GP group was enhanced (log-rank test, p = 0.036). The respective hazard ratios were 0.715 (HFD5GP) and 1.397 (HFD). Greater body weight positively correlated with longevity; the highest body weight of the HFD5GP group was attained later in life than the HFD group (p = 0.141). These results suggest the potential of dietary grapes to modulate hepatic gene expression, prevent oxidative damage, induce fatty acid metabolism, ameliorate NAFLD, and increase longevity when co-administered with a high-fat diet.

The Impact of the Coronavirus (COVID-19) Infection on the Drug-Metabolizing Enzymes Cytochrome P450s.

Coronaviruses cause disease in human and animals. In 2019 a novel coronavirus was first characterized in Wuhan, China. It causes acute respiratory disease and designated the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or COVID-19. The COVID-19 spread to all cities of China, and in 2020 to the whole world. Patients with COVID-19 may recover without medical treatment. However, some patients need medical care. The Cytochrome p450s (CYP450s) are large superfamily of enzymes catalyze the metabolism of endogenous substrates and xenobiotics. CYP450s catalyze the biotransformation of 80% of the drug in clinical use. The CYP450 present in liver, lungs, intestine and other tissues. COVID-19 has been reported to decrease the activity of certain isoforms of CYP450s in an isoform specific manner. Furthermore, the COVID-19 infection decreases the liver functions including the drug clearance or detoxification medicated by the CYP450s. The healthcare providers should be aware of this disease-drug interaction when prescribing drugs for treatment of COVID-19 and other comorbidities.

Cell membrane-coated nanoparticles for the treatment of bacterial infection.

Despite the enormous success of antibiotics in antimicrobial therapy, the rapid emergence of antibiotic resistance and the complexity of the bacterial infection microenvironment make traditional antibiotic therapy face critical challenges against resistant bacteria, antitoxin, and intracellular infections. Consequently, there is a critical need to design antimicrobial agents that target infection microenvironment and alleviate antibiotic resistance. Cell membrane-coated nanoparticles (CMCNPs) are biomimetic materials that can be obtained by wrapping the cell membrane vesicles directly onto the surface of the nanoparticles (NPs) through physical means. Incorporating the biological functions of cell membrane vesicles and the superior physicochemical properties of NPs, CMCNPs have shown great promise in recent years for targeting infections, neutralizing bacterial toxins, and designing bacterial infection vaccines. This review highlights topics where CMCNPs present great value in advancing the treatment of bacterial infections, including drug delivery, detoxification, and vaccination. Lastly, we discuss the future hurdles and prospects of translating this technique into clinical practice, providing a comprehensive review of the technological developments of CMCNPs in the treatment of bacterial infections. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Infectious Disease Therapeutic Approaches and Drug Discovery > Emerging Technologies Nanotechnology Approaches to Biology > Nanoscale Systems in Biology.