Morroniside ameliorates lipopolysaccharide-induced inflammatory damage in iris pigment epithelial cells through inhibition of TLR4/JAK2/STAT3 pathway

AIM:To investigate the effect of morroniside(Mor)on lipopolysaccharide(LPS)-treated iris pigment epithelial cells(IPE).METHODS:IPE cells were induced by LPS and treated with Mor.Cell proliferation was detected by cell counting kit(CCK)-8,apoptosis was detected by flow cytometry,the levels of tumor necrosis factor-α(TNF-α),interleukin(IL)-6,and IL-8 were measured by enzyme-linked immunosorbent assay(ELISA)kits,and the protein expression of TLR4,JAK2,p-JAK2,STAT3,and p-STAT3 was analyzed by Western blotting.In addition,overexpression of TLR4 and Mor treatment of LPS-stimulated IPE cells were also tested for the above indices.RESULTS:Mor effectively promoted the proliferation and inhibited the apoptosis of LPS-treated IPE cells.In addition,Mor significantly reduced the levels of TNF-α,IL-6,and IL-8 and significantly inhibited the expression of TLR4,p-JAK2,and p-STAT3 in LPS-treated IPE cells.The effect of Mor on LPS-treated IPE cells was markedly attenuated after overexpression of TLR4.CONCLUSION:These findings suggest that Mor may ameliorate LPS-induced inflammatory damage and apoptosis in IPE through inhibition of TLR4/JAK2/STAT3 pathway.

Inhibition of cerebral ischemia/reperfusion injuryinduced apoptosis:nicotiflorin and JAK2/STAT3 pathway

Nicotiflorin is a flavonoid extracted from Carthamus tinctorius.Previous studies have shown its cerebral protective effect,but the mechanism is undefined.In this study,we aimed to determine whether nicotiflorin protects against cerebral ischemia/reperfusion injury-induced apoptosis through the JAK2/STAT3 pathway.The cerebral ischemia/reperfusion injury model was established by middle cerebral artery occlusion/reperfusion.Nicotiflorin（10 mg/kg） was administered by tail vein injection.Cell apoptosis in the ischemic cerebral cortex was examined by hematoxylin-eosin staining and terminal deoxynucleotidyl transferase d UTP nick end labeling assay.Bcl-2 and Bax expression levels in ischemic cerebral cortex were examined by immunohistochemial staining.Additionally,p-JAK2,p-STAT3,Bcl-2,Bax,and caspase-3 levels in ischemic cerebral cortex were examined by western blot assay.Nicotiflorin altered the shape and structure of injured neurons,decreased the number of apoptotic cells,down-regulates expression of p-JAK2,p-STAT3,caspase-3,and Bax,decreased Bax immunoredactivity,and increased Bcl-2 protein expression and immunoreactivity.These results suggest that nicotiflorin protects against cerebral ischemia/reperfusion injury-induced apoptosis via the JAK2/STAT3 pathway.

KIAA1199 induces advanced biological behavior and development of ovarian cancer through activation of the IL-6/STAT3 pathway

Recently,abnormal expression of KIAA1199 has been detected in Epithelial Ovarian Cancer(EOC).However,the underlined anti-ovarian cancer mechanism of KIAA1199 remains to be enlightened.In our study,we performed to elucidate the effects of KIAA1199 on the advanced biological behavior of EOC cells through activation of the IL-6/STAT3 pathway.Confirmed by immunohistochemistry,KIAA1199 was highly expressed in ovarian borderline and malignant epithelial tumors.A retrospective analysis found that EOC patients with low expression of KIAA1199 had a significantly higher 5-year survival rate than those with high expression.Mechanistically,IL-6 was used to stimulate EOC cells,and the expression of KIAA1199,STAT3 and p-STAT3 increased after IL-6 stimulation.These results could show that KIAA1199 is transcriptionally activated by IL6/STAT3 pathway,thereby accelerating the deterioration of EOC.KIAA1199 could also be used as a poor prognosis factor and potential target in treatment.

Hepatocellular carcinoma-derived exosomal miRNA-761 regulates the tumor microenvironment by targeting the SOCS2/JAK2/STAT3 pathway

BACKGROUND:Exosomes and exosomal microRNAs have been implicated in tumor occurrence and metastasis.Our previous study showed that microRNA-761(miR-761)is overexpressed in hepatocellular carcinoma(HCC)tissues and that its inhibition affects mitochondrial function and inhibits HCC metastasis.The mechanism by which exosomal miR-761 modulates the tumor microenvironment has not been elucidated.METHODS:Exosomal miR-761 was detected in six cell lines.Cell counting kit-8(CCK-8)and transwell migration assays were performed to determine the function of exosomal miR-761 in HCC cells.The luciferase reporter assay was used to analyze miR-761 target genes in normal fi broblasts(NFs).The inhibitors AZD1480 and C188-9 were employed to determine the role of the Janus kinase 2/signal transducer and activator of transcription 3(JAK2/STAT3)signaling pathway in the transformation of cancer-associated fi broblasts(CAFs).RESULTS:In this study,we characterized the mechanism by which miR-761 reprogrammed the tumor microenvironment.We found that HCC-derived exosomal miR-761 was taken up by NFs.Moreover,HCC exosomes aff ected the tumor microenvironment by activating NFs via suppressor of cytokine signaling 2(SOCS2)and the JAK2/STAT3 signaling pathway.CONCLUSIONS:These results demonstrated that exosomal miR-761 modulated the tumor microenvironment via SOCS2/JAK2/STAT3 pathway-dependent activation of CAFs.Our fi ndings may inspire new strategies for HCC prevention and therapy.

Effects of plumbagin on migration and invasion of human hepatoma cell line via JAK2/STAT3 signaling pathway

Objective:To study the effect of plumbagin(PL)on the migration and invasion of human hepatocellular carcinoma(HCC)cells and its possible mechanism.Methods:The cell counting kit(CCK-8)was used to detect the effects of different concentrations of plumbagin on the proliferation of human hepatocellular carcinoma Huh-7 and LM3 cells.The effect of plumbagin on the migration ability of Huh-7 and LM3 cells was detected by scratch test and Transwell migration test,and the effect of on the invasion ability of Huh-7 and LM3 cells was detected by Transwell invasion test.Western Blot was used to detect the expression of E-cadherin,N-cadherin,matrix metalloproteinase-2 and related proteins in JAK2/STAT3 signaling pathway in Huh-7 and LM3 cells.Results:Plumbagin could inhibit the proliferation of Huh-7 and LM3 cells in a time-and concentration-dependent manner.Plumbagin inhibited the migration and invasion of Huh-7 and LM3 cells in a concentration dependent manner,and it can down-regulate the expression of N-cadherin and MMP-2 protein,up-regulate the expression of E-cadherin protein,and inhibit the activation of JAK2/STAT3 signaling pathway.Conclusion:Plumbagin can inhibit the migration and invasion of human hepatocellular carcinoma Huh-7 and LM3 cells,and the molecular mechanism of this process may be related to the inhibition of JAK2/STAT3 signaling pathway activation.

To explore the mechanism of Dahuang Lingxian Formula in relieving inflammatory response of bile duct cells based on IL-6/JAK/STAT3 signaling pathway

Objective:To explore the mechanism of action of Dahuang Lingxian Formula in alleviating the inflammatory response of bile duct cells in LPS-induced intrahepatic bile duct inflammation model rats based on IL-6/JAK/STAT3 signaling pathway.Methods:Fifty SD rats were randomly divided into five groups,blank group,model group,choling tablets(0.5 g/kg),and low and high concentration groups(2.4 g/kg and 4.8 g/kg)of Dahuang Lingxian Formula,ten rats in each group.Except for the blank group,the rats in each group were injected with 1.25 mg/kg LPS at the common bile duct at one time to construct an animal model of intrahepatic bile duct infection.After gavage on day 8,liver tissues were taken from rats at the hepatic hilum,and the histopathological changes of the hepatic hilum and biliary tree were observed by HE staining.The expression levels of serum glutamic alanine transaminase(ALT),glutamic oxalacetic transaminase(AST),malondialdehyde(MDA)and superoxide dismutase(SOD)were measured by biochemical method.The expression levels of interleukin 6(IL-6),Janus protein tyrosine kinase 2(JAK2),signal transducer and activator of transcription 3(STAT3)in rat serum were measured by enzyme-linked immunosorbent assay(ELISA).Protein immunoblotting(WB)and real-time fluorescence quantitative PCR(RT-qPCR)were used to detect the expression levels of IL-6,JAK2,STAT3 protein and mRNA in biliary tree tissues.Results:①Compared with the blank group,the structures such as interlobular bile ducts in the hepatic sinusoids and portal duct area of the model rats were destroyed,and inflammatory cells infiltrated around them.The expression of ALT,AST,MDA,IL-6,JAK2 and STAT3 in the serum increased significantly,the expression level of SOD decreased,and the expression levels of IL-6,JAK2 and STAT3 proteins and mRNA increased.②Compared with the model group,the degree of liver pathological damage in rats in the Chiling Ning tablet group and the low and high concentration groups of Dahuang Lingxian Formula were improved,which could significantly reduce the expression levels of ALT,AST,MDA,IL-6,JAK2,STAT3 and up-regulate SOD in serum,and down-regulate the expression of IL-6,JAK2,STAT3 protein and mRNA,with the best effect in the high concentration group of Dahuang Lingxian Formula.③Compared with the choling tablet group,the rats in the low and high concentration groups of Dahuang Lingxian Formula tended to normalize the degree of liver pathological damage,without obvious inflammatory cell infiltration,and the expression levels of ALT,AST,MDA,IL-6,JAK2,STAT3 and the expression levels of IL-6,JAK2,STAT3 protein and mRNA in serum were reduced,and the expression levels of SOD were increased,with the best effect of Dahuang Lingxian Formula The treatment effect was best in the high concentration group.Conclusion:The mechanism may be related to the down-regulation of IL-6/JAK/STAT3 signaling pathway activation,and the best therapeutic effect was achieved by the high concentration group of Dahuang Lingxian Formula.

Elevated retinol binding protein 4 levels are associated with atherosclerosis in diabetic rats via JAK2/STAT3 signaling pathway

BACKGROUND Atherosclerosis is a major cause of mortality worldwide and is driven by multiple risk factors,including diabetes,which results in an increased atherosclerotic burden,but the precise mechanisms for the occurrence and development of diabetic atheroscerosis have not been fully elucidated.AIM To summarize the potential role of retinol binding protein 4(RBP4) in the pathogenesis of diabetic atheroscerosis,particularly in relation to the RBP4-Janus kinase 2/signal transducer and activator of transcription 3(JAK2/STAT3)signaling pathway.METHODS Male Wistar rats were randomly divided into three groups,including a control group(NC group),diabetic rat group(DM group),and diabetic atherosclerotic rat group(DA group).The contents of total cholesterol(TC), high-density lipoprotein cholesterol(HDL-c), triglycerides(TG), low-density lipoprotein cholesterol(LDLc), fasting insulin(FINS),fasting plasma glucose,and hemoglobin A1 c(HbA1 c)were measured.Moreover,the adipose and serum levels of RBP4,along with the expression levels of JAK2, phosphorylated JAK2(p-JAK2), STAT3,phosphorylated STAT3(p-STAT3), B-cell lymphoma-2(Bcl-2), and Cyclin D1 in aortic tissues were also measured.Besides,homeostasis model assessment of insulin resistance(HOMA-IR) and atherogenic indexes(AI) were calculated.RESULTS Compared with the NC and DM groups,the levels LDL-c,TG,TC,FINS,HOMAIR,RBP4,and AI were upregulated,whereas that of HDL-c was downregulated in the DA group(P <0.05);the mRNA levels of JAK2,STAT3,Cyclin D1,and Bcl-2 in the DA group were significantly increased compared with the NC group and the DM group;P-JAK2,p-JAK2/JAK2 ratio,p-STAT3,p-STAT3/STAT3 ratio,Cyclin D1,and Bcl-2 at protein levels were significantly upregulated in the DA group compared with the NC group and DM group.In addition,as shown by Pearson analysis,serum RBP4 had a positive correlation with TG,TC,LDL-c,FINS,HbA1 C,p-JAK2,p-STAT3,Bcl-2,Cyclin D1,AI,and HOMA-IR but a negative correlation with HDL-c.In addition,multivariable logistic regression analysis showed that serum RBP4,p-JAK2,p-STAT3,and LDL-c were predictors of the presence of diabetic atherosclerosis.CONCLUSION RBP4 could be involved in the initiation or progression of diabetic atherosclerosis by regulating the JAK2/STAT3 signaling pathway.

3-epi-bufotalin suppresses the proliferation in colorectal cancer cells through the inhibition of the JAK1/STAT3 signaling pathway

Traditional Chinese medicine(TCM)has been increasingly employed in the last decades in China for both preventing and treating a variety of cancers.3-epi-bufotalin is an active ingredient of TCM“Chanpi”with anti-tumor potential.However,the effect and mechanism of 3-epi-bufotalin on colorectal cancers were not well disclosed.The present study demonstrated that 3-epi-bufotalin could reduce viability,trigger apoptosis,and block the cell cycle at the G2/M stage in colorectal cancer cell lines HT29,RKO,and COLO205 in vitro.Moreover,3-epi-bufotalin inhibited the JAK1/STAT3 signaling pathway.These results indicated the anti-proliferation ability of 3-epi-bufotalin in colorectal cancer cells.

HBP1 inhibits chicken preadipocyte differentiation by activating the STAT3 signaling via directly enhancing JAK2 expression

Obesity presents a serious threat to human health and broiler performance.The expansion of adipose tissue is mainly regulated by the differentiation of preadipocytes.The differentiation of preadipocytes is a complex biological process regulated by a variety of transcription factors and signaling pathways.Previous studies have shown that the transcription factor HMG-box protein 1(HBP1)can regulate the differentiation of mouse 3T3-L1 preadipocytes by activating the Wnt/β-catenin signaling pathway.However,it is unclear whether HBP1 involved in chicken preadipocyte differentiation and which signaling pathways it regulates.The aim of the current study was to explore the biological function and molecular regulatory mechanism of HBP1 in the differentiation of chicken preadipocytes.The expression patterns of chicken HBP1 in abdominal adipose tissue and during preadipocyte differentiation were analyzed by RT-qPCR and Western blot.The preadipocyte stably overexpressing HBP1 or knockout HBP1 and their control cell line were used to analyze the effect of HBP1 on preadipocyte differentiation by oil red O staining,RT-qPCR and Western blot.Cignal 45-Pathway Reporter Array was used to screen the signal pathways that HBP1 regulates in the differentiation of chicken preadipocytes.Chemical inhibitor and siRNA for signal transducer and activator of transcription 3(STAT3)were used to analyze the effect of STAT3 on preadipocyte differentiation.The preadipocyte stably overexpressing HBP1 was transfected by the siRNA of STAT3 or treated with a chemical inhibitor of STAT3 for the rescue experiment.The results of gene expression analysis showed that the expression of HBP1 was related to abdominal fat deposition and preadipocyte differentiation in chickens.The results of function gain and loss experiments indicated that overexpression/knockout of HBP1 in chicken preadipocytes could inhibit/promote(P<0.05)lipid droplet deposition and the expression of adipogenesis-related genes.Mechanismlly,HBP1 activates(P<0.05)the signal transducer and activator of transcription 3(STAT3)signaling pathway by targeting janus kinase 2(JAK2)transcription.The results of functional rescue experiments indicated that STAT3 signaling mediated the regulation of HBP1 on chicken preadipocyte differentiation.In conclusion,HBP1 inhibits chicken preadipocyte differentiation by activating the STAT3 signaling pathway via directly enhancing JAK2 expression.Our findings provided new insights for further analysis of the molecular genetic basis of chicken adipose tissue growth and development.

Blocking the JAK2/STAT3 and ERK pathways suppresses the proliferation of gastrointestinal cancers by inducing apoptosis

Dysregulated crosstalk between different signaling pathways contributes to tumor development,including resistance to cancer therapy.In the present study,we found that the mitogen-activated extracellular signal-regulated kinase(MEK)inhibitor trametinib failed to suppress the proliferation of PANC-1 and MGC803 cells by activating the Janus kinase 2(JAK2)/signal transducer and activator of transcription 3(STAT3)signaling pathway,while the JAK2 inhibitor fedratinib failed to inhibit the growth of the PANC-1 cells upon stimulation of extracellular signal-regulated kinase(ERK)signaling.In particular,the most prominent enhancement of the anti-proliferative effect resulted from the concurrent blockage of the JAK2/STAT3 and ERK signaling pathways.Furthermore,the combination of the two inhibitors resulted in a reduced tumor burden in mice.Our evidence suggests novel crosstalk between JAK2/STAT3 and ERK signaling in gastric cancer(GC)and pancreatic ductal adenocarcinoma(PDAC)cells and provides a therapeutic strategy to overcome potential resistance in gastrointestinal cancer.

Sphingosine kinase 1 promotes growth of glioblastoma by increasing inflammation mediated by the NF-κB/IL-6/STAT3 and JNK/PTX3 pathways

Glioblastoma(GBM)is the most challenging malignant tumor of the central nervous system because of its high morbidity,mortality,and recurrence rate.Currently,mechanisms of GBM are still unclear and there is no effective drug for GBM in the clinic.Therefore,it is urgent to identify new drug targets and corresponding drugs for GBM.In this study,in silico analyses and experimental data show that sphingosine kinase 1(SPHK1)is up-regulated in GBM patients,and is strongly correlated with poor prognosis and reduced overall survival.Overexpression of SPHK1 promoted the proliferation,invasion,metastasis,and clonogenicity of GBM cells,while silencing SPHK1 had the opposite effect.SPHK1 promoted inflammation through the NF-κB/IL-6/STAT3 signaling pathway and led to the phosphorylation of JNK,activating the JNK-JUN and JNK-ATF3 pathways and promoting inflammation and proliferation of GBM cells by transcriptional activation of PTX3.SPHK1 interacted with PTX3 and formed a positive feedback loop to reciprocally increase expression,promote inflammation and GBM growth.Inhibition of SPHK1 by the inhibitor,PF543,also decreased tumorigenesis in the U87-MG and U251-MG SPHK1 orthotopic mouse models.In summary,we have characterized the role and molecular mechanisms by which SPHK1 promotes GBM,which may provide opportunities for SPHK1-targeted therapy.

FOXO1 Alleviates Liver Ischemia-reperfusion Injury by Regulating the Th17/Treg Ratio through the AKT/Stat3/FOXO1 Pathway

Background and Aims:Hepatic ischemic reperfusion in-jury(IRI)occurring during surgery seriously affects patient prognosis.The specific mechanism of IRI has not been fully elucidated.The study aim was to explore the changes of in-flammatory environment,and the relationship of the Th17/Treg cell ratio and FOXO1 expression in hepatic IRI.Methods:Liver samples at different ischemic times were collected from patients and mice.The expression of inflammatory markers and FOXO1 in the liver was detected by western blotting and qPCR.Phenotypic changes of liver lymphocytes were analyzed by flow cytometry.The AKT/Stat3/FOXO1 pathway was veri-fied by targeting AKT with GSK2141795.The role of FOXO1 in liver inflammation and changes in lymphocyte phenotype was confirmed by upregulating FOXO1 with resveratrol.Re-sults:Prolonged ischemic time aggravates liver injury in both humans and mouse models of hepatic IRI.IR-stress caused Th17/Treg imbalance and FOXO1 down-regulation by activat-ing the AKT/Stat3/FOXO1 signaling pathway.Upregulation of FOXO1 reversed the Th17/Treg cytokine imbalance and altered the inflammation environment in the liver.Conclusions:Liver IRI induced Th17/Treg imbalance.Upregulation of FOXO1 re-versed the imbalance and alleviated liver inflammation.

Opposite Interplay Between the Canonical WNT/β-Catenin Pathway and PPAR Gamma： A Potential Therapeutic Target in Gliomas

In gliomas, the canonical Wingless/Int（WNT）/b-catenin pathway is increased while peroxisome proliferator-activated receptor gamma（PPAR-c） is downregulated.The two systems act in an opposite manner. This review focuses on the interplay between WNT/b-catenin signaling and PPAR-c and their metabolic implications as potential therapeutic target in gliomas. Activation of the WNT/bcatenin pathway stimulates the transcription of genes involved in proliferation, invasion, nucleotide synthesis,tumor growth, and angiogenesis. Activation of PPAR-c agonists inhibits various signaling pathways such as the JAK/STAT, WNT/b-catenin, and PI3 K/Akt pathways,which reduces tumor growth, cell proliferation, cell invasiveness, and angiogenesis. Nonsteroidal anti-inflammatory drugs, curcumin, antipsychotic drugs, adiponectin,and sulforaphane downregulate the WNT/b-catenin pathway through the upregulation of PPAR-c and thus appear to provide an interesting therapeutic approach for gliomas.Temozolomide（TMZ） is an antiangiogenic agent. The downstream action of this opposite interplay may explain the TMZ-resistance often reported in gliomas.

Sustained release of magnesium and zinc ions synergistically accelerates wound healing

Skin wounds are a major medical challenge that threaten human health.Functional hydrogel dressings demonstrate great potential to promote wound healing.In this study,magnesium(Mg)and zinc(Zn)are introduced into methacrylate gelatin(GelMA)hydrogel via low-temperature magnetic stirring and photocuring,and their effects on skin wounds and the underlying mechanisms are investigated.Degradation testing confirmed that the GelMA/Mg/Zn hydrogel released magnesium ions(Mg^(2+))and zinc ions(Zn^(2+))in a sustained manner.The Mg^(2+) and Zn^(2+)not only enhanced the migration of human skin fibroblasts(HSFs)and human immortalized keratinocytes(HaCats),but also promoted the transformation of HSFs into myofibroblasts and accelerated the production and remodeling of extracellular matrix.Moreover,the GelMA/Mg/Zn hydrogel enhanced the healing of full-thickness skin defects in rats via accelerated collagen deposition,angiogenesis and skin wound re-epithelialization.We also identified the mechanisms through which GelMA/Mg/Zn hydrogel promoted wound healing:the Mg^(2+) promoted Zn^(2+)entry into HSFs and increased the concentration of Zn^(2+)in HSFs,which effectively induced HSFs to differentiate into myofibroblasts by activating the STAT3 signaling pathway.The synergistic effect of Mg^(2+) and Zn^(2+)promoted wound healing.In conclusion,our study provides a promising strategy for skin wounds regeneration.

Hepatocyte growth factor protects pulmonary endothelial barrier against oxidative stress and mitochondria-dependent apoptosis

Background:Pulmonary microvascular endothelial cells(PMVECs)were not complex,and the endothelial barrier was destroyed in the pathogenesis progress of acute lung injury(ALI)/acute respiratory distress syndrome(ARDS).Previous studies have demonstrated that hepatocyte growth factor(HGF),which was secreted by bone marrow mesenchymal stem cells,could decrease endothelial apoptosis.We investigated whether mTOR/STAT3 signaling acted in HGF protective effects against oxidative stress and mitochondria-dependent apoptosis in lipopolysaccharide(LPS)-induced endothelial barrier dysfunction and ALI mice.Methods:In our current study,we introduced LPS-induced PMEVCs with HGF treatment.To investigate the effects of mammalian target of rapamycin(mTOR)/signal transducer and activator of transcription 3(STAT3)pathway in endothelial oxidative stress and mitochondria-dependent apoptosis,mTOR inhibitor rapamycin and STAT3 inhibitor S3I-201 were,respectively,used to inhibit mTOR/STAT3 signaling.Moreover,lentivirus vector-mediatedmTORC1(Raptor)andmTORC2(Rictor)gene knockdown modifications were introduced to evaluatemTORC1 andmTORC1 pathways.Calcium measurement,reactive oxygen species(ROS)production,mitochondrial membrane potential and protein,cell proliferation,apoptosis,and endothelial junction protein were detected to evaluate HGF effects.Moreover,we used the ALI mouse model to observe the mitochondria pathological changes with an electron microscopein vivo.Results:Our study demonstrated that HGF protected the endothelium via the suppression of ROS production and intracellular calcium uptake,which lead to increased mitochondrial membrane potential(JC-1 and mitochondria tracker green detection)and specific proteins(complex I),raised anti-apoptosis Messenger Ribonucleic Acid level(B-cell lymphoma 2 and Bcl-xL),and increased endothelial junction proteins(VE-cadherin and occludin).Reversely,mTOR inhibitor rapamycin and STAT3 inhibitor S3I-201 could raise oxidative stress and mitochondria-dependent apoptosis even with HGF treatment in LPS-induced endothelial cells.Similarly,mTORC1 as well as mTORC2 have the same protective effects in mitochondria damage and apoptosis.Inin vivo experiments of ALI mouse,HGF also increased mitochondria structural integrity via the mTOR/STAT3 pathway.Conclusion:In all,these reveal that mTOR/STAT3 signaling mediates the HGF suppression effects to oxidative level,mitochondria-dependent apoptosis,and endothelial junction protein in ARDS,contributing to the pulmonary endothelial survival and barrier integrity.