- Neurological melioidosis (Burkholderia pseudomallei) in a chronic psychotic patient treated with antipsychotics: A case report. [Case Reports]
- MMedicine (Baltimore) 2018; 97(24):e11110
- CONCLUSIONS: Because melioidosis is endemic in Southern Taiwan and the use of antipsychotics might mask the symptoms, physicians dealing with patients from endemic areas with a medical history of antipsychotics should always consider the possibility of neurological melioidosis and provide prompt empirical management to suspicious cases.
- Identifying key genes, pathways and screening therapeutic agents for manganese-induced Alzheimer disease using bioinformatics analysis. [Journal Article]
- MMedicine (Baltimore) 2018; 97(22):e10775
- Alzheimer disease (AD) is a progressive neurodegenerative disease, the etiology of which remains largely unknown. Accumulating evidence indicates that elevated manganese (Mn) in brain exerts toxic ef...
Alzheimer disease (AD) is a progressive neurodegenerative disease, the etiology of which remains largely unknown. Accumulating evidence indicates that elevated manganese (Mn) in brain exerts toxic effects on neurons and contributes to AD development. Thus, we aimed to explore the gene and pathway variations through analysis of high through-put data in this process.To screen the differentially expressed genes (DEGs) that may play critical roles in Mn-induced AD, public microarray data regarding Mn-treated neurocytes versus controls (GSE70845), and AD versus controls (GSE48350), were downloaded and the DEGs were screened out, respectively. The intersection of the DEGs of each datasets was obtained by using Venn analysis. Then, gene ontology (GO) function analysis and KEGG pathway analysis were carried out. For screening hub genes, protein-protein interaction network was constructed. At last, DEGs were analyzed in Connectivity Map (CMAP) for identification of small molecules that overcome Mn-induced neurotoxicity or AD development.The intersection of the DEGs obtained 140 upregulated and 267 downregulated genes. The top 5 items of biological processes of GO analysis were taxis, chemotaxis, cell-cell signaling, regulation of cellular physiological process, and response to wounding. The top 5 items of KEGG pathway analysis were cytokine-cytokine receptor interaction, apoptosis, oxidative phosphorylation, Toll-like receptor signaling pathway, and insulin signaling pathway. Afterwards, several hub genes such as INSR, VEGFA, PRKACB, DLG4, and BCL2 that might play key roles in Mn-induced AD were further screened out. Interestingly, tyrphostin AG-825, an inhibitor of tyrosine phosphorylation, was predicted to be a potential agent for overcoming Mn-induced neurotoxicity or AD development.The present study provided a novel insight into the molecular mechanisms of Mn-induced neurotoxicity or AD development and screened out several small molecular candidates that might be critical for Mn neurotoxicity prevention and Mn-induced AD treatment.
- Peroxisome proliferator-activated receptor alpha-mediated drug toxicity in the liver. [Journal Article]
- EOExpert Opin Drug Metab Toxicol 2018 Jun 07; :1-7
- Drug-induced hepatic injury is the most common cause of acute liver failure in the United States. Peroxisome proliferator-activated receptor alpha (PPARα)-mediated drugs are included among the approx...
Drug-induced hepatic injury is the most common cause of acute liver failure in the United States. Peroxisome proliferator-activated receptor alpha (PPARα)-mediated drugs are included among the approximately 900 natural and synthetic substances, which have shown hepatotoxicity. Areas covered: This review will focus on fibrates - PPARα agonists and their implication in causing liver injury. Expert opinion: Compelling evidence for fibrate-induced hepatotoxicity is not available. Results have been varying because several large randomized clinical trials have reported similar elevations of plasma transaminase levels in fibrate or placebo treated groups. On the other hand, one meta-analysis has reported an increased risk of hepatotoxicity when fibrates are combined with statins. Fibrate induced clinically apparent liver damage has been demonstrated in case reports. However, there is a wide spectrum of clinical phenotypic presentations of these cases (onset of injury, pattern of enzyme elevation and resolution of the symptoms), which reduces the ability to identify specific cause and effect of any putative fibrate-induced hepatotoxicity. Thus, the current recommendations for using fibrates include monitoring of aminotransferase levels especially if combined with statins and discontinuation of the treatment only if the levels persist above three times the upper limit of normal.
- In vitro PPARγ agonistic potential of chitin synthesis inhibitors and their energy metabolism-related hepatotoxicity. [Journal Article]
- STSci Total Environ 2018 Feb 15; 615:1126-1132
- The extensive use of chitin synthesis inhibitors (CSIs) in integrated pest management programs has a detrimental effect on the surrounding environment. Recent studies reveal that CSIs may affect non-...
The extensive use of chitin synthesis inhibitors (CSIs) in integrated pest management programs has a detrimental effect on the surrounding environment. Recent studies reveal that CSIs may affect non-target organisms at sublethal concentrations, highlighting the need for further ecological and health risk investigations of these compounds. In this study, we characterized the peroxisome proliferator-activated receptor γ (PPARγ) agonistic activity of fourteen CSIs in HepG2 cells using an in vitro reporter gene assay. Five of the tested CSIs showed remarkable PPARγ-mediated transactivation, and the relative agonistic potencies were diflubenzuron>chlorfluazuron>flucycloxuron>noviflumuron>flufenoxuron based on REC20 values. In addition, molecular docking indicated that different interactions may stabilize ligand binding to PPARγ. Next, we clarified that sublethal concentration of diflubenzuron caused a shift in cellular energy metabolism from the aerobic tricarboxylic acid (TCA) cycle to anaerobic glycolysis and this process was associated with the activation of PPARγ. These findings suggest that CSIs act as PPARγ agonists and exert diverse hepatotoxic effects by disrupting energy metabolism at sublethal concentrations.
- Amelioration of CCl4 induced liver injury in swiss albino mice by antioxidant rich leaf extract of Croton bonplandianus Baill. [Journal Article]
- PlosPLoS One 2018; 13(4):e0196411
- The progress in industrialization has blessed mankind with a technologically superior lifestyle but poor management of industrial waste has in turn poisoned nature. One such chemical is carbon tetra ...
The progress in industrialization has blessed mankind with a technologically superior lifestyle but poor management of industrial waste has in turn poisoned nature. One such chemical is carbon tetra chloride (CCl4), which is a potent environmental toxin emitted from chemical industries and its presence in the atmosphere is increasing at an alarming rate. Presence of CCl4 in human body is reported to cause liver damage through free radical mediated inflammatory processes. Kupffer cells present in the liver are potentially more sensitive to oxidative stress than hepatocytes. Kuffer cells produced tumor necrosis factor-α (TNF-α) in response to reactive oxygen species (ROS), that might further cause inflammation or apoptosis. In this study hepatoprotective capacity of antioxidant rich extract of Croton bonplandianus Baill. (CBL) was evaluated on CCl4 induced acute hepatotoxicity in murine model. Hydro-methanolic extract of C. bonplandianus leaf was used for evaluation of free radical scavenging activity. Liver cells of experimental mice were damaged using CCl4 and subsequently hepatoprotective potential of the plant extract was evaluated using series of in-vivo and in-vitro studies. In the hepatoprotective study, silymarin was used as a positive control. Antioxidant enzymes, pro-inflammatory markers, liver enzymatic and biochemical parameters were studied to evaluate hepatoprotective activity of Croton bonplandianus leaf extract. Free radical scavenging activity of CBL extract was also observed in WRL-68 cell line. The phytochemicals identified by GCMS analysis were scrutinized using in-silico molecular docking procedure. The results showed that CBL extract have potent free radical scavenging capacity. The biochemical parameters were over expressed due to CCl4 administration, which were significantly normalized by CBL extract treatment. This finding was also supported by histopathological evidences showing less hepatocellularnecrosis, inflammation and fibrosis in CBL and silymarin treated group, compared to CCl4 group. ROS generated due to H2O2 in WRL-68 cell line were normalize in the highest group (200 μg/ml) when compared with control and negative control (CCl4) group. After molecular docking analysis, it was observed that the compound α-amyrin present in the leaf extract of C. bonplandianus has better potentiality to protect hepatocellular damages than the standard drug Silymarin. The present study provided supportive evidence that CBL extract possesses potent hepatoprotective capacity by ameliorating haloalkane induced liver injury in the murine model. The antioxidant and anti-inflammatory activities also affirm the same. The synergistic effects of the phytochemicals present in CBL are to be credited for all the hepatoprotective activity claimed above.
- Unexpected metabolic disorders induced by endocrine disruptors in Xenopus tropicalis provide new lead for understanding amphibian decline. [Journal Article]
- PNProc Natl Acad Sci U S A 2018 05 08; 115(19):E4416-E4425
- Despite numerous studies suggesting that amphibians are highly sensitive to endocrine disruptors (EDs), both their role in the decline of populations and the underlying mechanisms remain unclear. Thi...
Despite numerous studies suggesting that amphibians are highly sensitive to endocrine disruptors (EDs), both their role in the decline of populations and the underlying mechanisms remain unclear. This study showed that frogs exposed throughout their life cycle to ED concentrations low enough to be considered safe for drinking water, developed a prediabetes phenotype and, more commonly, a metabolic syndrome. Female Xenopus tropicalis exposed from tadpole stage to benzo(a)pyrene or triclosan at concentrations of 50 ng⋅L-1 displayed glucose intolerance syndrome, liver steatosis, liver mitochondrial dysfunction, liver transcriptomic signature, and pancreatic insulin hypersecretion, all typical of a prediabetes state. This metabolic syndrome led to progeny whose metamorphosis was delayed and occurred while the individuals were both smaller and lighter, all factors that have been linked to reduced adult recruitment and likelihood of reproduction. We found that F1 animals did indeed have reduced reproductive success, demonstrating a lower fitness in ED-exposed Xenopus Moreover, after 1 year of depuration, Xenopus that had been exposed to benzo(a)pyrene still displayed hepatic disorders and a marked insulin secretory defect resulting in glucose intolerance. Our results demonstrate that amphibians are highly sensitive to EDs at concentrations well below the thresholds reported to induce stress in other vertebrates. This study introduces EDs as a possible key contributing factor to amphibian population decline through metabolism disruption. Overall, our results show that EDs cause metabolic disorders, which is in agreement with epidemiological studies suggesting that environmental EDs might be one of the principal causes of metabolic disease in humans.
- Thrombin generation test: A reliable tool to evaluate the pharmacodynamics of vitamin K antagonist rodenticides in rats. [Journal Article]
- PBPestic Biochem Physiol 2018; 146:19-24
- Vitamin K antagonist rodenticide pharmacodynamics (PD) is studied in rodents with traditional laboratory tests. We wondered if thrombin generation test (TGT) could add value. Difethialone (10 mg/kg) ...
Vitamin K antagonist rodenticide pharmacodynamics (PD) is studied in rodents with traditional laboratory tests. We wondered if thrombin generation test (TGT) could add value. Difethialone (10 mg/kg) was administered per os to 97 OFA-Sprague Dawley rats. PD was studied over a 72 h-period using the Calibrated Automated Thrombogram on platelet poor plasma before and after intoxication (3 female and 3 male rats for each 13 time points) and TGT parameters were compared with the prothrombin time (PT) and vitamin K dependent factor activities previously reported. Following intoxication, preliminary tests evidenced rapid and full inhibition of thrombin generation triggered with 5 or 20 pM human recombinant tissue factor. To study the evolution of TGT parameters following difethialone intake, we adapted the test by complementing intoxicated rat samples with pooled normal rat plasma (3/1, v/v). Adapted TGT confirmed the known higher procoagulant basal level in females compared to males through higher endogenous thrombin potential (ETP) and peak height (PH) (p < 0.0001 and p = 0.0003, respectively). An exponential model fitted well the PH and ETP decay after intoxication. In contrast to PT, the decreases were observed immediately following VKA intake and had comparable time to halving values: 10.5 h (95% CI [8.2; 13.6]) for ETP and 10.4 h (95% CI [7.8; 14.1]) for PH. The decrease of FVII and FX preceded that of PH, ETP and FII while FIX decreased later on, contributing to the severe hypo-coagulability. We demonstrated that TGT performed in samples of intoxicated rats complemented with normal plasma is a reliable tool for evaluation of VKA rodenticide PD in rats.
- Zafirlukast and vincamine ameliorate tamoxifen-induced oxidative stress and inflammation: Role of the JNK/ERK pathway. [Journal Article]
- LSLife Sci 2018 Jun 01; 202:78-88
- CONCLUSIONS: Zafirlukast and vincamine may be regarded as potential therapeutic strategies with antioxidant and anti-inflammatory activities against tamoxifen-induced oxidative damage in rat liver.
- New therapeutic approaches and novel alternatives for organophosphate toxicity. [Journal Article]
- TLToxicol Lett 2018; 291:1-10
- Organophosphate compounds (OPCs) are commonly used as pesticides and were developed as nerve agents for chemical warfare. Exposure to OPCs results in toxicity due to their covalent binding and inhibi...
Organophosphate compounds (OPCs) are commonly used as pesticides and were developed as nerve agents for chemical warfare. Exposure to OPCs results in toxicity due to their covalent binding and inhibition of acetylcholinesterase (AChE). Treatment for toxicity due to OPC exposure has been largely focused on the reactivation of AChE by oxime-based compounds via direct nucleophilic attack on the phosphorous center. However, due to the disadvantages to existing oxime-based reactivators for treatment of OPC poisoning, we considered non-oxime mechanisms of reactivation. A high throughput screen of compound libraries was performed to discover previously unidentified reactivation compounds, followed by studies on their analogs. In the process, we discovered multiple non-oxime classes of compounds, the most robust of which we have already reported . Herein, we report other classes of compounds we identified in our screen that are efficient at reactivation. During biochemical characterization, we also found some compounds with other activities that may inspire novel therapeutic approaches to OPC toxicity. Specifically, we found compounds that  increase the rate of substrate hydrolysis by AChE and,  protect the enzyme from inhibition by OPC. Further, we discovered that a subset of reactivator compounds recover activity from both AChE and the related enzyme butyrylcholinesterase (BuChE). We now report these compounds, their activities and discuss how each relates to therapeutic approaches that would provide alternatives to traditional oxime-based reactivation.
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- Mechanism of bisphenol AF-induced progesterone inhibition in human chorionic gonadotrophin-stimulated mouse Leydig tumor cell line (mLTC-1) cells. [Journal Article]
- ETEnviron Toxicol 2018; 33(6):670-678
- Bisphenol AF (BPAF) has been shown to inhibit testicular steroidogenesis in male rats. However, the precise mechanisms related to the toxic effects of BPAF on reproduction remain poorly understood. I...
Bisphenol AF (BPAF) has been shown to inhibit testicular steroidogenesis in male rats. However, the precise mechanisms related to the toxic effects of BPAF on reproduction remain poorly understood. In the present study, a mouse Leydig tumor cell line (mLTC-1) was used as a model to investigate the mechanism of steroidogenic inhibition and to identify the molecular target of BPAF. Levels of progesterone and the concentration of cyclic adenosine monophosphate (cAMP) in cells exposed to BPAF were detected, and expression of key genes and proteins in steroid biosynthesis was assessed. The results showed that BPAF exposure decreased human chorionic gonadotrophin (hCG)-stimulated progesterone production in a dose-dependent manner. The 24-h IC50 (half maximal inhibitory concentration) value for BPAF regarding progesterone production was 70.2 µM. A dramatic decrease in cellular cAMP concentration was also observed. Furthermore, BPAF exposure inhibited expression of genes and proteins involved in cholesterol transport and progesterone biosynthesis. Conversely, the protein levels of steroidogenic acute regulatory protein (StAR) were not altered, and those of progesterone were still decreased upon 22R-hydroxycholesterol treatment of cells exposed to higher doses of BPAF. Together, these data indicate that BPAF exposure inhibits progesterone secretion in hCG-stimulated mLTC-1 cells by reducing expression of scavenger receptor class B type I (SR-B1) and cytochrome P450 (P450scc) due to the adverse effects of cAMP. However, StAR might not be the molecular target in this process.