Upregulated SOCC and IP3R calcium channels and subsequent elevated cytoplasmic calcium signaling promote nonalcoholic fatty liver disease by inhibiting autophagy.

Nonalcoholic fatty liver disease (NAFLD) is related to elevated cytoplasmic calcium signaling in hepatocytes, which may be mediated by store-operated calcium channel (SOCC) and inositol triphosphate receptor (IP3R). However, the regulatory effect of calcium signaling on lipid accumulation and degeneration in hepatocytes and the underlying molecular mechanism remain unknown. Autophagy inhibition promotes lipid accumulation and steatosis in hepatocytes. However, the association between elevated calcium signaling and autophagy inhibition in hepatocytes and its effect on hepatocyte fatty lesions remain unclear. Here, we established a mouse hepatocyte fatty gradient model using oleic acid. SOCC and IP3R channel opening and cytoplasmic calcium levels gradually increased with the hepatocyte pimelosis degree, whereas autophagy gradually decreased. We also established an optimal oleic acid (OOA) hepatocyte model, observing significantly increased SOCC and IP3R channel opening and calcium influx alongside significantly decreased autophagy and aggravated cellular fatty lesion. Calcium channel blockers (CCBs) and calcium channel gene silencing reagents (CCGSRs), respectively, reversed these effects, indicating that elevated cytoplasmic calcium signaling promotes NAFLD occurrence and the development by inhibiting hepatocyte autophagy. In the OOA model, upregulated extracellular regulated protein kinases 1/2 (ERK1/2), which can be regulated by SOCC and IP3R proteins transient receptor potential canonical 1 (TRPC1)/IP3R with elevated cytoplasmic calcium signaling, over-inhibited forkhead/winged helix O (FOXO) signaling and over-activated mammalian target of rapamycin complex 1 (mTORC1) signaling. Over-inhibited FOXO signaling significantly downregulated autophagy-related gene 12, which inhibits autophagosome maturation, while over-activated mTORC1 signaling over-inactivated Unc-51 like autophagy activating kinase 1, which inhibits preautophagosome formation. CCBs and CCGSRs recovered autophagy by significantly downregulating ERK1/2 to block abnormal changes in FOXO and mTORC1 signaling. Our findings indicate that upregulated SOCC and IP3R channels and subsequent elevated cytoplasmic calcium signaling in hepatocyte fatty lesions inhibits hepatocyte autophagy through (TRPC1/IP3R)/ERK/(FOXO/mTORC1) signaling pathways, causes lipid accumulation and degeneration in hepatocytes, and promotes NAFLD occurrence and development.

Pharmacological review of isobavachalcone, a naturally occurring chalcone.

Isobavachalcone (IBC), a naturally occurring chalcone, is mainly isolated from the seeds of Psoralea corylifolia Linn. IBC demonstrates multiple pharmacological activities, including anti-cancer, anti-microbial, anti-inflammatory, antioxidative, neuroprotective, and among others. Several potential targets of IBC, such as AKT, dihydroorotate dehydrogenase (DHODH), have been identified. The pharmacokinetic profiles of IBC have been reported as well. In this review, the pharmacological activities, the underlying mechanisms, the potential targets, and the pharmacokinetic profiles of IBC were summarized. IBC might be a promising lead compound for drug discovery.

A Bifunctional Coordination Polymer for Al3+ Ion Detection and its Treatment Effect on Nonalcoholic Fatty Liver Disease by Promoting Lipoxygenases and Reducing Intrahepatic Triglyceride Content.

In this study, a new Cd(II)-bearing coordination polymer with the chemical formula of {[Cd4(meda)3(dpe)4(H2O)4]·(NO3)2·2(H2O)}n (1, H2meda = 3,3'-methylenedibenzoic acid, dpe = 1,2-di(pyridin-4-yl)ethane) has been successfully prepared by reaction of Cd(NO3)·4H2O with a V-shape carboxyl ligand H2meda along with the linear dipyridine ligand dpe under the hydrothermal conditions. Due to its intensive luminescence, complex 1 could be utilized as the sensor of detecting Al3+ ion, and its detection limit is 4 × 10-6 M. Firstly, the toxicity of the compound on the normal liver cells was determined with Cell Counting Kit-8 detection kit. The triglyceride in liver cells was detected by detection kit after compound treatment and the relative expression of 15-lox and 12-lox in L02 cells was also measured by RT-PCR after compound treatment. In addition, multiple functional groups that provided by the synthesized Cd(II) complex have been studied by using molecular docking simulation for the confirmation of possible binding modes that formed between ligand and receptor.

Draft Genome Sequence of a Multidrug-Resistant bla NDM-1-Producing Acinetobacter soli Isolate in China.

Acinetobacter spp. are one of the most prevalent opportunistic pathogens causing nosocomial infections and have become a major clinical and public health threat. In this study, we presented the first draft genome sequence of A. soli TCM341, a multidrug resistant isolate that carried the bla NDM-1 gene in China. Genome sequencing of A. soli TCM341 was carried out in Illumina Hiseq 2000 next-generation sequencer. The data obtained revealed 74 contigs with genome size of 3.49 Mb and G+C content of 41.37 %.

Fighting cancer by triggering non-canonical mitochondrial permeability transition-driven necrosis through reactive oxygen species induction.

Non-apoptotic necrosis shows therapeutic potential for the treatment of various diseases, especially cancer. Mitochondrial permeability transition (MPT)-driven necrosis is a form of non-apoptotic cell death triggered by oxidative stress and cytosolic Ca2+ overload, and relies on cyclophilin D (CypD). Previous reports demonstrated that isobavachalcone (IBC), a natural chalcone, has anticancer effect by apoptosis induction. Here, we found that IBC induced regulated necrosis in cancer cells. IBC triggered non-apoptotic cell death in lung and breast cancer cells mediated by reactive oxygen species (ROS). IBC caused mitochondrial injury and dysfunction as evidenced by mitochondrial Ca2+ overload, the opening of MPT pore, mitochondrial membrane potential collapse, and structural damages. IBC-triggered cell death could be remarkably reversed by the ROS scavengers, cyclosporin A (CsA) and hemin, whereas CypD silence and heme oxygenase-1 overexpression failed to do so. Protein kinase B, dihydroorotate dehydrogenase, and mitogen-activated protein kinases were not involved in IBC-induced necrosis as well. In addition, IBC showed an anticancer effect in a 4T1 breast cancer cell-derived allograft mouse model, and this effect was considerably reversed by CsA. Collectively, our results showed that IBC triggered non-canonical MPT-driven necrosis mediated by ROS in cancer cells, which might provide a novel strategy for fighting against cancer.

Downregulation of OCTN2 by cytokines plays an important role in the progression of inflammatory bowel disease.

Inflammatory bowel diseases (IBD) are characterized by chronic relapsing disorders of the gastrointestinal tract. OCTN2 (SLC22A5) and its substrate l-carnitine (l-Car) play crucial roles in maintaining normal intestinal function. An aim of this study was to delineate the expression alteration of OCTN2 in IBD and its underlying mechanism. We also investigated the impact of OCTN2 on IBD progression and the possibility of improving IBD through OCTN2 regulation. Our results showed decreased OCTN2 expression levels and l-Car content in inflamed colon tissues of IBD patients and mice, which negatively correlated with the degree of colonic inflammation in IBD mice. Mixed proinflammatory cytokines TNF-α, IL-1ß and IFNγ downregulated the expression of OCTN2 and subsequently reduced the l-Car content through PPARγ/RXRα pathways in FHC cells. OCTN2 silencing reduced the proliferation rate of the colon cells, whereas OCTN2 overexpression increased the proliferation rate. Furthermore, the ability of PPARγ agonist, luteolin, to increase OCTN2 expression resulted in the alleviation of colonic inflammatory responses. In conclusion, OCTN2 was downregulated in IBD by proinflammatory cytokines via the PPARγ/RXRα pathways, which reduced l-Car concentration and subsequently induced IBD deterioration. Upregulation of OCTN2 by the PPARγ agonist alleviated colonic inflammation. Our findings suggest that, OCTN2 may serve as a therapeutic target for IBD therapy.

Prognostic role of the long non-coding RNA, SPRY4 Intronic Transcript 1, in patients with cancer: a meta-analysis.

Recent studies have emphasized the important role of long non-coding RNAs (lncRNAs) in cancer development. The present study performed a meta-analysis to investigate whether lncRNA, SPRY4 Intronic Transcript 1(SPRY4-IT1) can be served as a potential biomarker for prognosis in human cancers. The eligible studies were collected by searching multiple online databases (Pubmed, EMBASE, CNKI, Web of Science and Google Scholar) and meta-analysis was performed to explore the association between the expression levels of SPRY4-IT1 and overall survival (OS), disease-free survival (DFS) and clinicopathological parameters. A total of 1329 patients from 13 studies were included for meta-analysis. The meta-analysis results showed that high expression level of SPRY4-IT1 was significantly associated with shorter OS in cancer patients (HR = 3.20, 95% CI: 2.59-3.90, P<0.001) except in the patients with non-small cell lung cancer (NSCLC). Increased SPRY4-IT1 expression level was correlated with shorter DFS in patients with gastric cancer and ovarian cancer. SPRY4-IT1 expression level was not correlated with the clinicopathological parameters including age (P = 0.37), gender (P = 0.87), tumor size (P = 0.47) and invasion depth (P = 0.52), and increased SPRY4-IT1 expression level was significantly associated with distant metastasis (odds ratio (OR) = 1.96, 95% CI: 1.24-3.08, P = 0.004), lymph node metastasis (OR = 3.96, 95% CI: 1.48-5.54, P<0.001), advanced tumor/node/metastasis stage (OR = 3.72, 95% CI = 2.91-4.76, P<0.001) and poor tumor differentiation (OR = 1.86, 95% CI = 1.35-2.58, P<0.001) in cancer patients except in patients with NSCLC. In summary, the meta-analysis results suggested that increased expression level of SPRY4-IT1 was positively associated with unfavorable prognosis and advanced features of cancers in cancer patients but not in patients with NSCLC.

Draft genome sequence of a multidrug-resistant blaOXA-23-producing Acinetobacter baumannii ST381 isolate from China.

Acinetobacter baumannii is one of the most prevalent opportunistic pathogens causing nosocomial infections and has become a major clinical and public health concern. In this study, we present the first draft genome sequence of A. baumannii TCM206 (ST381/CC92), a multidrug-resistant isolate carrying the blaOXA-23 gene in China. We observed important resistance genes in an estimated genome size of 3,944,450bp with 3694 predicted protein-coding regions. These data might facilitate further understanding of the antibiotic resistance mechanisms of A. baumannii at the genomic level.