Caveolin-1-ACE2 axis modulates xenobiotic metabolism-linked chemoresistance in ovarian clear cell carcinoma.

Among epithelial ovarian cancers, ovarian clear cell carcinoma (OCCC) remains markedly resistant to platinum-based chemotherapy, leading to poor clinical outcomes. In response to xenobiotic insults, caveolar platforms play crucial roles in modulating stress signaling responses in cancer cells. It has been hypothesized that caveolin-1 (Cav-1), a main component of the lipid raft, may regulate the response to platinum-based treatment in OCCC. The clinical transcriptomic evaluation demonstrated that high Cav-1 expression was positively associated with a favorable prognosis in patients with ovarian cancer. Cav-1 overexpression enhanced sensitivity to cisplatin (CDDP) treatment, whereas Cav-1 deficiency promoted chemoresistance in OCCC cells. Mechanistically, although Cav-1 counteracted angiotensin-converting enzyme 2 (ACE2) expression, ACE2 positively facilitated resistance to CDDP in OCCC cells. Furthermore, ACE2 restricted aryl hydrocarbon receptor expression and subsequent transcription of drug-metabolizing enzymes. Of note, ACE2 positively regulated the expression of the platinum-clearing enzyme CYP3A4. These findings suggest that the Cav-1-ACE2 axis modulates xenobiotic metabolism-linked chemoresistance in OCCC, predicting potential roles for the stress sentinel networks in oncogenic processes.

VARIDT 2.0: structural variability of drug transporter.

The structural variability data of drug transporter (DT) are key for research on precision medicine and rational drug use. However, these valuable data are not sufficiently covered by the available databases. In this study, a major update of VARIDT (a database previously constructed to provide DTs' variability data) was thus described. First, the experimentally resolved structures of all DTs reported in the original VARIDT were discovered from PubMed and Protein Data Bank. Second, the structural variability data of each DT were collected by literature review, which included: (a) mutation-induced spatial variations in folded state, (b) difference among DT structures of human and model organisms, (c) outward/inward-facing DT conformations and (d) xenobiotics-driven alterations in the 3D complexes. Third, for those DTs without experimentally resolved structural variabilities, homology modeling was further applied as well-established protocol to enrich such valuable data. As a result, 145 mutation-induced spatial variations of 42 DTs, 1622 inter-species structures originating from 292 DTs, 118 outward/inward-facing conformations belonging to 59 DTs, and 822 xenobiotics-regulated structures in complex with 57 DTs were updated to VARIDT (https://idrblab.org/varidt/ and http://varidt.idrblab.net/). All in all, the newly collected structural variabilities will be indispensable for explaining drug sensitivity/selectivity, bridging preclinical research with clinical trial, revealing the mechanism underlying drug-drug interaction, and so on.

Comparative Studies on the Hepatoprotective Effect of White and Coloured Rice Bran Oil against Acetaminophen-Induced Oxidative Stress in Mice through Antioxidant- and Xenobiotic-Metabolizing Systems.

Rice bran oil (RBO) comprises various nutrients and phytochemicals which exhibit several health benefits. There are no studies regarding the functional effects of different colours of RBO. This study was aimed to compare the constituents and antioxidant activities of white rice bran oil (WRBO) and coloured rice bran oil (CRBO). Each RBO showed similar free fatty acid profiles. However, greater amounts of vitamin E, phytosterols, carotenoids, and chlorophylls were found in CRBO, which had lower γ-oryzanol content than WRBO. Oxidative stress was induced in male mice by an overdose of acetaminophen (APAP) at 300 mg/kg body weight. The mice were then fed with RBO at the equivalent dose to 100 mg/kg body weight of γ-oryzanol three hours later and sacrificed six hours after APAP treatment. The administration of 100 mg γ-oryzanol equivalent in CRBO ameliorated APAP-induced hepatotoxicity in mice more strongly than 100 mg γ-oryzanol equivalent in WRBO, as evidenced by the significant reduction of serum ALT, hepatocellular necrosis, and hepatic lipid peroxidation. CRBO could improve xenobiotic-metabolizing and antioxidant enzyme activities, including glutathione S-transferase, superoxide dismutase, glutathione peroxidase, and glutathione reductase, and also increase mRNA expression of various antioxidant-responsive genes. Vitamin E, phytosterols, carotenoids, and chlorophyll might be the protective compounds in CRBO that alleviate APAP-induced hepatotoxicity through the interruption of APAP metabolism and the activation of antioxidant systems at both transcriptional and enzymatic levels. These findings might provide a protective role of CRBO on oxidative stress associated with several degenerative diseases.

Association of xenobiotic-metabolizing enzymes (GSTM1 and GSTT 1), and pro-inflammatory cytokines (TNF-α and IL-6) genetic polymorphisms with non-alcoholic fatty liver disease.

Previous studies have revealed that genetic polymorphisms of the Glutathione S-transferase M1 and T1 (GSTM1 and GSTT1), tumor necrosis factor-α (TNF-α), and interleukin 6 (IL-6) are associated with the presence of non-alcoholic fatty liver disease (NAFLD) in many populations. This study was conducted to investigate the association of the GSTM1, GSTT1, TNF-α rs1800629, and IL-6 rs1800795 with NAFLD in the general Iranian population. A case-control analysis included 242 NAFLD patients and 324 healthy controls from Iranian adults. After the physical examination, the genotypes were determined by polymerase chain reaction(PCR). The GSTM1 null, GSTT1 null, TNF-α AG/AA, and IL-6 CG/CC genotypes were deemed to be high-risk. The null allele of GSTM1 and A allele of TNF-α were more frequent in NAFLD patients even after Bonferroni's correction (P values<0.005, adjusted odds ratio (OR), 1.66 and 2.02; 95% confidence intervals (CI), (1.18-2.32) and (1.34-3.34), respectively. The IL-6 CC/CG genotype association with NAFLD was not significant after correction (P value = 0.04) Polymorphisms of xenobiotic and pro-inflammatory genes are associated with NAFLD in the Iranian population and seem to be a useful tool for NAFLD prevention and care.

Mitochondrial Dysfunction as a Hallmark of Environmental Injury.

Environmental factors including diet, sedentary lifestyle and exposure to pollutants largely influence human health throughout life. Cellular and molecular events triggered by an exposure to environmental pollutants are extremely variable and depend on the age, the chronicity and the doses of exposure. Only a fraction of all relevant mechanisms involved in the onset and progression of pathologies in response to toxicants has probably been identified. Mitochondria are central hubs of metabolic and cell signaling responsible for a large variety of biochemical processes, including oxidative stress, metabolite production, energy transduction, hormone synthesis, and apoptosis. Growing evidence highlights mitochondrial dysfunction as a major hallmark of environmental insults. Here, we present mitochondria as crucial organelles for healthy metabolic homeostasis and whose dysfunction induces critical adverse effects. Then, we review the multiple mechanisms of action of pollutants causing mitochondrial toxicity in link with chronic diseases. We propose the Aryl hydrocarbon Receptor (AhR) as a model of "exposome receptor", whose activation by environmental pollutants leads to various toxic events through mitochondrial dysfunction. Finally, we provide some remarks related to mitotoxicity and risk assessment.

Nonexperimental Xenobiotics: Unintended Consequences of Intentionally Administered Substances in Terrestrial Animal Models.

Review of the use of nonexperimental xenobiotics in terrestrial animal models and the potential unintended consequences of these compounds, including drug-related side effects and adverse reactions.

Genetic variations of the xenoreceptors NR1I2 and NR1I3 and their effect on drug disposition and response variability.

NR1I2 (PXR) and NR1I3 (CAR) are nuclear receptors that are classified as xenoreceptors. Upon activation by various xenobiotics, including marketed drugs, they regulate the transcription level of major drug-metabolizing enzymes and transporters and facilitate the elimination of xenobiotics from the body. The modulation of the activity of these two xenoreceptors by various ligands is a major source of pharmacokinetic variability of environmental origin. NR1I2 and NR1I3 genetic polymorphisms can affect the pharmacokinetics and therapeutic response to many drugs, such as irinotecan, tacrolimus and atazanavir. This review provides an overview of NR1I2 and NR1I3 pharmacogenetic studies in various therapeutic fields (oncology, immunomodulation and infectiology) and discusses the implementation of NR1I2 and NR1I3 genetic polymorphism testing in the clinical routine.

Pharmacoepigenetics and Toxicoepigenetics: Novel Mechanistic Insights and Therapeutic Opportunities.

Pharmacological treatment and exposure to xenobiotics can cause substantial changes in epigenetic signatures. The majority of these epigenetic changes, caused by the compounds in question, occur downstream of transcriptional activation mechanisms, whereby the epigenetic alterations can create a transcriptional memory and stably modulate cell function. The increasing understanding of epigenetic mechanisms and their importance in disease has prompted the development of therapeutic interventions that target epigenetic modulatory mechanisms, particularly in oncology where inhibitors of epigenetic-modifying proteins (epidrugs) have been successfully used in treatment, mostly in combination with standard-of-care chemotherapy, either provoking direct cytotoxicity or inhibiting resistance to anticancer drugs. In addition, emerging methods for detecting epigenetically modified DNA in bodily fluids may provide information about tumor phenotype or drug treatment success. However, it is important to note that many technical pitfalls, such as the nondeconvolution of methylcytosine and hydroxymethylcytosine, compromise epigenetic analyses and the interpretation of results. In this review, we provide an update on the field, with an emphasis on the novel therapeutic opportunities made possible by epidrugs.

The Intricate Link among Gut "Immunological Niche," Microbiota, and Xenobiotics in Intestinal Pathology.

Inflammatory bowel diseases (IBDs) are diseases characterized by various degrees of inflammation involving the gastrointestinal tract. Ulcerative colitis and Crohn's disease are characterized by a dysregulated immune response leading to structural gut alterations in genetically predisposed individuals. Diverticular disease is characterized by abnormal immune response to normal gut microbiota. IBDs are linked to a lack of physiological tolerance of the mucosal immune system to resident gut microbiota and pathogens. The disruption of immune tolerance involves inflammatory pathways characterized by an unbalance between the anti-inflammatory regulatory T cells and the proinflammatory Th1/Th17 cells. The interaction among T cell subpopulations and their related cytokines, mediators of inflammation, gut microbiota, and the intestinal mucosa constitute the gut "immunological niche." Several evidences have shown that xenobiotics, such as rifaximin, can positively modulate the inflammatory pathways at the site of gut immunological niche, acting as anti-inflammatory agents. Xenobiotics may interfere with components of the immunological niche, leading to activation of anti-inflammatory pathways and inhibition of several mediators of inflammation. In summary, xenobiotics may reduce disease-related gut mucosal alterations and clinical symptoms. Studying the complex interplay between gut immunological niche and xenobiotics will certainly open new horizons in the knowledge and therapy of intestinal pathologies.

Natural diversity facilitates the discovery of conserved chemotherapeutic response mechanisms.

Organismal fitness depends on adaptation to complex niches where chemical compounds and pathogens are omnipresent. These stresses can lead to the fixation of alleles in both xenobiotic responses and proliferative signaling pathways that promote survival in these niches. However, both xenobiotic responses and proliferative pathways vary within and among species. For example, genetic differences can accumulate within populations because xenobiotic exposures are not constant and selection is variable. Additionally, neutral genetic variation can accumulate in conserved proliferative pathway genes because these systems are robust to genetic perturbations given their essential roles in normal cell-fate specification. For these reasons, sensitizing mutations or chemical perturbations can disrupt pathways and reveal cryptic variation. With this fundamental view of how organisms respond to cytotoxic compounds and cryptic variation in conserved signaling pathways, it is not surprising that human patients have highly variable responses to chemotherapeutic compounds. These different responses result in the low FDA-approval rates for chemotherapeutics and underscore the need for new approaches to understand these diseases and therapeutic interventions. Model organisms, especially the classic invertebrate systems of Caenorhabditis elegans and Drosophila melanogaster, can be used to combine studies of natural variation across populations with responses to both xenobiotic compounds and chemotherapeutics targeted to conserved proliferative signaling pathways.

Tumoral expression of drug and xenobiotic metabolizing enzymes in breast cancer patients of different ethnicities with implications to personalized medicine.

Drug and xenobiotic metabolizing enzymes (DXME) play important roles in drug responses and carcinogenesis. Recent studies have found that expression of DXME in cancer cells significantly affects drug clearance and the onset of drug resistance. In this study we compared the expression of DXME in breast tumor tissue samples from patients representing three ethnic groups: Caucasian Americans (CA), African Americans (AA), and Asian Americans (AS). We further combined DXME gene expression data with eQTL data from the GTEx project and with allele frequency data from the 1000 Genomes project to identify SNPs that may be associated with differential expression of DXME genes. We identified substantial differences among CA, AA, and AS populations in the expression of DXME genes and in activation of pathways involved in drug metabolism, including those involved in metabolizing chemotherapy drugs that are commonly used in the treatment of breast cancer. These data suggest that differential expression of DXME may associate with health disparities in breast cancer outcomes observed among these three ethnic groups. Our study suggests that development of personalized treatment strategies for breast cancer patients could be improved by considering both germline genotypes and tumor specific mutations and expression profiles related to DXME genes.

Inhibition and inactivation of human CYP2J2: Implications in cardiac pathophysiology and opportunities in cancer therapy.

Extrahepatic cytochrome P450 enzymes (CYP450) are pivotal in the metabolism of endogenous substrates and xenobiotics. CYP2J2 is a major cardiac CYP450 and primarily metabolizes polyunsaturated fatty acids such as arachidonic acid to cardioactive epoxyeicosatrienoic acids. Due to its role in endobiotic metabolism, CYP2J2 has been actively studied in recent years with the focus on its biological functions in cardiac pathophysiology. Additionally, CYP2J2 metabolizes a number of xenobiotics such as astemizole and terfenadine and is potently inhibited by danazol and telmisartan. Notably, CYP2J2 is found to be upregulated in multiple cancers. Hence a number of specific CYP2J2 inhibitors have been developed and their efficacy in inhibiting tumor progression has been actively studied. CYP2J2 inhibitor such as C26 (1-[4-(vinyl)phenyl]-4-[4-(diphenyl-hydroxymethyl)-piperidinyl]-butanone hydrochloride) caused marked reduction in tumor proliferation and migration as well as promoted apoptosis in cancer cells. In this review, we discuss the role of CYP2J2 in cardiac pathophysiology and cancer therapeutics. Additionally, we provide an update on the substrates, reversible inhibitors and irreversible inhibitors of CYP2J2. Finally, we discuss the current gaps and future directions in CYP2J2 research.

Regulations of Xenobiotics and Endobiotics on Carboxylesterases: A Comprehensive Review.

Carboxylesterases (CESs) play major roles in catalyzing the hydrolysis of a wide range of ester- and amide-containing compounds. CESs dominate both the biotransformation of numerous therapeutic drugs and the detoxification of environmental toxicants, and the activity alteration of CESs may be a determinant reason for modification of the resultant pharmacokinetic/pharmacodynamic profile when two or more drugs are concurrently used. Herein, we provide a comprehensive review of the current literature involving of induction and inhibition on CESs by both exogenous and endogenous compounds. In particular, the inhibition constant and inhibition pattern of inhibitors on CESs in studies using animal microsomes or human recombinant CESs are summarized. Further studies are needed to clarify the underlying regulation mechanism, and alterations in CESs activity should be taken into consideration for safe clinical therapy.

Recent prospective of surface engineered Nanoparticles in the management of Neurodegenerative disorders.

Clinically, the therapeutic outcomes in neurodegenerative disorders (NDs) by drug treatment are very limited, and the most insurmountable obstacle in the treatment of NDs is the blood-brain barrier (BBB), which provides the highest level of protection from xenobiotics. A great deal of attention still needs to be paid to overcome these barriers, and surface-engineered polymeric nanoparticles are emerging as innovative tools that are able to interact with the biological system at a molecular level for the desired response. The present review covers the potential importance of surface-structure-engineered nanoparticles to overcome the BBB for good bioavailability, and the evaluation of drug therapy in NDs.

Xenobiotic and non-xenobiotic interventions in the microbiome therapeutics.

It is now very much clear that the microbiome plays an important part in human health. Microbiome is associated with several diseases and targeting the whole microbiome is certainly a challenge before the scientists. The "Human Microbiome Project" is continually exploring certain therapeutic targets inside microbiome landscape that could be utilized for the treatment of microbiome associated diseases. Additionally, associated research across the globe is going on and now some potential targets are available that might be beneficial for the designing and synthesis of novel drugs. In this review, we made an effort to discuss all the potential targets and corresponding possible drugs/treatments available for each of them. However, it is not possible to treat all microbiome associated diseases with a single drug/drug combination. Therefore, for different diseases, different treatments/drugs (whether xenobiotic or non-xenobiotic) could be used for better therapeutic efficacy.

Targeting the Toll of Drug Abuse: The Translational Potential of Toll-Like Receptor 4.

There is growing recognition that glial proinflammatory activation importantly contributes to the rewarding and reinforcing effects of a variety of drugs of abuse, including cocaine, methamphetamine, opioids, and alcohol. It has recently been proposed that glia are recognizing, and becoming activated by, such drugs as a CNS immunological response to these agents being xenobiotics; that is, substances foreign to the brain. Activation of glia, primarily microglia, by various drugs of abuse occurs via toll like receptor 4 (TLR4). The detection of such xenobiotics by TLR4 results in the release of glial neuroexcitatory and neurotoxic substances. These glial products of TLR4 activation enhance neuronal excitability within brain reward circuitry, thereby enhancing their rewarding and reinforcing effects. Indeed, selective pharmacological blockade of TLR4 activation, such as with the non-opioid TLR4 antagonist (+)-naltrexone, suppresses a number of indices of drug reward/reinforcement. These include: conditioned place preference, self-administration, drugprimed reinstatement, incubation of craving, and elevations of nucleus accumbens shell dopamine. Notably, TLR4 blockade fails to alter self-administration of food, indicative of a selective effect on drugs of abuse. Genetic disruption of TLR4 signaling recapitulates the effects of pharmacological TLR4 blockade, providing converging lines of evidence of a central importance of TLR4. Taken together, multiple lines of evidence converge to raise TLR4 as a promising therapeutic target for drug abuse.

Dose-dependent functionality and toxicity of green tea polyphenols in experimental rodents.

A large number of physiologically functional foods are comprised of plant polyphenols. Their antioxidative activities have been intensively studied for a long period and proposed to be one of the major mechanisms of action accounting for their health promotional and disease preventive effects. Green tea polyphenols (GTPs) are considered to possess marked anti-oxidative properties and versatile beneficial functions, including anti-inflammation and cancer prevention. On the other hand, some investigators, including us, have uncovered their toxicity at high doses presumably due to pro-oxidative properties. For instance, both experimental animal studies and epidemiological surveys have demonstrated that GTPs may cause hepatotoxicity. We also recently showed that diets containing high doses (0.5-1%) of a GTP deteriorated dextran sodium sulfate (DSS)-induced intestinal inflammation and carcinogenesis. In addition, colitis mode mice fed a 1% GTP exhibited symptoms of nephrotoxicity, as indicated by marked elevation of serum creatinine level. This diet also increased thiobarbituric acid-reactive substances, a reliable marker of oxidative damage, in both kidneys and livers even in normal mice, while the expression levels of antioxidant enzymes and heat shock proteins (HSPs) were diminished in colitis and normal mice. Intriguingly, GTPs at 0.01% and 0.1% showed hepato-protective activities, i.e., they significantly suppressed DSS-increased serum aspartate aminotransferase and alanine aminotransferase levels. Moreover, those diets remarkably restored DSS-down-regulated expressions of heme oxygenase-1 and HSP70 in livers and kidneys. Taken together, while low and medium doses of GTPs are beneficial in colitis model mice, unwanted side-effects occasionally emerge with high doses. This dose-dependent functionality and toxicity of GTPs are in accordance with the concept of hormesis, in which mild, but not severe, stress activates defense systems for adaptation and survival.