查看更多>>摘要：The formation of death-inducing signaling complex (DISC) and death effector domain (DED) filament initiates extrinsic apoptosis。 Recruitment and activation of procaspase-8 at the DISC are regulated by c-FLIP。 The interaction between c-FLIP and procaspase-8 is mediated by their tandem DEDs (tDED)。 However， the structure of c-FLIPtDED and how c-FLIP interferes with procaspase-8 activation at the DISC remain elusive。 Here， we solved the monomeric structure of c-FLIPtDED (F114G) at near physiological pH by solution nuclear magnetic resonance (NMR)。 Structural superimposition reveals c-FLIPtDED (F114G) adopts a structural topology similar to that of procaspase-8tDED。 Our results provide a structural basis for understanding how c-FLIP interacts with procaspase-8 and the molecular mechanisms of c-FLIP in regulating cell death。
查看更多>>摘要：With the continuous deepening of international research in the field of biology， more and more studies have found that polysaccharides have multiple biological functions， so that polysaccharides have gradually become the research objects of more and more scientists in the world， and a large number of relevant researchers have carried out Glycobiology research， most of the current research is on the separation， extraction， structural characterization and activity experiments of polysaccharides。 However， at this stage， research on the structure-activity relationship of various polysaccharides extracted from plants is relatively rare， and the representation method of polysaccharide structures is not perfect， not unified， complicated in drawing， and not beautiful and convenient to read。 The SNFG (Symbol Nomenclature For Glycans) method， which is the symbolic nomenclature of polysaccharides and the 3D-SNFG method， can solve the above problems well， and can use unified rules to describe and describe the molecular structure of polysaccharides， and the painting process is more convenient and more convenient。 It is beautiful and makes it easier for readers to read。 In this paper， the fern hemp polysaccharide molecule is taken as an example。 After drawing it with chemoffice， SNFG and 3D-SNFG are used to describe it， and then compared。 It is clear at a glance that the use of SNFG and 3D-SNFG methods has been widely recognized and accepted internationally， which can provide great convenience for sugar-related research and information exchange。
查看更多>>摘要：Exposure to particulate matter 2。5 (PM2。5) has been linked to ocular surface diseases， yet knowledge of the molecular mechanism impacted on retina pathogenesis is limited。 Therefore， the purpose of this study was to explore the effects and involved factors of PM2。5 exposure in human retinal pigment epithelial APRE-19 cells。 Our data revealed a decreased cell viability and an increased migratory ability in APRE-19 cells after PM2。5 stimulation。 The MMP-2 and MMP-9 protein levels were markedly increased while the MMPs regulators TIMP-1 and TIMP-2 were significantly reduced in PM2。5-exposed APRE-19 cells。 PM2。5 also increased pro-MMP-2 expression in the cell culture supernatants。 Additionally， PM2。5 promoted the EMT markers through the activation of PI3K/AKT/mTOR pathway。 Moreover， the ICAM-1 production was also remarkably increased by PM2。5 but reduced by PI3K/AKT inhibitor LY294002 in APRE-19 cells。 Taken together， these results suggest that PM2。5 promotes EMT in a PI3K/ AKT/mTOR-dependent manner in the retinal pigment epithelium。
Sathiya Priya KrishnamoorthySwathi Chran ManimegalaiAngel Mary ArulanuRamesh Thiyagarajan...
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查看更多>>摘要：Endometriosis is known to be a gynaecological condition characterised by persistent inflammation and abnormal development of endometrial stroma and glands。 Researchers require a rodent model to analyse the disease environment。 Animal models are the best option for investigating the etiology and effective treatment of debilitating illnesses in women since rodents， like humans， menstruate。 In order to develop the model system， diethylstilbestrol (DES) was examined for its ability to induce endometriosis in rats by investigating its effect on the estrus cycle， hormones， and key markers。 The results demonstrated that animals given DES had an erratic estrus cycle and aberrant hormone levels。 Histomorphology revealed the development of an endometriosis environment with degenerative epithelium and enlarged glandular cells after DES induction。 The higher levels of estrogen， progesterone， and MCP-1 were shown in the endometriosis induced animals。 Endometriosis-induced groups had decreased levels of HOXA10 and HOXA11 and increased levels ofVEGFand COX-2。 Finally， the DES demonstrated endometriosis induction efficacy， implying that it might be a viable replacement for endometriosis induction。
查看更多>>摘要：In assisted reproductive technology (ART)-derived embryos of non-rodent mammals， including humans and cattle， chromosome segregation errors are highly likely to occur during early cleavage division， resulting in aneuploidy， including mosaicism。 However， the relationship between chromosomal segregation errors during early cleavage and subsequent embryonic development has not been detailed in these mammals。 In the present study， we developed non-invasive live-cell imaging of chromosome segregation dynamics using a histone H2B-mCherry mRNA probe in bovine preimplantation embryos。 Chromosome segregation errors in early cleavage affected blastocyst formation。 Especially， embryos that underwent abnormal chromosome segregation (ACS) with multiple or large micronucleus formation rarely developed into blastocysts。 Embryos with the severe ACS had prolonged cell cycle duration。 After transfer of blastocysts with live-cell imaging of chromosome segregation to ten cows， six became pregnant and four of them gave full-term offspring。 Interestingly， two of them were derived from blastocysts with ACS。 Hence， chromosomal segregation errors with micronucleus formation during early cleavage can be a fatal hallmark of preimplantation embryogenesis in cattle。 This technique has shown potential for understanding the relationship between chromosome segregation error and subsequent embryo development， and for selecting viable ART-derived embryos for medical and livestock production。
查看更多>>摘要：Programmed death-ligand 1 (PD-L1)， a critical immune checkpoint ligand， is commonly overexpressed on the surface of many tumor types including lung and prostate cancer。 PD-L1 can exert cancerpromoting activity through either suppressing T cell-mediated immune response or activating tumor-intrinsic signaling。 Here， we demonstrated that β-tocotrienol (P-T3)， an isomer of vitamin E， effectively inhibited PD-L1 expression both in vitro and in vivo， which was mechanistically associated inactivating JAK2/STAT3 pathway。 Down-regulating PD-L1 expression by P-T3 led to enhanced immune response and inactivation of PD-L1-induced tumor-intrinsic signaling， which in turn contributed to its anticancer activity。 This study uncovered a novel mechanism involved in the anticancer effect of P-T3。
查看更多>>摘要：Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide， with the incidence in men being about twice as compared to women。 Gender differences may provide clues for finding key targets that mediate the death of dopaminergic (DA) neurons in PD。 Luteinizing hormone (LH)， analog of human chorionic gonadotropin (hCG)， and their receptor， luteinizing hormone/chorio-gonadotropin receptor (LHCGR)， are associated with the pathogenesis of PD。 Movement-related symptoms are partially improved by hCG in PD patients。 However， the relationship between hCG and PD， as well as its roles in mediating DA neuronal death， has not been elucidated。 In this study， we investigated the potential of hCG as a treatment during PD progression。 After establishment of 1-methyl-4-phenyl-1，2，3，6-tetrahydropyridine (MPTP)-induced PD mouse models， we found that hCG restored the decrease of LHCGR activity caused by down-regulation of LH in the substantia nigra。 Furthermore， the reduction of LHCGR activity led to DA neuronal death through knocking down the LHCGR in DA neurons by AAV-mTH-shRNA。 Treatment with hCG alleviated the DA neuronal death induced by MPTP。 Finally， hCG exerted neuroprotective effects by inhibiting the activation of glycogen synthase kinase 3 beta (GSK313) in our MPTP-induced PD mouse and MPP+-treated SH-SY5Y cell models。 Together， these results demonstrate that hCG exerts neuroprotective effects for PD through LHCGR， and the inhibition of GSK3P activation is involved in this protective effect， suggesting that hCG can be taken as a potential therapeutic for the treatment of PD。
查看更多>>摘要：The epithelial-mesenchymal transition (EMT) is a biological process that occurs in the pathogenesis of kidney diseases in which injured tubular epithelial cells transform into myofibroblasts。 We previously showed that mannitol-mediated hyperosmotic stress induces EMT of tubular epithelial cells。 Although Ca2+ signaling is essential for the induction of EMT in tubular epithelial cells， the role of specific calcium channels is unknown。 In this study， we assessed the transient receptor potential vanilloid 4 (TRPV4)-mediated Ca2+ influx in the hyperosmolarity-induced EMT。 The Fluo-4 assay was used to examine the effect of hyperosmotic stress on the intracellular Ca2+ level of normal rat kidney (NRK)-52E cells。 Expression of a mesenchymal marker a-smooth muscle actin (a-SMA) and an epithelial marker E-cadherin was also observed by fluorescence microscopy。 The hyperosmotic stress caused a transient increase in intracellular Ca2+ concentration as well as a decrease in E-cadherin and an increase in a-SMA expressions in tubular epithelial cells， indicating the induction of EMT。 A TRPV4 channel antagonist inhibited hyperosmotic stress-induced Ca2+ influx and the EMT， whereas， a TRPV4 channel agonist increased Ca2+ influx and EMT induction in tubular epithelial cells without the hyperosmotic stress。 These findings suggest that Ca2+ influx through TRPV4 channels contributes to the hyperosmotic stress-induced EMT of tubular epithelial cells。
查看更多>>摘要：The molecular mechanisms of uric acid (UA)-induced liver injury has not been clearly elucidated。 In this study， we aimed to investigate the effect and action mechanisms of UA in liver injury。 We analyzed the damaging effect of UA on mouse liver and L02 cells and subsequently performed metabolomics studies on L02 cells to identify abnormal metabolic pathways。 Finally， we verified transcription factors that regulate related metabolic enzymes。 UA directly activated the hepatic NLRP3 inflammasome and Bax apoptosis pathway in vivo and in vitro。 Related metabolites in the arginine biosynthesis pathway (or urea cycle)， L-arginine and L-argininosuccinate were decreased， and ammonia was increased in UA-stimulated L02 cells， which was mediated by carbamoyl phosphate synthase 1 (CPS1)， argininosuccinate synthase (ASS) and argininosuccinate lyase (ASL) downregulation。 UA upregulated hypoxia inducible factor-lalpha (HIF-la) in vivo and in vitro， and HIF-la inhibition alleviated the UA-induced ASS downregulation and hepatocyte injury。 In conclusion， UA upregulates HIF-la and inhibits urea cycle enzymes (UCEs)。 This leads to liver injury， with evidence of hepatocyte inflammation， apoptosis and oxidative stress。
查看更多>>摘要：Ovarian cancer is the eminent gynecological malignancy and chemoresistance remains a major reason for poor in ovarian cancer patients。 Taxol has been proved as the most effective chemotherapeutic agent against ovarian cancer。 However development of Taxol resistance remains a major problem。 Here， we report that STAT3， directly activates pentose-phosphate pathway to exert pro-oncogenic effects on Taxol resistance of ovarian cancer。 In addition， we found that STAT3， p-STAT3 and glucose-6-phosphate dehydrogenase (G6PD) protein levels are upregulated in Taxol resistant cell lines compared with Taxol sensitive cell lines。 Furthermore， inhibition of STAT3 decreased G6PD mRNA expression level and enhanced the sensitivity of Taxol resistant cell to Taxol。 Finally， we found that STAT3 directly binds to the G6PD promoter region and promotes the expression of G6PD at transcriptional level。 Taken together， our data indicate that activation of STAT3 promotes ovarian cancer cell proliferation， colony formation， and Taxol resistance via augmenting G6PD expression and pentose-phosphate metabolism flux， which provides a potential therapeutic target that may improve prognosis by decreasing G6PD expression and enhancing Taxol-sensitivity。
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