Let G be a reductive Nash group,acting on a Nash manifold X.Let Z be a G-stable closed Nash submanifold of X and denote by U the complement of Z in X.Letχbe a character of G and denote by g the complexified Lie algeb...Let G be a reductive Nash group,acting on a Nash manifold X.Let Z be a G-stable closed Nash submanifold of X and denote by U the complement of Z in X.Letχbe a character of G and denote by g the complexified Lie algebra of G.We give a sufficient condition for the natural linear map H_(k)(g,S(U)×χ)→H_k(g,S(X)×χ)between the Lie algebra homologies of Schwartz functions to be an isomorphism.For k=0,by considering the dual,we obtain the automatic extensions of g-invariant(twisted by-χ)Schwartz distributions.展开更多
Recently,Niculescu published an interesting paper^(1)con-cerning“deep homologies”between the formation of cancer stem cells by polyploidization and reproductive polyploidization of entamoeba.The life cycle of both s...Recently,Niculescu published an interesting paper^(1)con-cerning“deep homologies”between the formation of cancer stem cells by polyploidization and reproductive polyploidization of entamoeba.The life cycle of both sys-tems shares the same genetic machinery inherited from the Last Eukaryote Common Ancestor(LECA).This theory claims that cancer is nothing more than the expression of a pre-existing life cycle that was reactivated in“sick and weakened metazoan cell that cannot continue its multi-cellular life and finds itself in the same dead-end situation”.展开更多
Towards higher impact velocities,ballistic events are increasingly determined by the material temperatures.Related effects might range from moderate thermal softening to full phase transition.In particular,it is of gr...Towards higher impact velocities,ballistic events are increasingly determined by the material temperatures.Related effects might range from moderate thermal softening to full phase transition.In particular,it is of great interest to quantify the conditions for incipient or full melting of metals during impact interactions,which result in a transition from still strength-affected to hydrodynamic material behavior.In this work,we investigate to which extent the respective melting thresholds are also dependent on the initial,and generally elevated,temperatures of projectiles and targets before impact.This is studied through the application of a model developed recently by the authors to characterize the transition regime between high-velocity and hypervelocity impact,for which the melting thresholds of materials were used as the defining quantities.The obtained results are expected to be of general interest for ballistic application cases where projectiles or targets are preheated.Such conditions might result,for example,from aerodynamic forces acting onto a projectile during atmospheric flight,explosive shapedcharge-jet formation or armor exposure to environmental conditions.The performed analyses also broaden the scientific understanding of the relevance of temperature in penetration events,generally known since the 1960s,but often not considered thoroughly in impact studies.展开更多
Bone biomaterials have been increasingly used to reconstruct maxillary atrophic ridges.Thus,the aim of this study was to evaluate bone reconstruction in the maxilla using a homologous cortico-cancellous FFB(lyophilize...Bone biomaterials have been increasingly used to reconstruct maxillary atrophic ridges.Thus,the aim of this study was to evaluate bone reconstruction in the maxilla using a homologous cortico-cancellous FFB(lyophilized)graft and verify its reliability.Eight individuals were included from 2014 to 2018.The first surgery was performed to install homologous bone blocks in the maxilla.The period of the second intervention varied between 5 months and 15 days to 11 months(≈7.93 months).The biopsies were taken from the central region of the matured graft during the surgery for implant placement.All patients presented clinical and radiographic conditions for the installation of dental implants.There was a 100%of survival rate.The histological assessment showed that the homologous block bone graft was an osteoconductive biomaterial,with connective tissue present,and newly formed bone juxtaposed on its surface.There were bone trabeculae with osteocytes and active osteoblasts with connective tissue in the mineralization process;the remodeling process can be found through the reverse lines.A limited focus of necrosis with fibrosis was detected,with small resorption and areas of inflammatory infiltrate,but without clinical significance.The homologous block bone graft can be considered a feasible option to substitute the autogenous bone graft(gold standard),with predictable clinical and favorable histological results.The patients had a shorter surgical period,low morbidity,and an unlimited amount of biomaterial available at an accessible cost.展开更多
Reducing the secondary inflammatory response, which is partly mediated by microglia, is a key focus in the treatment of spinal cord injury. Src homology 2-containing protein tyrosine phosphatase 2(SHP2), encoded by PT...Reducing the secondary inflammatory response, which is partly mediated by microglia, is a key focus in the treatment of spinal cord injury. Src homology 2-containing protein tyrosine phosphatase 2(SHP2), encoded by PTPN11, is widely expressed in the human body and plays a role in inflammation through various mechanisms. Therefore, SHP2 is considered a potential target for the treatment of inflammation-related diseases. However, its role in secondary inflammation after spinal cord injury remains unclear. In this study, SHP2 was found to be abundantly expressed in microglia at the site of spinal cord injury. Inhibition of SHP2 expression using siRNA and SHP2 inhibitors attenuated the microglial inflammatory response in an in vitro lipopolysaccharide-induced model of inflammation. Notably, after treatment with SHP2 inhibitors, mice with spinal cord injury exhibited significantly improved hind limb locomotor function and reduced residual urine volume in the bladder. Subsequent in vitro experiments showed that, in microglia stimulated with lipopolysaccharide, inhibiting SHP2 expression promoted M2 polarization and inhibited M1 polarization. Finally, a co-culture experiment was conducted to assess the effect of microglia treated with SHP2 inhibitors on neuronal cells. The results demonstrated that inflammatory factors produced by microglia promoted neuronal apoptosis, while inhibiting SHP2 expression mitigated these effects. Collectively, our findings suggest that SHP2 enhances secondary inflammation and neuronal damage subsequent to spinal cord injury by modulating microglial phenotype. Therefore, inhibiting SHP2 alleviates the inflammatory response in mice with spinal cord injury and promotes functional recovery postinjury.展开更多
Objective:The clinical significance of homologous recombination deficiency(HRD)in breast cancer,ovarian cancer,and prostate cancer has been established,but the value of HRD in non-small cell lung cancer(NSCLC)has not ...Objective:The clinical significance of homologous recombination deficiency(HRD)in breast cancer,ovarian cancer,and prostate cancer has been established,but the value of HRD in non-small cell lung cancer(NSCLC)has not been fully investigated.This study aimed to systematically analyze the HRD status of untreated NSCLC and its relationship with patient prognosis to further guide clinical care.Methods:A total of 355 treatment-naïve NSCLC patients were retrospectively enrolled.HRD status was assessed using the AmoyDx Genomic Scar Score(GSS),with a score of≥50 considered HRD-positive.Genomic,transcriptomic,tumor microenvironmental characteristics and prognosis between HRD-positive and HRDnegative patients were analyzed.Results:Of the patients,25.1%(89/355)were HRD-positive.Compared to HRD-negative patients,HRDpositive patients had more somatic pathogenic homologous recombination repair(HRR)mutations,higher tumor mutation burden(TMB)(P<0.001),and fewer driver gene mutations(P<0.001).Furthermore,HRD-positive NSCLC had more amplifications in PI3K pathway and cell cycle genes,MET and MYC in epidermal growth factor receptor(EGFR)/anaplastic lymphoma kinase(ALK)mutant NSCLC,and more PIK3CA and AURKA in EGFR/ALK wild-type NSCLC.HRD-positive NSCLC displayed higher tumor proliferation and immunosuppression activity.HRD-negative NSCLC showed activated signatures of major histocompatibility complex(MHC)-II,interferon(IFN)-γand effector memory CD8+T cells.HRD-positive patients had a worse prognosis and shorter progressionfree survival(PFS)to targeted therapy(first-and third-generation EGFR-TKIs)(P=0.042).Additionally,HRDpositive,EGFR/ALK wild-type patients showed a numerically lower response to platinum-free immunotherapy regimens.Conclusions:Unique genomic and transcriptional characteristics were found in HRD-positive NSCLC.Poor prognosis and poor response to EGFR-TKIs and immunotherapy were observed in HRD-positive NSCLC.This study highlights potential actionable alterations in HRD-positive NSCLC,suggesting possible combinational therapeutic strategies for these patients.展开更多
Several studies have shown that activation of unfolded protein response and endoplasmic reticulum(ER)stress plays a crucial role in severe cerebral ischemia/reperfusion injury.Autophagy occurs within hours after cereb...Several studies have shown that activation of unfolded protein response and endoplasmic reticulum(ER)stress plays a crucial role in severe cerebral ischemia/reperfusion injury.Autophagy occurs within hours after cerebral ischemia,but the relationship between ER stress and autophagy remains unclear.In this study,we established experimental models using oxygen-glucose deprivation/reoxygenation in PC12 cells and primary neurons to simulate cerebral ischemia/reperfusion injury.We found that prolongation of oxygen-glucose deprivation activated the ER stress pathway protein kinase-like endoplasmic reticulum kinase(PERK)/eukaryotic translation initiation factor 2 subunit alpha(e IF2α)-activating transcription factor 4(ATF4)-C/EBP homologous protein(CHOP),increased neuronal apoptosis,and induced autophagy.Furthermore,inhibition of ER stress using inhibitors or by si RNA knockdown of the PERK gene significantly attenuated excessive autophagy and neuronal apoptosis,indicating an interaction between autophagy and ER stress and suggesting PERK as an essential target for regulating autophagy.Blocking autophagy with chloroquine exacerbated ER stress-induced apoptosis,indicating that normal levels of autophagy play a protective role in neuronal injury following cerebral ischemia/reperfusion injury.Findings from this study indicate that cerebral ischemia/reperfusion injury can trigger neuronal ER stress and promote autophagy,and suggest that PERK is a possible target for inhibiting excessive autophagy in cerebral ischemia/reperfusion injury.展开更多
We previously reported that miR-124-3p is markedly upregulated in microglia-derived exosomes following repetitive mild traumatic brain injury.However,its impact on neuronal endoplasmic reticulum stress following repet...We previously reported that miR-124-3p is markedly upregulated in microglia-derived exosomes following repetitive mild traumatic brain injury.However,its impact on neuronal endoplasmic reticulum stress following repetitive mild traumatic brain injury remains unclear.In this study,we first used an HT22 scratch injury model to mimic traumatic brain injury,then co-cultured the HT22 cells with BV2 microglia expressing high levels of miR-124-3p.We found that exosomes containing high levels of miR-124-3p attenuated apoptosis and endoplasmic reticulum stress.Furthermore,luciferase reporter assay analysis confirmed that miR-124-3p bound specifically to the endoplasmic reticulum stress-related protein IRE1α,while an IRE1αfunctional salvage experiment confirmed that miR-124-3p targeted IRE1αand reduced its expression,thereby inhibiting endoplasmic reticulum stress in injured neurons.Finally,we delivered microglia-derived exosomes containing miR-124-3p intranasally to a mouse model of repetitive mild traumatic brain injury and found that endoplasmic reticulum stress and apoptosis levels in hippocampal neurons were significantly reduced.These findings suggest that,after repetitive mild traumatic brain injury,miR-124-3 can be transferred from microglia-derived exosomes to injured neurons,where it exerts a neuroprotective effect by inhibiting endoplasmic reticulum stress.Therefore,microglia-derived exosomes containing miR-124-3p may represent a novel therapeutic strategy for repetitive mild traumatic brain injury.展开更多
BACKGROUND The precise role of mitochondrial carrier homolog 2(MTCH2)in promoting malignancy in gastric mucosal cells and its involvement in gastric cancer cell metastasis have not been fully elucidated.AIM To determi...BACKGROUND The precise role of mitochondrial carrier homolog 2(MTCH2)in promoting malignancy in gastric mucosal cells and its involvement in gastric cancer cell metastasis have not been fully elucidated.AIM To determine the role of MTCH2 in gastric cancer.METHODS We collected 65 samples of poorly differentiated gastric cancer tissue and adjacent tissues,constructed MTCH2-overexpressing and MTCH2-knockdown cell models,and evaluated the proliferation,migration,and invasion of human gastric epithelial cells(GES-1)and human gastric cancer cells(AGS)cells.The mito-chondrial membrane potential(MMP),mitochondrial permeability transformation pore(mPTP)and ATP fluorescence probe were used to detect mitochondrial function.Mitochondrial function and ATP synthase protein levels were detected via Western blotting.RESULTS The expression of MTCH2 and ATP2A2 in gastric cancer tissues was significantly greater than that in adjacent tissues.Overexpression of MTCH2 promoted colony formation,invasion,migration,MMP expression and ATP production in GES-1 and AGS cells while upregulating ATP2A2 expression and inhibiting cell apoptosis;knockdown of MTCH2 had the opposite effect,promoting overactivation of the mPTP and promoting apoptosis.CONCLUSION MTCH2 can increase the malignant phenotype of GES-1 cells and promote the proliferation,invasion,and migration of gastric cancer cells by regulating mitochondrial function,providing a basis for targeted therapy for gastric cancer cells.展开更多
Objective:The choice of chemotherapeutic regimen for triple-negative breast cancer(TNBC)remains controversial.Homologous recombination deficiency(HRD)has attracted increasing attention in informing chemotherapy treatm...Objective:The choice of chemotherapeutic regimen for triple-negative breast cancer(TNBC)remains controversial.Homologous recombination deficiency(HRD)has attracted increasing attention in informing chemotherapy treatment.This study was aimed at investigating the feasibility of HRD as a clinically actionable biomarker for platinum-containing and platinum-free therapy.Methods:Chinese patients with TNBC who received chemotherapy between May 1,2008 and March 31,2020 were retrospectively analyzed with a customized 3D-HRD panel.HRD positivity was defined by an HRD score≥30 or deleterious BRCA1/2 mutation.A total of 386 chemotherapy-treated patients with TNBC were screened from a surgical cohort(NCT01150513)and a metastatic cohort,and 189 patients with available clinical and tumor sequencing data were included.Results:In the entire cohort,49.2%(93/189)of patients were identified as HRD positive(40 with deleterious BRCA1/2 mutations and 53 with BRCA1/2 intact with an HRD score of≥30).In the first-line metastatic setting,platinum therapy was associated with longer median progression-free survival(mPFS)than platinum-free therapy[9.1 vs.3.0 months;hazard ratio(HR),0.43;95%confidence interval 0.22–0.84;P=0.01].Among HRD-positive patients,the mPFS was significantly longer in those treated with platinum rather than platinum-free therapy(13.6 vs.2.0 months;HR,0.11;P=0.001).Among patients administered a platinum-free regimen,HRD-negative patients showed a PFS significantly superior to that of HRD-positive patients(P=0.02;treatment-biomarker P-interaction=0.001).Similar results were observed in the BRCA1/2-intact subset.In the adjuvant setting,HRD-positive patients tended to benefit more from platinum chemotherapy than from platinum-free chemotherapy(P=0.05,P-interaction=0.02).Conclusions:HRD characterization may guide decision-making regarding the use of platinum treatment in patients with TNBC in both adjuvant and metastatic settings.展开更多
The retinal ganglion cells of the optic nerve have a limited capacity for self-repair after injury.Valproate is a histone deacetylase inhibitor and multitarget drug,which has been demonstrated to protect retinal neuro...The retinal ganglion cells of the optic nerve have a limited capacity for self-repair after injury.Valproate is a histone deacetylase inhibitor and multitarget drug,which has been demonstrated to protect retinal neurons.In this study,we established rat models of optic nerve-crush injury and injected valproate into the vitreous cavity immediately after modeling.We evaluated changes in the ultrastructure morphology of the endoplasmic reticulum of retinal ganglion cells over time via transmission electron microscope.Immunohistochemistry and western blot assay revealed that valproate upregulated the expression of the endoplasmic reticulum stress marker glucose-regulated protein 78 and downregulated the expression of transcription factor C/EBP homologous protein,phosphorylated eukaryotic translation initiation factor 2α,and caspase-12 in the endoplasmic reticulum of retinal ganglion cells.These findings suggest that valproate reduces apoptosis of retinal ganglion cells in the rat after optic nerve-crush injury by attenuating phosphorylated eukaryotic translation initiation factor 2α-C/EBP homologous protein signaling and caspase-12 activation during endoplasmic reticulum stress.These findings represent a newly discovered mechanism that regulates how valproate protects neurons.展开更多
Activating V600E in v-Raf murine sarcoma viral oncogene homolog B(BRAF)is a common driver mutation in cancers of multiple tissue origins,including melanoma and glioma.BRAF^(V600E) has also been implicated in neurodege...Activating V600E in v-Raf murine sarcoma viral oncogene homolog B(BRAF)is a common driver mutation in cancers of multiple tissue origins,including melanoma and glioma.BRAF^(V600E) has also been implicated in neurodegeneration.The present study aims to characterize BRAF^(V600E) during cell death and proliferation of three major cell types of the central nervous system:neurons,astrocytes,and microglia.Multiple primary cultures(primary cortical mixed culture)and cell lines of glial cells(BV2)and neurons(SH-SY5Y)were employed.BRAF^(V600E) and BRAF^(WT) expression was mediated by lentivirus or retrovirus.Blockage of downstream effectors(extracellular signal-regulated kinase 1/2 and JNK1/2)were achieved by siRNA.In astrocytes and microglia,BRAF^(V600E) induces cell proliferation,and the proliferative effect in microglia is mediated by activated extracellular signal-regulated kinase,but not c-Jun N-terminal kinase.Conditioned medium from BRAF^(V600E)-expressing microglia induced neuronal death.In neuronal cells,BRAF^(V600E) directly induces neuronal death,through c-Jun N-terminal kinase but not extracellular signal-regulated kinase.We further show that BRAF-related genes are enriched in pathways in patients with Parkinson’s disease.Our study identifies distinct consequences mediated by distinct downstream effectors in dividing glial cells and in neurons following the same BRAF mutational activation and a causal link between BRAF-activated microglia and neuronal cell death that does not require physical proximity.It provides insight into a possibly important role of BRAF in neurodegeneration as a result of either dysregulated BRAF in neurons or its impact on glial cells.展开更多
Objective:Histone modification has a significant effect on gene expression.Enhancer of zeste homolog 2(EZH2)contributes to the epigenetic silencing of target chromatin through its roles as a histone-lysine N-methyltra...Objective:Histone modification has a significant effect on gene expression.Enhancer of zeste homolog 2(EZH2)contributes to the epigenetic silencing of target chromatin through its roles as a histone-lysine N-methyltransferase enzyme.The development of anoikis resistance in tumor cells is considered to be a critical step in the metastatic process of primary malignant tumors.The purpose of this study was to investigate the effect and mechanism of anoikis resistance in ovarian adenocarcinoma peritoneal metastasis.Methods:In addition to examining EZH2 protein expression in ovarian cancer omental metastatic tissues,we established a model of ovarian cancer cell anoikis and a xenograft tumor model in nude mice.Anoikis resistance and ovarian cancer progression were tested after EZH2 and N6-methyladenosine(m6A)levels were modified.Results:EZH2 expression was significantly higher in ovarian cancer omental metastatic tissues than in normal ovarian tissues.Reducing the level of EZH2 decreased the level of m6A and ovarian cancer cell anoikis resistance in vitro and inhibited ovarian cancer progression in vivo.M6a regulation altered the effect of EZH2 on anoikis resistance.Conclusion:Our results indicate that EZH2 contributes to anoikis resistance and promotes ovarian adenocarcinoma abdominal metastasis by m6A modification.Our findings imply the potential of the clinical application of m6A and EZH2 for patients with ovarian cancer.展开更多
BACKGROUND Diabetes is a chronic metabolic disease,and a variety of miRNA are involved in the occurrence and development of diabetes.In clinical studies,miR-124 is highly expressed in the serum of patients with diabet...BACKGROUND Diabetes is a chronic metabolic disease,and a variety of miRNA are involved in the occurrence and development of diabetes.In clinical studies,miR-124 is highly expressed in the serum of patients with diabetes and in pancreatic isletβ-cells.However,few reports exist concerning the role and mechanism of action of miR-124 in diabetes.AIM To investigate the expression of miR-124 in diabetic mice and the potential mechanism of action in isletβ-cells.METHODS The expression levels of miR-124 and enhancer of zeste homolog 2(EZH2)in pancreatic tissues of diabetic mice were detected.The targeted relationship between miR-124 and EZH2 was predicted by Targetscan software and verified by a double luciferase reporter assay.Mouse isletβ-cells Min6 were grown in a high glucose(HG)medium to mimic a diabetes model.The insulin secretion,proliferation,cell cycle and apoptosis of HG-induced Min6 cells were detected after interference of miR-124a and/or EZH2.RESULTS The expression of miR-124 was upregulated and EZH2 was downregulated in the pancreatic tissue of diabetic mice compared with control mice,and the expression of miR-124 was negatively correlated with that of EZH2.miR-124 was highly expressed in HG-induced Min6 cells.Inhibition of miR-124 promoted insulin secretion and cell proliferation,induced the transition from the G0/G1 phase to the S phase of the cell cycle,and inhibited cell apoptosis in HG-induced Min6 cells.EZH2 was one of the targets of miR-124.Co-transfection of miR-124 inhibitor and siRNA-EZH2 could reverse the effects of the miR-124 inhibitor in HG-induced Min6 cells.CONCLUSION miR-124 is highly expressed in diabetic mice and HG-induced Min6 cells and regulates insulin secretion,proliferation and apoptosis of isletβ-cells by targeting EZH2.展开更多
BACKGROUND Hepatocellular carcinoma(HCC)is one of the most common digestive system cancers with high mortality rates worldwide.The main ingredients in Mu Ji Fang Granules(MJF)are alkaloids,flavonoids,and polysaccharid...BACKGROUND Hepatocellular carcinoma(HCC)is one of the most common digestive system cancers with high mortality rates worldwide.The main ingredients in Mu Ji Fang Granules(MJF)are alkaloids,flavonoids,and polysaccharides.MJF has been used in the clinical treatment of hepatitis,cirrhosis and HCC for more than 30 years.Few previous studies have focused on the mechanism of MJF on tumor immunology in the treatment of HCC.AIM To explore the mechanism of action of MJF on tumor immunology in the treatment of HCC.METHODS The absorbable ingredients of MJF were identified using Molecule Network related to High Performance Liquid Chromatography-Electron Spray Ionization-Time of Flight-Mass Spectrometry,and hub potential anti-HCC targets were screened using network pharmacology and pathway enrichment analysis.Forty male mice were randomly divided into the Blank,Model,and MJF groups(1.8,5.4,and 10.8 g/kg/d)following 7 d of oral administration.Average body weight gain,spleen and thymus indices were calculated,tumor tissues were stained with hematoxylin and eosin,and Interferon gamma(IFN-γ),Tumor necrosis factorα(TNF-α),Interleukin-2,aspartate aminotransferase,alanine aminotransferase,alpha-fetoprotein(AFP),Fas,and FasL were measured by Enzyme-linked Immunosorbent Assay.Relevant mRNA expression of Bax and Bcl2 was evaluated by Real Time Quantitative PCR(RTqPCR)and protein expression of Transforming growth factorβ1(TGF-β1)and Mothers against decapentaplegic homolog(SMAD)4 was assessed by Western blotting.The HepG2 cell line was treated with 10 mg/mL,20 mg/mL,30 mg/mL,40 mg/mL of MJF,and another 3 groups were treated with TGF-β1 inhibitor(LY364947)and different doses of MJF.Relevant mRNA expression of TNF-α,IFN-γ,Bax and Bcl2 was evaluated by RT-qPCR and protein expression of TGF-β1,SMAD2,p-SMAD2,SMAD4,and SMAD7 was assessed by Western blotting.RESULTS It was shown that MJF improved body weight gain and tumor inhibition rate in H22 tumorbearing mice,protected immune organs and liver function,reduced the HCC indicator AFP,affected immunity and apoptosis,and up-regulated the TGF-β1/SMAD signaling pathway,by increasing the relative expression of TGF-β1,SMAD2,p-SMAD2 and SMAD4 and decreasing SMAD7,reducing immune factors TNF-αand IFN-γ,decreasing apoptosis cytokines Fas,FasL and Bcl2/Bax,and inhibiting the effect of LY364947 in HepG2 cells.CONCLUSION MJF inhibits HCC by activating the TGF-β1/SMAD signaling pathway,and affecting immune and apoptotic cytokines,which may be due to MJF adjusting immune escape and apoptosis.展开更多
Axonal growth inhibitors are released during traumatic injuries to the adult mammalian central nervous system, including after spinal cord injury. These molecules accumulate at the injury site and form a highly inhibi...Axonal growth inhibitors are released during traumatic injuries to the adult mammalian central nervous system, including after spinal cord injury. These molecules accumulate at the injury site and form a highly inhibitory environment for axonal regeneration. Among these inhibitory molecules, myelinassociated inhibitors, including neurite outgrowth inhibitor A, oligodendrocyte myelin glycoprotein, myelin-associated glycoprotein, chondroitin sulfate proteoglycans and repulsive guidance molecule A are of particular importance. Due to their inhibitory nature, they represent exciting molecular targets to study axonal inhibition and regeneration after central injuries. These molecules are mainly produced by neurons, oligodendrocytes, and astrocytes within the scar and in its immediate vicinity. They exert their effects by binding to specific receptors, localized in the membranes of neurons. Receptors for these inhibitory cues include Nogo receptor 1, leucine-rich repeat, and Ig domain containing 1 and p75 neurotrophin receptor/tumor necrosis factor receptor superfamily member 19(that form a receptor complex that binds all myelin-associated inhibitors), and also paired immunoglobulin-like receptor B. Chondroitin sulfate proteoglycans and repulsive guidance molecule A bind to Nogo receptor 1, Nogo receptor 3, receptor protein tyrosine phosphatase σ and leucocyte common antigen related phosphatase, and neogenin, respectively. Once activated, these receptors initiate downstream signaling pathways, the most common amongst them being the Rho A/ROCK signaling pathway. These signaling cascades result in actin depolymerization, neurite outgrowth inhibition, and failure to regenerate after spinal cord injury. Currently, there are no approved pharmacological treatments to overcome spinal cord injuries other than physical rehabilitation and management of the array of symptoms brought on by spinal cord injuries. However, several novel therapies aiming to modulate these inhibitory proteins and/or their receptors are under investigation in ongoing clinical trials. Investigation has also been demonstrating that combinatorial therapies of growth inhibitors with other therapies, such as growth factors or stem-cell therapies, produce stronger results and their potential application in the clinics opens new venues in spinal cord injury treatment.展开更多
Shoot architecture in maize is critical since it determines resource use,impacts wind and rain damage tolerance,and affects yield stability.Quantifying the diversity among inbred lines in heterosis breeding is essenti...Shoot architecture in maize is critical since it determines resource use,impacts wind and rain damage tolerance,and affects yield stability.Quantifying the diversity among inbred lines in heterosis breeding is essential,especially when describing germplasm resources.However,traditional geometric description methods oversimplify shoot architecture and ignore the plant’s overall architecture,making it difficult to reflect and illustrate diversity.This study presents a new method to describe maize shoot architecture and quantifies its diversity by combining computer vision algorithms and persistent homology.Our results reveal that persistent homology can capture key characteristics of shoot architecture in maize and other details often overlooked by traditional geometric analysis.Based on this method,the morphological diversity of shoot architecture can be mined(quantified),and the main shoot architecture types can be obtained.Consequently,this method can easily describe the diversity of shoot architecture in many maize materials.展开更多
Artemisia annua is the only known plant source of the potent antimalarial artemisinin,which occurs as the low-and high-artemisinin producing(LAP and HAP)chemotypes.Nevertheless,the different mechanisms of artemisinin ...Artemisia annua is the only known plant source of the potent antimalarial artemisinin,which occurs as the low-and high-artemisinin producing(LAP and HAP)chemotypes.Nevertheless,the different mechanisms of artemisinin producing between these two chemotypes were still not fully understood.Here,we performed a comprehensive analysis of genome resequencing,metabolome,and transcriptome data to systematically compare the difference in the LAP chemotype JL and HAP chemotype HAN.Metabolites analysis revealed that 72.18%of sesquiterpenes was highly accumulated in HAN compared to JL.Integrated omics analysis found a DBR2-Like(DBR2L)gene may be involved in artemisinin biosynthesis.DBR2L was highly homologous with DBR2,belonged to ORR3 family,and had the DBR2 activity of catalyzing artemisinic aldehyde to dihydroartemisinic aldehyde.Genome resequencing and promoter cloning revealed that complicated variations existed in DBR2L promoters among different varieties of A.annua and were clustered into three variation types.The promoter activity of diverse variant types showed obvious differences.Furthermore,the core region(-625 to 0)of the DBR2L promoter was identified and candidate transcription factors involved in DBR2L regulation were screened.Thus,the result indicates that DBR2L is another key enzyme involved in artemisinin biosynthesis.The promoter variation in DBR2L affects its expression level,and thereby may result in the different yield of artemisinin in varieties of A.annua.It provides a novel insight into the mechanism of artemisinin-producing difference in LAP and HAP chemotypes of A.annua,and will assist in a high yield of artemisinin in A.annua.展开更多
BACKGROUND Obesity plays a vital role in the occurrence and development of non-alcoholic steatohepatitis(NASH).However,the underlining mechanism is still unclear,where adipose tissue(AT)derived exosomes may actively p...BACKGROUND Obesity plays a vital role in the occurrence and development of non-alcoholic steatohepatitis(NASH).However,the underlining mechanism is still unclear,where adipose tissue(AT)derived exosomes may actively participate.MicroRNAs(miRNAs)are commonly secreted from exosomes for cell communication.Though the regulation of miR-103 on insulin sensitivity has been reported,the specific role of AT-derived exosomes miR-103 in NASH is still vague and further investigation may provide novel therapeutic choices.AIM To determine the specific role of AT-derived exosomes miR-103 in developing NASH through various methods.METHODS The expression levels of miR-103 in the AT-derived exosomes and livers were detected and compared between NASH mice and control.The effect of miR-103 on NASH progression was also explored by antagonizing miR-103,including steatosis and inflammation degree changes.The interaction between miR-103 and the autophagy-related gene phosphatase and tensin homolog(PTEN)was confirmed by dual-luciferase reporter assay.The role of the interaction between miR-103 and PTEN on autophagy was verified in NASH-like cells.Finally,the effects of miR-103 from adipose-derived exosomes on NASH and autophagy were analyzed through animal experiments.RESULTS The expression of miR-103 was increased in NASH mice,compared to the control,and inhibition of miR-103 could alleviate NASH.The results of the dual-luciferase reporter assay showed miR-103 could interact with PTEN.MiR-103-anta decreased p-AMPKa,p-mammalian target of rapamycin(mTOR),and p62 but increased the protein levels of PTEN and LC3-II/I and the number of autophagosomes in NASH mice.Similar results were also observed in NASH-like cells,and further experiments showed PTEN silencing inhibited the effect of miR-103-anta.AT derivedexosome miR-103 aggravated NASH and increased the expressions of p-AMPKa,p-mTOR,and p62 but decreased the protein levels of PTEN and LC3-II/I and the number of autophagosomes in mice.CONCLUSION AT derived-exosome increased the levels of miR-103 in the liver,and miR-103 aggravated NASH.Mechanically,miR-103 could interact with PTEN and inhibit autophagy.展开更多
基金the Fundamental Research Funds for the Central Universities(JUSRP121045)the NSF of Jiangsu Province(BK20221057)。
文摘Let G be a reductive Nash group,acting on a Nash manifold X.Let Z be a G-stable closed Nash submanifold of X and denote by U the complement of Z in X.Letχbe a character of G and denote by g the complexified Lie algebra of G.We give a sufficient condition for the natural linear map H_(k)(g,S(U)×χ)→H_k(g,S(X)×χ)between the Lie algebra homologies of Schwartz functions to be an isomorphism.For k=0,by considering the dual,we obtain the automatic extensions of g-invariant(twisted by-χ)Schwartz distributions.
文摘Recently,Niculescu published an interesting paper^(1)con-cerning“deep homologies”between the formation of cancer stem cells by polyploidization and reproductive polyploidization of entamoeba.The life cycle of both sys-tems shares the same genetic machinery inherited from the Last Eukaryote Common Ancestor(LECA).This theory claims that cancer is nothing more than the expression of a pre-existing life cycle that was reactivated in“sick and weakened metazoan cell that cannot continue its multi-cellular life and finds itself in the same dead-end situation”.
基金funding by Bundesministerium der Verteidigung(BMVg),Germany。
文摘Towards higher impact velocities,ballistic events are increasingly determined by the material temperatures.Related effects might range from moderate thermal softening to full phase transition.In particular,it is of great interest to quantify the conditions for incipient or full melting of metals during impact interactions,which result in a transition from still strength-affected to hydrodynamic material behavior.In this work,we investigate to which extent the respective melting thresholds are also dependent on the initial,and generally elevated,temperatures of projectiles and targets before impact.This is studied through the application of a model developed recently by the authors to characterize the transition regime between high-velocity and hypervelocity impact,for which the melting thresholds of materials were used as the defining quantities.The obtained results are expected to be of general interest for ballistic application cases where projectiles or targets are preheated.Such conditions might result,for example,from aerodynamic forces acting onto a projectile during atmospheric flight,explosive shapedcharge-jet formation or armor exposure to environmental conditions.The performed analyses also broaden the scientific understanding of the relevance of temperature in penetration events,generally known since the 1960s,but often not considered thoroughly in impact studies.
文摘Bone biomaterials have been increasingly used to reconstruct maxillary atrophic ridges.Thus,the aim of this study was to evaluate bone reconstruction in the maxilla using a homologous cortico-cancellous FFB(lyophilized)graft and verify its reliability.Eight individuals were included from 2014 to 2018.The first surgery was performed to install homologous bone blocks in the maxilla.The period of the second intervention varied between 5 months and 15 days to 11 months(≈7.93 months).The biopsies were taken from the central region of the matured graft during the surgery for implant placement.All patients presented clinical and radiographic conditions for the installation of dental implants.There was a 100%of survival rate.The histological assessment showed that the homologous block bone graft was an osteoconductive biomaterial,with connective tissue present,and newly formed bone juxtaposed on its surface.There were bone trabeculae with osteocytes and active osteoblasts with connective tissue in the mineralization process;the remodeling process can be found through the reverse lines.A limited focus of necrosis with fibrosis was detected,with small resorption and areas of inflammatory infiltrate,but without clinical significance.The homologous block bone graft can be considered a feasible option to substitute the autogenous bone graft(gold standard),with predictable clinical and favorable histological results.The patients had a shorter surgical period,low morbidity,and an unlimited amount of biomaterial available at an accessible cost.
基金supported by the Natural Science Research Project of Anhui Province University, No.2023AH040394 (to TY)Hefei Comprehensive National Science Center Leading Medicine and Frontier Technology Research Institute Project, No.2023IHM01073 (to TY)the Natural Science Foundation of Anhui Province, Nos.2308085QH258 (to JW), 2008085MH246 (to TY)。
文摘Reducing the secondary inflammatory response, which is partly mediated by microglia, is a key focus in the treatment of spinal cord injury. Src homology 2-containing protein tyrosine phosphatase 2(SHP2), encoded by PTPN11, is widely expressed in the human body and plays a role in inflammation through various mechanisms. Therefore, SHP2 is considered a potential target for the treatment of inflammation-related diseases. However, its role in secondary inflammation after spinal cord injury remains unclear. In this study, SHP2 was found to be abundantly expressed in microglia at the site of spinal cord injury. Inhibition of SHP2 expression using siRNA and SHP2 inhibitors attenuated the microglial inflammatory response in an in vitro lipopolysaccharide-induced model of inflammation. Notably, after treatment with SHP2 inhibitors, mice with spinal cord injury exhibited significantly improved hind limb locomotor function and reduced residual urine volume in the bladder. Subsequent in vitro experiments showed that, in microglia stimulated with lipopolysaccharide, inhibiting SHP2 expression promoted M2 polarization and inhibited M1 polarization. Finally, a co-culture experiment was conducted to assess the effect of microglia treated with SHP2 inhibitors on neuronal cells. The results demonstrated that inflammatory factors produced by microglia promoted neuronal apoptosis, while inhibiting SHP2 expression mitigated these effects. Collectively, our findings suggest that SHP2 enhances secondary inflammation and neuronal damage subsequent to spinal cord injury by modulating microglial phenotype. Therefore, inhibiting SHP2 alleviates the inflammatory response in mice with spinal cord injury and promotes functional recovery postinjury.
基金supported by the National High Level Hospital Clinical Research Funding(No.BJ-2219-195 and No.BJ-2023-090).
文摘Objective:The clinical significance of homologous recombination deficiency(HRD)in breast cancer,ovarian cancer,and prostate cancer has been established,but the value of HRD in non-small cell lung cancer(NSCLC)has not been fully investigated.This study aimed to systematically analyze the HRD status of untreated NSCLC and its relationship with patient prognosis to further guide clinical care.Methods:A total of 355 treatment-naïve NSCLC patients were retrospectively enrolled.HRD status was assessed using the AmoyDx Genomic Scar Score(GSS),with a score of≥50 considered HRD-positive.Genomic,transcriptomic,tumor microenvironmental characteristics and prognosis between HRD-positive and HRDnegative patients were analyzed.Results:Of the patients,25.1%(89/355)were HRD-positive.Compared to HRD-negative patients,HRDpositive patients had more somatic pathogenic homologous recombination repair(HRR)mutations,higher tumor mutation burden(TMB)(P<0.001),and fewer driver gene mutations(P<0.001).Furthermore,HRD-positive NSCLC had more amplifications in PI3K pathway and cell cycle genes,MET and MYC in epidermal growth factor receptor(EGFR)/anaplastic lymphoma kinase(ALK)mutant NSCLC,and more PIK3CA and AURKA in EGFR/ALK wild-type NSCLC.HRD-positive NSCLC displayed higher tumor proliferation and immunosuppression activity.HRD-negative NSCLC showed activated signatures of major histocompatibility complex(MHC)-II,interferon(IFN)-γand effector memory CD8+T cells.HRD-positive patients had a worse prognosis and shorter progressionfree survival(PFS)to targeted therapy(first-and third-generation EGFR-TKIs)(P=0.042).Additionally,HRDpositive,EGFR/ALK wild-type patients showed a numerically lower response to platinum-free immunotherapy regimens.Conclusions:Unique genomic and transcriptional characteristics were found in HRD-positive NSCLC.Poor prognosis and poor response to EGFR-TKIs and immunotherapy were observed in HRD-positive NSCLC.This study highlights potential actionable alterations in HRD-positive NSCLC,suggesting possible combinational therapeutic strategies for these patients.
基金supported by the National Natural Science Foundation of China,Nos.82260245(to YX),81660207(to YX),81960253(to YL),82160268(to YL),U1812403(to ZG)Science and Technology Projects of Guizhou Province,Nos.[2019]1440(to YX),[2020]1Z067(to WH)+1 种基金Cultivation Foundation of Guizhou Medical University,No.[20NSP069](to YX)Excellent Young Talents Plan of Guizhou Medical University,No.(2022)101(to WH)。
文摘Several studies have shown that activation of unfolded protein response and endoplasmic reticulum(ER)stress plays a crucial role in severe cerebral ischemia/reperfusion injury.Autophagy occurs within hours after cerebral ischemia,but the relationship between ER stress and autophagy remains unclear.In this study,we established experimental models using oxygen-glucose deprivation/reoxygenation in PC12 cells and primary neurons to simulate cerebral ischemia/reperfusion injury.We found that prolongation of oxygen-glucose deprivation activated the ER stress pathway protein kinase-like endoplasmic reticulum kinase(PERK)/eukaryotic translation initiation factor 2 subunit alpha(e IF2α)-activating transcription factor 4(ATF4)-C/EBP homologous protein(CHOP),increased neuronal apoptosis,and induced autophagy.Furthermore,inhibition of ER stress using inhibitors or by si RNA knockdown of the PERK gene significantly attenuated excessive autophagy and neuronal apoptosis,indicating an interaction between autophagy and ER stress and suggesting PERK as an essential target for regulating autophagy.Blocking autophagy with chloroquine exacerbated ER stress-induced apoptosis,indicating that normal levels of autophagy play a protective role in neuronal injury following cerebral ischemia/reperfusion injury.Findings from this study indicate that cerebral ischemia/reperfusion injury can trigger neuronal ER stress and promote autophagy,and suggest that PERK is a possible target for inhibiting excessive autophagy in cerebral ischemia/reperfusion injury.
基金supported by the Haihe Laboratory of Cell Ecosystem Innovation Fund,No.22HHXBSS00047(to PL)the National Natural Science Foundation of China,Nos.82072166(to PL),82071394(to XG)+4 种基金Science and Technology Planning Project of Tianjin,No.20YFZCSY00030(to PL)Science and Technology Project of Tianjin Municipal Health Commission,No.TJWJ2021QN005(to XG)Tianjin Key Medical Discipline(Specialty)Construction Project,No.TJYXZDXK-006ATianjin Municipal Education Commission Scientific Research Program Project,No.2020KJ164(to JZ)China Postdoctoral Science Foundation,No.2022M712392(to ZY).
文摘We previously reported that miR-124-3p is markedly upregulated in microglia-derived exosomes following repetitive mild traumatic brain injury.However,its impact on neuronal endoplasmic reticulum stress following repetitive mild traumatic brain injury remains unclear.In this study,we first used an HT22 scratch injury model to mimic traumatic brain injury,then co-cultured the HT22 cells with BV2 microglia expressing high levels of miR-124-3p.We found that exosomes containing high levels of miR-124-3p attenuated apoptosis and endoplasmic reticulum stress.Furthermore,luciferase reporter assay analysis confirmed that miR-124-3p bound specifically to the endoplasmic reticulum stress-related protein IRE1α,while an IRE1αfunctional salvage experiment confirmed that miR-124-3p targeted IRE1αand reduced its expression,thereby inhibiting endoplasmic reticulum stress in injured neurons.Finally,we delivered microglia-derived exosomes containing miR-124-3p intranasally to a mouse model of repetitive mild traumatic brain injury and found that endoplasmic reticulum stress and apoptosis levels in hippocampal neurons were significantly reduced.These findings suggest that,after repetitive mild traumatic brain injury,miR-124-3 can be transferred from microglia-derived exosomes to injured neurons,where it exerts a neuroprotective effect by inhibiting endoplasmic reticulum stress.Therefore,microglia-derived exosomes containing miR-124-3p may represent a novel therapeutic strategy for repetitive mild traumatic brain injury.
基金the Medical Science Research Projects in Hebei Province,No.20221526and Natural Science Foundation,No.2022-271.
文摘BACKGROUND The precise role of mitochondrial carrier homolog 2(MTCH2)in promoting malignancy in gastric mucosal cells and its involvement in gastric cancer cell metastasis have not been fully elucidated.AIM To determine the role of MTCH2 in gastric cancer.METHODS We collected 65 samples of poorly differentiated gastric cancer tissue and adjacent tissues,constructed MTCH2-overexpressing and MTCH2-knockdown cell models,and evaluated the proliferation,migration,and invasion of human gastric epithelial cells(GES-1)and human gastric cancer cells(AGS)cells.The mito-chondrial membrane potential(MMP),mitochondrial permeability transformation pore(mPTP)and ATP fluorescence probe were used to detect mitochondrial function.Mitochondrial function and ATP synthase protein levels were detected via Western blotting.RESULTS The expression of MTCH2 and ATP2A2 in gastric cancer tissues was significantly greater than that in adjacent tissues.Overexpression of MTCH2 promoted colony formation,invasion,migration,MMP expression and ATP production in GES-1 and AGS cells while upregulating ATP2A2 expression and inhibiting cell apoptosis;knockdown of MTCH2 had the opposite effect,promoting overactivation of the mPTP and promoting apoptosis.CONCLUSION MTCH2 can increase the malignant phenotype of GES-1 cells and promote the proliferation,invasion,and migration of gastric cancer cells by regulating mitochondrial function,providing a basis for targeted therapy for gastric cancer cells.
基金granted by Capital’s Funds for Health Improvement and Research(Grant No.2018-2-4023)the National Natural Science Foundation of China(Grant No.82001559)。
文摘Objective:The choice of chemotherapeutic regimen for triple-negative breast cancer(TNBC)remains controversial.Homologous recombination deficiency(HRD)has attracted increasing attention in informing chemotherapy treatment.This study was aimed at investigating the feasibility of HRD as a clinically actionable biomarker for platinum-containing and platinum-free therapy.Methods:Chinese patients with TNBC who received chemotherapy between May 1,2008 and March 31,2020 were retrospectively analyzed with a customized 3D-HRD panel.HRD positivity was defined by an HRD score≥30 or deleterious BRCA1/2 mutation.A total of 386 chemotherapy-treated patients with TNBC were screened from a surgical cohort(NCT01150513)and a metastatic cohort,and 189 patients with available clinical and tumor sequencing data were included.Results:In the entire cohort,49.2%(93/189)of patients were identified as HRD positive(40 with deleterious BRCA1/2 mutations and 53 with BRCA1/2 intact with an HRD score of≥30).In the first-line metastatic setting,platinum therapy was associated with longer median progression-free survival(mPFS)than platinum-free therapy[9.1 vs.3.0 months;hazard ratio(HR),0.43;95%confidence interval 0.22–0.84;P=0.01].Among HRD-positive patients,the mPFS was significantly longer in those treated with platinum rather than platinum-free therapy(13.6 vs.2.0 months;HR,0.11;P=0.001).Among patients administered a platinum-free regimen,HRD-negative patients showed a PFS significantly superior to that of HRD-positive patients(P=0.02;treatment-biomarker P-interaction=0.001).Similar results were observed in the BRCA1/2-intact subset.In the adjuvant setting,HRD-positive patients tended to benefit more from platinum chemotherapy than from platinum-free chemotherapy(P=0.05,P-interaction=0.02).Conclusions:HRD characterization may guide decision-making regarding the use of platinum treatment in patients with TNBC in both adjuvant and metastatic settings.
基金supported by the National Natural Science Foundation of China,Nos.30772368(to DH),81371034(to XH)the Key Project of Natural Science Foundation of Shaanxi Province,No.2017JZ025(to DH).
文摘The retinal ganglion cells of the optic nerve have a limited capacity for self-repair after injury.Valproate is a histone deacetylase inhibitor and multitarget drug,which has been demonstrated to protect retinal neurons.In this study,we established rat models of optic nerve-crush injury and injected valproate into the vitreous cavity immediately after modeling.We evaluated changes in the ultrastructure morphology of the endoplasmic reticulum of retinal ganglion cells over time via transmission electron microscope.Immunohistochemistry and western blot assay revealed that valproate upregulated the expression of the endoplasmic reticulum stress marker glucose-regulated protein 78 and downregulated the expression of transcription factor C/EBP homologous protein,phosphorylated eukaryotic translation initiation factor 2α,and caspase-12 in the endoplasmic reticulum of retinal ganglion cells.These findings suggest that valproate reduces apoptosis of retinal ganglion cells in the rat after optic nerve-crush injury by attenuating phosphorylated eukaryotic translation initiation factor 2α-C/EBP homologous protein signaling and caspase-12 activation during endoplasmic reticulum stress.These findings represent a newly discovered mechanism that regulates how valproate protects neurons.
基金supported by the National Institutes of Health,No. R01NS102735 (to XC)the National Natural Science Foundation of China,No. 82073072 (to XC)+1 种基金the Michael J. Fox Foundation for Parkinson’s Research (MJFF)the Aligning Science Across Parkinson’s Initiative (ASAP),No. ASAP-000312 (to XC)
文摘Activating V600E in v-Raf murine sarcoma viral oncogene homolog B(BRAF)is a common driver mutation in cancers of multiple tissue origins,including melanoma and glioma.BRAF^(V600E) has also been implicated in neurodegeneration.The present study aims to characterize BRAF^(V600E) during cell death and proliferation of three major cell types of the central nervous system:neurons,astrocytes,and microglia.Multiple primary cultures(primary cortical mixed culture)and cell lines of glial cells(BV2)and neurons(SH-SY5Y)were employed.BRAF^(V600E) and BRAF^(WT) expression was mediated by lentivirus or retrovirus.Blockage of downstream effectors(extracellular signal-regulated kinase 1/2 and JNK1/2)were achieved by siRNA.In astrocytes and microglia,BRAF^(V600E) induces cell proliferation,and the proliferative effect in microglia is mediated by activated extracellular signal-regulated kinase,but not c-Jun N-terminal kinase.Conditioned medium from BRAF^(V600E)-expressing microglia induced neuronal death.In neuronal cells,BRAF^(V600E) directly induces neuronal death,through c-Jun N-terminal kinase but not extracellular signal-regulated kinase.We further show that BRAF-related genes are enriched in pathways in patients with Parkinson’s disease.Our study identifies distinct consequences mediated by distinct downstream effectors in dividing glial cells and in neurons following the same BRAF mutational activation and a causal link between BRAF-activated microglia and neuronal cell death that does not require physical proximity.It provides insight into a possibly important role of BRAF in neurodegeneration as a result of either dysregulated BRAF in neurons or its impact on glial cells.
基金funded by the National Natural Science Foundation of China(No.81672573)Natural Science Foundation of Xinjiang Uygur Autonomous Region(No.2021D01F21)Natural Science Foundation of Hubei Province(No.2021CFB474)。
文摘Objective:Histone modification has a significant effect on gene expression.Enhancer of zeste homolog 2(EZH2)contributes to the epigenetic silencing of target chromatin through its roles as a histone-lysine N-methyltransferase enzyme.The development of anoikis resistance in tumor cells is considered to be a critical step in the metastatic process of primary malignant tumors.The purpose of this study was to investigate the effect and mechanism of anoikis resistance in ovarian adenocarcinoma peritoneal metastasis.Methods:In addition to examining EZH2 protein expression in ovarian cancer omental metastatic tissues,we established a model of ovarian cancer cell anoikis and a xenograft tumor model in nude mice.Anoikis resistance and ovarian cancer progression were tested after EZH2 and N6-methyladenosine(m6A)levels were modified.Results:EZH2 expression was significantly higher in ovarian cancer omental metastatic tissues than in normal ovarian tissues.Reducing the level of EZH2 decreased the level of m6A and ovarian cancer cell anoikis resistance in vitro and inhibited ovarian cancer progression in vivo.M6a regulation altered the effect of EZH2 on anoikis resistance.Conclusion:Our results indicate that EZH2 contributes to anoikis resistance and promotes ovarian adenocarcinoma abdominal metastasis by m6A modification.Our findings imply the potential of the clinical application of m6A and EZH2 for patients with ovarian cancer.
基金Supported by The Medical Science and Technology Key Project of Henan Province,No.2018020733.
文摘BACKGROUND Diabetes is a chronic metabolic disease,and a variety of miRNA are involved in the occurrence and development of diabetes.In clinical studies,miR-124 is highly expressed in the serum of patients with diabetes and in pancreatic isletβ-cells.However,few reports exist concerning the role and mechanism of action of miR-124 in diabetes.AIM To investigate the expression of miR-124 in diabetic mice and the potential mechanism of action in isletβ-cells.METHODS The expression levels of miR-124 and enhancer of zeste homolog 2(EZH2)in pancreatic tissues of diabetic mice were detected.The targeted relationship between miR-124 and EZH2 was predicted by Targetscan software and verified by a double luciferase reporter assay.Mouse isletβ-cells Min6 were grown in a high glucose(HG)medium to mimic a diabetes model.The insulin secretion,proliferation,cell cycle and apoptosis of HG-induced Min6 cells were detected after interference of miR-124a and/or EZH2.RESULTS The expression of miR-124 was upregulated and EZH2 was downregulated in the pancreatic tissue of diabetic mice compared with control mice,and the expression of miR-124 was negatively correlated with that of EZH2.miR-124 was highly expressed in HG-induced Min6 cells.Inhibition of miR-124 promoted insulin secretion and cell proliferation,induced the transition from the G0/G1 phase to the S phase of the cell cycle,and inhibited cell apoptosis in HG-induced Min6 cells.EZH2 was one of the targets of miR-124.Co-transfection of miR-124 inhibitor and siRNA-EZH2 could reverse the effects of the miR-124 inhibitor in HG-induced Min6 cells.CONCLUSION miR-124 is highly expressed in diabetic mice and HG-induced Min6 cells and regulates insulin secretion,proliferation and apoptosis of isletβ-cells by targeting EZH2.
基金Supported by National Natural Science Foundation of China,No.81874342Natural Science Foundation of Liaoning Province,No.2020-MZLH-35.
文摘BACKGROUND Hepatocellular carcinoma(HCC)is one of the most common digestive system cancers with high mortality rates worldwide.The main ingredients in Mu Ji Fang Granules(MJF)are alkaloids,flavonoids,and polysaccharides.MJF has been used in the clinical treatment of hepatitis,cirrhosis and HCC for more than 30 years.Few previous studies have focused on the mechanism of MJF on tumor immunology in the treatment of HCC.AIM To explore the mechanism of action of MJF on tumor immunology in the treatment of HCC.METHODS The absorbable ingredients of MJF were identified using Molecule Network related to High Performance Liquid Chromatography-Electron Spray Ionization-Time of Flight-Mass Spectrometry,and hub potential anti-HCC targets were screened using network pharmacology and pathway enrichment analysis.Forty male mice were randomly divided into the Blank,Model,and MJF groups(1.8,5.4,and 10.8 g/kg/d)following 7 d of oral administration.Average body weight gain,spleen and thymus indices were calculated,tumor tissues were stained with hematoxylin and eosin,and Interferon gamma(IFN-γ),Tumor necrosis factorα(TNF-α),Interleukin-2,aspartate aminotransferase,alanine aminotransferase,alpha-fetoprotein(AFP),Fas,and FasL were measured by Enzyme-linked Immunosorbent Assay.Relevant mRNA expression of Bax and Bcl2 was evaluated by Real Time Quantitative PCR(RTqPCR)and protein expression of Transforming growth factorβ1(TGF-β1)and Mothers against decapentaplegic homolog(SMAD)4 was assessed by Western blotting.The HepG2 cell line was treated with 10 mg/mL,20 mg/mL,30 mg/mL,40 mg/mL of MJF,and another 3 groups were treated with TGF-β1 inhibitor(LY364947)and different doses of MJF.Relevant mRNA expression of TNF-α,IFN-γ,Bax and Bcl2 was evaluated by RT-qPCR and protein expression of TGF-β1,SMAD2,p-SMAD2,SMAD4,and SMAD7 was assessed by Western blotting.RESULTS It was shown that MJF improved body weight gain and tumor inhibition rate in H22 tumorbearing mice,protected immune organs and liver function,reduced the HCC indicator AFP,affected immunity and apoptosis,and up-regulated the TGF-β1/SMAD signaling pathway,by increasing the relative expression of TGF-β1,SMAD2,p-SMAD2 and SMAD4 and decreasing SMAD7,reducing immune factors TNF-αand IFN-γ,decreasing apoptosis cytokines Fas,FasL and Bcl2/Bax,and inhibiting the effect of LY364947 in HepG2 cells.CONCLUSION MJF inhibits HCC by activating the TGF-β1/SMAD signaling pathway,and affecting immune and apoptotic cytokines,which may be due to MJF adjusting immune escape and apoptosis.
基金a Ph D fellowship by FCT-Fundacao para a Ciência Tecnologia (SFRH/BD/135868/2018)(to SSC)。
文摘Axonal growth inhibitors are released during traumatic injuries to the adult mammalian central nervous system, including after spinal cord injury. These molecules accumulate at the injury site and form a highly inhibitory environment for axonal regeneration. Among these inhibitory molecules, myelinassociated inhibitors, including neurite outgrowth inhibitor A, oligodendrocyte myelin glycoprotein, myelin-associated glycoprotein, chondroitin sulfate proteoglycans and repulsive guidance molecule A are of particular importance. Due to their inhibitory nature, they represent exciting molecular targets to study axonal inhibition and regeneration after central injuries. These molecules are mainly produced by neurons, oligodendrocytes, and astrocytes within the scar and in its immediate vicinity. They exert their effects by binding to specific receptors, localized in the membranes of neurons. Receptors for these inhibitory cues include Nogo receptor 1, leucine-rich repeat, and Ig domain containing 1 and p75 neurotrophin receptor/tumor necrosis factor receptor superfamily member 19(that form a receptor complex that binds all myelin-associated inhibitors), and also paired immunoglobulin-like receptor B. Chondroitin sulfate proteoglycans and repulsive guidance molecule A bind to Nogo receptor 1, Nogo receptor 3, receptor protein tyrosine phosphatase σ and leucocyte common antigen related phosphatase, and neogenin, respectively. Once activated, these receptors initiate downstream signaling pathways, the most common amongst them being the Rho A/ROCK signaling pathway. These signaling cascades result in actin depolymerization, neurite outgrowth inhibition, and failure to regenerate after spinal cord injury. Currently, there are no approved pharmacological treatments to overcome spinal cord injuries other than physical rehabilitation and management of the array of symptoms brought on by spinal cord injuries. However, several novel therapies aiming to modulate these inhibitory proteins and/or their receptors are under investigation in ongoing clinical trials. Investigation has also been demonstrating that combinatorial therapies of growth inhibitors with other therapies, such as growth factors or stem-cell therapies, produce stronger results and their potential application in the clinics opens new venues in spinal cord injury treatment.
基金The study work was supported by the National Key Research and Development Program of China(2022ZD0401801)the Chinese Universities Scientific Funds(2023TC107).
文摘Shoot architecture in maize is critical since it determines resource use,impacts wind and rain damage tolerance,and affects yield stability.Quantifying the diversity among inbred lines in heterosis breeding is essential,especially when describing germplasm resources.However,traditional geometric description methods oversimplify shoot architecture and ignore the plant’s overall architecture,making it difficult to reflect and illustrate diversity.This study presents a new method to describe maize shoot architecture and quantifies its diversity by combining computer vision algorithms and persistent homology.Our results reveal that persistent homology can capture key characteristics of shoot architecture in maize and other details often overlooked by traditional geometric analysis.Based on this method,the morphological diversity of shoot architecture can be mined(quantified),and the main shoot architecture types can be obtained.Consequently,this method can easily describe the diversity of shoot architecture in many maize materials.
基金supported by the Fundamental Research Funds for the Central Public Welfare Research Institutes(ZZ13-YQ-101,ZZ16-ND-10-09,ZZ16-ND-10-28)the CACMS Innovation Fund(CI2021A04107),the National Natural Science Foundation of China(U1812403-1)+1 种基金the National Key Research and Development Project(2019YFE0108700,China)the Fundamental Research Funds for the Central Universities(3332022051).
文摘Artemisia annua is the only known plant source of the potent antimalarial artemisinin,which occurs as the low-and high-artemisinin producing(LAP and HAP)chemotypes.Nevertheless,the different mechanisms of artemisinin producing between these two chemotypes were still not fully understood.Here,we performed a comprehensive analysis of genome resequencing,metabolome,and transcriptome data to systematically compare the difference in the LAP chemotype JL and HAP chemotype HAN.Metabolites analysis revealed that 72.18%of sesquiterpenes was highly accumulated in HAN compared to JL.Integrated omics analysis found a DBR2-Like(DBR2L)gene may be involved in artemisinin biosynthesis.DBR2L was highly homologous with DBR2,belonged to ORR3 family,and had the DBR2 activity of catalyzing artemisinic aldehyde to dihydroartemisinic aldehyde.Genome resequencing and promoter cloning revealed that complicated variations existed in DBR2L promoters among different varieties of A.annua and were clustered into three variation types.The promoter activity of diverse variant types showed obvious differences.Furthermore,the core region(-625 to 0)of the DBR2L promoter was identified and candidate transcription factors involved in DBR2L regulation were screened.Thus,the result indicates that DBR2L is another key enzyme involved in artemisinin biosynthesis.The promoter variation in DBR2L affects its expression level,and thereby may result in the different yield of artemisinin in varieties of A.annua.It provides a novel insight into the mechanism of artemisinin-producing difference in LAP and HAP chemotypes of A.annua,and will assist in a high yield of artemisinin in A.annua.
基金the Natural Science Foundation of Zhejiang Province,No.LZ21H030002。
文摘BACKGROUND Obesity plays a vital role in the occurrence and development of non-alcoholic steatohepatitis(NASH).However,the underlining mechanism is still unclear,where adipose tissue(AT)derived exosomes may actively participate.MicroRNAs(miRNAs)are commonly secreted from exosomes for cell communication.Though the regulation of miR-103 on insulin sensitivity has been reported,the specific role of AT-derived exosomes miR-103 in NASH is still vague and further investigation may provide novel therapeutic choices.AIM To determine the specific role of AT-derived exosomes miR-103 in developing NASH through various methods.METHODS The expression levels of miR-103 in the AT-derived exosomes and livers were detected and compared between NASH mice and control.The effect of miR-103 on NASH progression was also explored by antagonizing miR-103,including steatosis and inflammation degree changes.The interaction between miR-103 and the autophagy-related gene phosphatase and tensin homolog(PTEN)was confirmed by dual-luciferase reporter assay.The role of the interaction between miR-103 and PTEN on autophagy was verified in NASH-like cells.Finally,the effects of miR-103 from adipose-derived exosomes on NASH and autophagy were analyzed through animal experiments.RESULTS The expression of miR-103 was increased in NASH mice,compared to the control,and inhibition of miR-103 could alleviate NASH.The results of the dual-luciferase reporter assay showed miR-103 could interact with PTEN.MiR-103-anta decreased p-AMPKa,p-mammalian target of rapamycin(mTOR),and p62 but increased the protein levels of PTEN and LC3-II/I and the number of autophagosomes in NASH mice.Similar results were also observed in NASH-like cells,and further experiments showed PTEN silencing inhibited the effect of miR-103-anta.AT derivedexosome miR-103 aggravated NASH and increased the expressions of p-AMPKa,p-mTOR,and p62 but decreased the protein levels of PTEN and LC3-II/I and the number of autophagosomes in mice.CONCLUSION AT derived-exosome increased the levels of miR-103 in the liver,and miR-103 aggravated NASH.Mechanically,miR-103 could interact with PTEN and inhibit autophagy.