Bainandersson5082

Human sepsis is the result of a multifaceted pathological process causing marked dysregulation of cardiovascular responses. A more sophisticated understanding of the pathogenesis of sepsis is certainly prerequisite. Evidence from studies provide further insight into the role of inducible nitric oxide synthase (iNOS) isoform. Results on inhibition of iNOS in sepsis models remain inconclusive. Concern has been devoted to improving our knowledge and understanding of the role of iNOS. The aim of this review is to define the role of iNOS in redox homeostasis disturbance, the detailed mechanisms linking iNOS and posttranslational modifications (PTMs) to cardiovascular dysfunctions, and their future implications in sepsis settings. Many questions related to the iNOS and PTMs still remain open, and much more work is needed on this.Objectives To investigate the effect of glucagon-like peptide-1 (GLP-1) receptor and glucose dependent insulinotrophic polypeptide (GIP) receptor dual agonist DA-JC4 on alleviating Parkinson's disease (PD) and unveil related cellular mechanisms. Methods Rotenone was injected to generate a rat PD model, on which the effect of DA-JC4 on motor functions was evaluated by rotational behavioral assay and open field test. The survival of dopaminergic neurons was analyzed, in addition to assays for mitochondrial stress and quantification of neurotransmitter levels using high performance liquid chromatography (HPLC). In cultured hippocampal neurons, the effect of DA-JC4 on mitochondrial stress and related cellular mechanism was analyzed by Flow cytometry, western blotting and reactive oxygen species (ROS). Results DA-JC4 significantly improved motor functions in PD rats, and elevated levels of major neurotransmitters. By histological analysis, DA-JC4 protected dopaminergic neurons from rotenone-induced cell death, which was associated with reduced mitochondrial stress. Experiments in cultured rat hippocampal neurons validated the neuroprotective role of DA-JC4 against cell apoptosis and mitochondrial stress induced by rotenone. The protective effect of DA-JC4 was later found to be dependent on AKT/JNK signal pathway, as treatment using AKT inhibitor or JNK activator abolished such effects. Conclusion Our results showed that the dual agonist of GLP-1/GIP receptor could ameliorate motor dysfunctions of PD by protecting dopaminergic neurons which was mediated by relieved mitochondrial stress and apoptosis via AKT/JNK signal pathway.Activation of hepatic stellate cells (HSCs) is a central event in the pathogenesis of liver fibrosis and is characterized by the disappearance of lipid droplets. Although the exogenous supplementation of lipid droplet content can effectively reverse the activation of HSCs, the underlying molecular mechanisms are largely unknown. In our current study, we sought to investigate the role of lncRNA-H19 in the process of lipid droplets disappearance and to further examine the underlying molecular mechanisms. We found that the lncRNA-H19 level was increased in CCl4-induced fibrotic liver, which activated HSCs. Further research showed that hypoxia inducible factor-1α (HIF-1α) significantly increased lncRNA-H19 expression by binding to the lncRNA-H19 promoter at two hypoxia response element (HRE) sites located at 492-499 and 515-522 bp. Importantly, lncRNA-H19 knockdown markedly inhibited HSC activation and alleviated liver fibrosis, indicating that lncRNA-H19 may be a potential target for anti-fibrosis therapeutic approaches. Moreover, lncRNA-H19 knockdown could reverse the lipid droplet phenotype of activated HSCs, inhibiting the phosphorylated AMPKα-mediated lipid oxidation signaling pathway. The AMPK agonist AICAR promoted AMPKα phosphorylation and abrogated lipid droplets restoration in HSCs transfected with the lncRNA-H19 knockdown plasmid. Experimental molecular analysis showed that lncRNA-H19 triggered AMPKα to interact with LKB1 and resulted in AMPKα phosphorylation, which accelerating lipid droplets degradation and lipid oxidation. Taken together, our results highlighted the role of lncRNA-H19 in the metabolism of lipid droplets in HSCs, and revealed a new molecular target for alleviating liver fibrosis.The c-MYC is one of the most commonly discussed oncogenes in almost all cancers. c-MYC, as a proto-oncogene in normal cells, has found to be tightly controlled and regulated, both genetically and epigenetically. Evasion of the controlled checkpoint mechanisms during cancer causes a deregulated expression of c-MYC. Overexpression of c-MYC causes the onset of many hallmarks of cancer. Despite c-MYC being centrally located in several cancers, it is not feasible to target c-MYC in therapeutic resistant cancers. Similarly, long non-coding RNAs (lncRNAs) are deregulated during the genesis and progression of different cancers. LncRNAs contribute to almost 27% human genome and recent findings by tumor genome sequencing revealed many of the lncRNAs loci that are modified, deleted, amplified, and mutated during the different stages of cancer development. selleck Recent studies also reported that multiple lncRNAs regulate c-MYC by different mechanisms and vice versa. Thus, oncogenic lncRNAs and c-MYC interaction are positioned to provide an interesting choice for therapeutic interventions in cancers. In this mini-review, we summarize the recent discoveries and explain how the interaction between oncogenic lncRNAs and c-MYC could be used as a possible target for therapeutic intervention in cancers, especially the therapeutic resistant metastatic cancers.Background Nonalcoholic fatty liver disease (NAFLD), a major cause of chronic liver disease in the Western countries with increasing prevalence worldwide, may substantially affect chemical toxicokinetics and thereby modulate chemical toxicity. Objectives This study aims to use physiologically-based pharmacokinetic (PBPK) modeling to characterize the impact of NAFLD on toxicokinetics of perchloroethylene (perc). Methods Quantitative measures of physiological and biochemical changes associated with the presence of NAFLD induced by high-fat or methionine/choline-deficient diets in C57B1/6 J mice are incorporated into a previously developed PBPK model for perc and its oxidative and conjugative metabolites. Impacts on liver fat and volume, as well as bloodair and liverair partition coefficients, are incorporated into the model. Hierarchical Bayesian population analysis using Markov chain Monte Carlo simulation is conducted to characterize uncertainty, as well as disease-induced variability in toxicokinetics. Results NAFLD has a major effect on toxicokinetics of perc, with greater oxidative and lower conjugative metabolism as compared to healthy mice.