MicroRNAs(miRNAs)have been demonstrated to control chicken skeletal muscle growth,however,the potential function of the miR-181-5p family in chicken myogenesis remains largely unknown.Here,our study identified the two...MicroRNAs(miRNAs)have been demonstrated to control chicken skeletal muscle growth,however,the potential function of the miR-181-5p family in chicken myogenesis remains largely unknown.Here,our study identified the two chicken(Gallus gallus;Gga)miR-181-5p family members widely expressed in various tissues,specifically miR-181a-5p and miR-181b-5p.Besides,the breast muscles of fast-growing broilers expressed higher levels of miR-181a-5p and miR-181b-5p than those of slow-growing layers.Functionally,miR-181a-5p and miR-181b-5p both promote the expression level of myogenic factors including myogenin(MyoG),myogenic differentiation 1(MyoD1),and myosin heavy chain(MyHC),meanwhile accelerating the myotube formation of skeletal muscle satellite cells(SMSCs).Mechanistically,miR-181a-5p and miR-181b-5p directly bind to the 3′untranslated region(UTR)of the transforming growth factor beta receptor 1(TGFBR1)mRNA,further reducing the expression of TGFBR1.TGFBR1 is a key Transforming growth factor beta(TGF-β)signaling transduction receptor and had a negative function in muscle cell differentiation.Furthermore,knockdown of TGFBR1 facilitated the expression of chicken myogenic factors,boosted myotube formation,and decreased the SMAD family member 2/3(SMAD2/3)phosphorylation in chicken SMSCs.SMAD2/3 are downstream of TGF-βsignaling,and miR-181a-5p and miR-181b-5p could reduce the expression of TGFBR1 to further diminish the SMAD2/3 phosphorylation.Our findings revealed that the miR-181-5p family targets TGFBR1 to break the TGF-βsignaling transduction,which resulted in promoting chicken skeletal muscle development.展开更多
Growing evidence suggests an association between epithelial-mesenchymal transition(EMT),a hallmark of tumor malignancy,and chemoresistance to a number of anti-cancer drugs.However,the mechanism of EMT induction in the...Growing evidence suggests an association between epithelial-mesenchymal transition(EMT),a hallmark of tumor malignancy,and chemoresistance to a number of anti-cancer drugs.However,the mechanism of EMT induction in the process of acquiring anti-cancer drug resistance remains unclear.To address this issue,we obtained a number of cisplatin-resistant clones from LoVo cells and found that almost all of them lost cell-cell contacts.In these clones,the epithelial marker E-cadherin was downregulated,whereas the mesenchymal marker N-cadherin was upregulated.Moreover,the expression of EMT-related transcription factors,including Slug,was elevated.On the other hand,the upregulation of other mesenchymal marker Vimentin was weak,suggesting that the mesenchymal-like phenotypic changes occurred in these cisplatin-resistant clones.These mesenchymal-like features of cisplatin-resistant clones were partially reversed to parental epithelial-like features by treatment with transforming growth factor-β(TGF-β)receptor kinase inhibitors,indicating that TGF-βsignaling is involved in cisplatin-induced the mesenchymallike phenotypic changes.Moreover,cisplatin was observed to enhance the secretion of TGF-βinto the culture media without influencing TGF-βgene transcription.These results suggest that cisplatin may induce the mesenchymal-like phenotypic changes by enhancing TGF-βsecretion,ultimately resulting in drug resistance.展开更多
Objective:To investigate possible mechanism of toxicarioside A in HS-5 bone stromal cells.Methods:HS-5 bone stromal cells were cultured in media supplemented with various concentrations of toxicarioside A or control D...Objective:To investigate possible mechanism of toxicarioside A in HS-5 bone stromal cells.Methods:HS-5 bone stromal cells were cultured in media supplemented with various concentrations of toxicarioside A or control DMSO(not treatment).Endoglin and TGF-βwere detected by Northern and Western blot analysis and quantified in a standard method. Downstream molecules of endoglin and TGF-β(Smad1,Smad2 and their active phosphorylated counterparts,pSmad1 and pSmad2) were also detected and quantified by Western blot analysis. In addition,cell proliferation assay and small interfering RNA(siRNA) against endoglin were used to certificate the function of endolgin in the HS-5 cells.Results:Compared with the not treated(0μg/mL) or DMSO treated control HS-5 cells,HS-5 cells treated with toxicarioside A were found significant attenuation of endolgin and TGF-βexpression.Significant inhibition of cell proliferation was also found in the HS-5 cells treated with toxicarioside A.ALK1-related Smad1 and ALK5-related Smad2 were decreased in HS-5 cells treated with toxicarioside A.In addition,phosphorylated Smad1(pSmad1) and Smad2(pSmad2) were also found attenuation in toxicarioside A-treated HS-5 cells.RNA interference showed that blockage of endoglin by siRNA also decreased Smad1 and Smad2 expression in HS-5 cells.Conclusions:Our results indicate that toxicarioside A can influence bone marrow stromal HS-5’s function and inhibit HS-5 cell proliferation by alteration of endoglin-related ALK1(Smad1) and ALK5(Smad2) signaling.展开更多
Background: To explore the effects of electroacupuncture on cardiac function and myocardial fibrosis in rat models of heart failure, and to elucidate the underlying mechanism of electroacupuncture in heart failure tre...Background: To explore the effects of electroacupuncture on cardiac function and myocardial fibrosis in rat models of heart failure, and to elucidate the underlying mechanism of electroacupuncture in heart failure treatment. Methods: Healthy male Sprague-Dawley rats were allocated into three groups: Sham group, Model group, and electroacupuncture (Model + EA) group, with each group comprising 8 rats. The model underwent a procedure involving the ligation of the left anterior descending coronary artery to induce a model of heart failure. The Model + EA group was used for 7 consecutive days for electroacupuncture of bilateral Shenmen (HT7) and Tongli (HT5), once a day for 30 min each time. Left ventricular parameters in rats were assessed using a small-animal ultrasound machine to analyze changes in left ventricular end-diastolic volume, left ventricular end-systolic volume, left ventricular ejection fraction, and left ventricular fractional shortening. Serum interleukin-1β (IL-1β), cardiac troponin (cTn), and N-terminal brain natriuretic peptide precursor levels were measured using ELISA. Histopathological changes in rat myocardium were observed through HE staining, while collagen deposition in rat myocardial tissue was assessed using the Masson staining method. Picro sirius red staining, immunohistochemical staining, and RT-qPCR were utilized to distinguish between the various types of collagen deposition. The expression level of TGF-β1 and SMAD2/3/4/7 mRNA in rat myocardial tissues was determined using RT-qPCR. Additionally, western blot analysis was conducted to assess the protein expression levels of TGF-β1, SMAD3/7, and p-SMAD3 in rat myocardial tissues. Results: Compared with the Sham group, the left ventricular ejection fraction and left ventricular fractional shortening values of the Model group were significantly decreased (P < 0.01);the left ventricular end-diastolic volume and left ventricular end-systolic volume values were remarkably increased (P < 0.01);serum N-terminal brain natriuretic peptide precursor content was increased (P < 0.01);serum IL-1β and cTn levels were increased (P < 0.01);myocardial collagen volume fraction were increased (P < 0.01);and those of the expression of TGF-β1 and SMAD2/3/4 mRNA was increased (P < 0.01);the expression of SMAD7 mRNA was decreased (P < 0.01);the protein expression levels of TGF-β1, SMAD3, and p-Smad3 were increased (P < 0.01);the protein expression level of SMAD7 was decreased (P < 0.01) in the Model group. Compared to the Model group, the expression levels of the proteins TGF-β1, SMAD3, and p-Smad3 in myocardial tissue were found to be decreased (P < 0.01), and the expression level of the protein SMAD7 was found to be increased (P < 0.01) in the Model + EA group;the collagen volume fraction and deposition of type Ⅰ /Ⅲ collagen were decreased (P < 0.01) in the Model + EA group. Conclusion: Electroacupuncture alleviates myocardial fibrosis in rats with heart failure, and this effect is likely due to attributed to the modulation of the TGF-β1/Smads signaling pathway, which helps reduce collagen deposition in the extracellular matrix.展开更多
Tumor-derived exosomes (TEXs) enriched in immune suppressive molecules predominantly drive T-cell dysfunction and impair antitumor immunity. Chimeric antigen receptor (CAR) T-cell therapy has emerged as a promising tr...Tumor-derived exosomes (TEXs) enriched in immune suppressive molecules predominantly drive T-cell dysfunction and impair antitumor immunity. Chimeric antigen receptor (CAR) T-cell therapy has emerged as a promising treatment for refractory and relapsed hematological malignancies, but whether lymphoma TEXs have the same impact on CAR T-cell remains unclear. Here, we demonstrated that B-cell lymphoma-derived exosomes induce the initial activation of CD19-CAR T-cells upon stimulation with exosomal CD19. However, lymphoma TEXs might subsequently induce CAR T-cell apoptosis and impair the tumor cytotoxicity of the cells because of the upregulated expression of the inhibitory receptors PD-1, TIM3, and LAG3 upon prolonged exposure. Similar results were observed in the CAR T-cells exposed to plasma exosomes from patients with lymphoma. More importantly, single-cell RNA sequencing revealed that CAR T-cells typically showed differentiated phenotypes and regulatory T-cell (Treg) phenotype conversion. By blocking transforming growth factor β (TGF-β)-Smad3 signaling with TGF-β inhibitor LY2109761, the negative effects of TEXs on Treg conversion, terminal differentiation, and immune checkpoint expression were rescued. Collectively, although TEXs lead to the initial activation of CAR T-cells, the effect of TEXs suppressed CAR T-cells, which can be rescued by LY2109761. A treatment regimen combining CAR T-cell therapy and TGF-β inhibitors might be a novel therapeutic strategy for refractory and relapsed B-cell lymphoma.展开更多
Background:Nonalcoholic fatty liver disease(NAFLD)is a chronic condition characterized by a progressive decline in liver function,leading to disruptions in liver integrity and metabolic function,resulting in lipid dep...Background:Nonalcoholic fatty liver disease(NAFLD)is a chronic condition characterized by a progressive decline in liver function,leading to disruptions in liver integrity and metabolic function,resulting in lipid deposition and excessive accumulation of extracellular matrix(ECM).The pathogenesis of NAFLD is complex and not yet fully understood,contributing to the absence of specific therapeutic strategies.Peroxisome proliferator-activated receptor gamma(PPARγ)is a ligand-activated transcription factor pivotal in regulating lipid and glucose metabolism.However,the impacts of PPARγon NAFLD remains insufficiently explored.Thus,this study aimed to investigate the role of PPARγin NAFLD and its underlying molecular mechanisms.Methods:Chemical detection kits were utilized to quantify collagen content,alanine aminotransferase(ALT),and aspartate aminotransferase(AST)level variations.Quantitative real-time polymerase chain reaction(qRT-PCR)was employed to assess alterations in extracellular matrix-related genes and inflammatory response genes in liver tissue and HepG2 cells,while western blotting was conducted to analyze the levels of both PPARγand the TGF-β/Smad signaling pathway.Results:Our findings unveiled significantly reduced PPARγexpression in a rat model of NAFLD,leading to subsequent activation of the TGF-β/Smad signaling pathway.Furthermore,PPARγactivation effectively mitigated NAFLD progression by inhibiting inflammation and fibrosis-related gene expression and collagen production.On a cellular level,PPARγactivation was found to inhibit the expression of extracellular matrix-related genes such as matrix metalloproteinase 2(MMP2)and matrix metalloproteinase 9(MMP9),along with inflammatory response genes interleukin(IL)-1βand IL-6.Additionally,PPARγactivation led to a significant decrease in the levels of ALT and AST.At the molecular level,PPARγnotably down-regulated the TGF-β/Smad signaling pathway,which is known to promote liver fibrosis.Conclusion:These groundbreaking findings underscore PPARγactivation as a promising therapeutic approach to delay NAFLD progression by targeting the TGF-β/Smad signaling pathway in hepatic cells.This highlights the potential of PPARγas a promising therapeutic target for NAFLD management in clinical settings.展开更多
The current study aimed to assess the effect of timosaponin AⅢ(T-AⅢ)on drug-metabolizing enzymes during anticancer therapy.The in vivo experiments were conducted on nude and ICR mice.Following a 24-day administratio...The current study aimed to assess the effect of timosaponin AⅢ(T-AⅢ)on drug-metabolizing enzymes during anticancer therapy.The in vivo experiments were conducted on nude and ICR mice.Following a 24-day administration of T-AⅢ,the nude mice exhibited an induction of CYP2B10,MDR1,and CYP3A11 expression in the liver tissues.In the ICR mice,the expression levels of CYP2B10 and MDR1 increased after a three-day T-AⅢ administration.The in vitro assessments with HepG2 cells revealed that T-AⅢ induced the expression of CYP2B6,MDR1,and CYP3A4,along with constitutive androstane receptor(CAR)activation.Treatment with CAR siRNA reversed the T-AⅢ-induced increases in CYP2B6 and CYP3A4 expression.Furthermore,other CAR target genes also showed a significant increase in the expression.The up-regulation of murine CAR was observed in the liver tissues of both nude and ICR mice.Subsequent findings demonstrated that T-AⅢ activated CAR by inhibiting ERK1/2 phosphorylation,with this effect being partially reversed by the ERK activator t-BHQ.Inhibition of the ERK1/2 signaling pathway was also observed in vivo.Additionally,T-AⅢ inhibited the phosphorylation of EGFR at Tyr1173 and Tyr845,and suppressed EGF-induced phosphorylation of EGFR,ERK,and CAR.In the nude mice,T-AⅢ also inhibited EGFR phosphorylation.These results collectively indicate that T-AⅢ is a novel CAR activator through inhibition of the EGFR pathway.展开更多
Parkinson’s disease is a neurodegenerative disease characterized by motor and gastrointestinal dysfunction.Gastrointestinal dysfunction can precede the onset of motor symptoms by several years.Gut microbiota dysbiosi...Parkinson’s disease is a neurodegenerative disease characterized by motor and gastrointestinal dysfunction.Gastrointestinal dysfunction can precede the onset of motor symptoms by several years.Gut microbiota dysbiosis is involved in the pathogenesis of Parkinson’s disease,whether it plays a causal role in motor dysfunction,and the mechanism underlying this potential effect,remain unknown.CCAAT/enhancer binding proteinβ/asparagine endopeptidase(C/EBPβ/AEP)signaling,activated by bacterial endotoxin,can promoteα-synuclein transcription,thereby contributing to Parkinson’s disease pathology.In this study,we aimed to investigate the role of the gut microbiota in C/EBPβ/AEP signaling,α-synuclein-related pathology,and motor symptoms using a rotenone-induced mouse model of Parkinson’s disease combined with antibiotic-induced microbiome depletion and fecal microbiota transplantation.We found that rotenone administration resulted in gut microbiota dysbiosis and perturbation of the intestinal barrier,as well as activation of the C/EBP/AEP pathway,α-synuclein aggregation,and tyrosine hydroxylase-positive neuron loss in the substantia nigra in mice with motor deficits.However,treatment with rotenone did not have any of these adverse effects in mice whose gut microbiota was depleted by pretreatment with antibiotics.Importantly,we found that transplanting gut microbiota derived from mice treated with rotenone induced motor deficits,intestinal inflammation,and endotoxemia.Transplantation of fecal microbiota from healthy control mice alleviated rotenone-induced motor deficits,intestinal inflammation,endotoxemia,and intestinal barrier impairment.These results highlight the vital role that gut microbiota dysbiosis plays in inducing motor deficits,C/EBPβ/AEP signaling activation,andα-synuclein-related pathology in a rotenone-induced mouse model of Parkinson’s disease.Additionally,our findings suggest that supplementing with healthy microbiota may be a safe and effective treatment that could help ameliorate the progression of motor deficits in patients with Parkinson’s disease.展开更多
Autism spectrum disorders are a group of neurodevelopmental disorders involving more than 1100 genes,including Ctnnd2 as a candidate gene.Ctnnd2knockout mice,serving as an animal model of autis m,have been demonstrate...Autism spectrum disorders are a group of neurodevelopmental disorders involving more than 1100 genes,including Ctnnd2 as a candidate gene.Ctnnd2knockout mice,serving as an animal model of autis m,have been demonstrated to exhibit decreased density of dendritic spines.The role of melatonin,as a neuro hormone capable of effectively alleviating social interaction deficits and regulating the development of dendritic spines,in Ctnnd2 deletion-induced nerve injury remains unclea r.In the present study,we discove red that the deletion of exon 2 of the Ctnnd2 gene was linked to social interaction deficits,spine loss,impaired inhibitory neurons,and suppressed phosphatidylinositol-3-kinase(PI3K)/protein kinase B(Akt) signal pathway in the prefrontal cortex.Our findings demonstrated that the long-term oral administration of melatonin for 28 days effectively alleviated the aforementioned abnormalities in Ctnnd2 gene-knockout mice.Furthermore,the administration of melatonin in the prefro ntal cortex was found to improve synaptic function and activate the PI3K/Akt signal pathway in this region.The pharmacological blockade of the PI3K/Akt signal pathway with a PI3K/Akt inhibitor,wo rtmannin,and melatonin receptor antagonists,luzindole and 4-phenyl-2-propionamidotetralin,prevented the melatonin-induced enhancement of GABAergic synaptic function.These findings suggest that melatonin treatment can ameliorate GABAe rgic synaptic function by activating the PI3K/Akt signal pathway,which may contribute to the improvement of dendritic spine abnormalities in autism spectrum disorders.展开更多
Preclinical and clinical studies have shown that microglia and macrophages participate in a multiphasic brain damage repair process following intracerebral hemorrhage.The E26 transformation-specific sequence-related t...Preclinical and clinical studies have shown that microglia and macrophages participate in a multiphasic brain damage repair process following intracerebral hemorrhage.The E26 transformation-specific sequence-related transcription factor Spi1 regulates microglial/macrophage commitment and maturation.However,the effect of Spi1 on intracerebral hemorrhage remains unclear.In this study,we found that Spi1 may regulate recovery from the neuroinflammation and neurofunctional damage caused by intracerebral hemorrhage by modulating the microglial/macrophage transcriptome.We showed that high Spi1expression in microglia/macrophages after intracerebral hemorrhage is associated with the activation of many pathways that promote phagocytosis,glycolysis,and autophagy,as well as debris clearance and sustained remyelination.Notably,microglia with higher levels of Soil expression were chara cterized by activation of pathways associated with a variety of hemorrhage-related cellular processes,such as complement activation,angiogenesis,and coagulation.In conclusion,our results suggest that Spi1 plays a vital role in the microglial/macrophage inflammatory response following intracerebral hemorrhage.This new insight into the regulation of Spi1 and its target genes may advance our understanding of neuroinflammation in intracerebral hemorrhage and provide therapeutic targets for patients with intracerebral hemorrhage.展开更多
Type 2 diabetes mellitus(T2DM)is a complex metabolic disease threatening human health.We investigated the effects of Tegillarca granosa polysaccharide(TGP)and determined its potential mechanisms in a mouse model of T2...Type 2 diabetes mellitus(T2DM)is a complex metabolic disease threatening human health.We investigated the effects of Tegillarca granosa polysaccharide(TGP)and determined its potential mechanisms in a mouse model of T2DM established through a high-fat diet and streptozotocin.TGP(5.1×10^(3) Da)was composed of mannose,glucosamine,rhamnose,glucuronic acid,galactosamine,glucose,galactose,xylose,and fucose.It could significantly alleviate weight loss,reduce fasting blood glucose levels,reverse dyslipidemia,reduce liver damage from oxidative stress,and improve insulin sensitivity.RT-PCR and Western blotting indicated that TGP could activate the phosphatidylinositol-3-kinase/protein kinase B signaling pathway to regulate disorders in glucolipid metabolism and improve insulin resistance.TGP increased the abundance of Allobaculum,Akkermansia,and Bifidobacterium,restored the microbiota abundance in the intestinal tracts of mice with T2DM,and promoted short-chain fatty acid production.This study provides new insights into the antidiabetic effects of TGP and highlights its potential as a natural hypoglycemic nutraceutical.展开更多
BACKGROUND Fanlian Huazhuo Formula(FLHZF)has the functions of invigorating spleen and resolving phlegm,clearing heat and purging turbidity.It has been identified to have therapeutic effects on type 2 diabetes mellitus...BACKGROUND Fanlian Huazhuo Formula(FLHZF)has the functions of invigorating spleen and resolving phlegm,clearing heat and purging turbidity.It has been identified to have therapeutic effects on type 2 diabetes mellitus(T2DM)in clinical application.Non-alcoholic fatty liver disease(NAFLD)is frequently diagnosed in patients with T2DM.However,the therapeutic potential of FLHZF on NAFLD and the underlying mechanisms need further investigation.AIM To elucidate the effects of FLHZF on NAFLD and explore the underlying hepatoprotective mechanisms in vivo and in vitro.METHODS HepG2 cells were treated with free fatty acid for 24 hours to induce lipid accumulation cell model.Subsequently,experiments were conducted with the different concentrations of freeze-dried powder of FLHZF for 24 hours.C57BL/6 mice were fed a high-fat diet for 8-week to establish a mouse model of NAFLD,and then treated with the different concentrations of FLHZF for 10 weeks.RESULTS FLHZF had therapeutic potential against lipid accumulation and abnormal changes in biochemical indicators in vivo and in vitro.Further experiments verified that FLHZF alleviated abnormal lipid metabolism might by reducing oxidative stress,regulating the AMPKα/SREBP-1C signaling pathway,activating autophagy,and inhibiting hepatocyte apoptosis.CONCLUSION FLHZF alleviates abnormal lipid metabolism in NAFLD models by regulating reactive oxygen species,autophagy,apoptosis,and lipid synthesis signaling pathways,indicating its potential for clinical application in NAFLD.展开更多
Colorectal cancer(CRC)remains one of the most commonly diagnosed and deadliest types of cancer worldwide.CRC displays a desmoplastic reaction(DR)that has been inversely associated with poor prognosis;less DR is associ...Colorectal cancer(CRC)remains one of the most commonly diagnosed and deadliest types of cancer worldwide.CRC displays a desmoplastic reaction(DR)that has been inversely associated with poor prognosis;less DR is associated with a better prognosis.This reaction generates excessive connective tissue,in which cancer-associated fibroblasts(CAFs)are critical cells that form a part of the tumor microenvironment.CAFs are directly involved in tumorigenesis through different mechanisms.However,their role in immunosuppression in CRC is not well understood,and the precise role of signal transducers and activators of transcription(STATs)in mediating CAF activity in CRC remains unclear.Among the myriad chemical and biological factors that affect CAFs,different cytokines mediate their function by activating STAT signaling pathways.Thus,the harmful effects of CAFs in favoring tumor growth and invasion may be modulated using STAT inhibitors.Here,we analyze the impact of different STATs on CAF activity and their immunoregulatory role.展开更多
Ependymoma is a rare and chemotherapy-resistant brain tumor, which has resulted in a delay in the development of drugs to treat it. A subclass of supratentorial ependymomas (ST-EPN), designated ST-EPN-zinc finger-tran...Ependymoma is a rare and chemotherapy-resistant brain tumor, which has resulted in a delay in the development of drugs to treat it. A subclass of supratentorial ependymomas (ST-EPN), designated ST-EPN-zinc finger-translocation-associated (ZFTA, ST-EPN-ZFTA), exhibits the expression of a fusion protein comprising ZFTA and v-rel reticuloendotheliosis viral oncogene homolog A (RELA), an effector transcription factor of the nuclear factor-kappa B (NF-κB) pathway (ZFTA-RELA). The expression of ZFTA-RELA results in the hyperactivation of the oncogenic NF-κB signaling pathway, which ultimately leads to the development of ST-EPN-ZFTA. To identify inhibitors of the NF-κB signaling pathway activated by the expression of ZFTA-RELA, we used a doxycycline-inducible ZFTA-RELA-expressing NF-κB reporter cell line and found that extracts of the fungus Neosartorya spinosa IFM 47025 exhibited NF-κB inhibitory activity. We identified eight compounds [aszonapyrone A (2), sartorypyrone A (3), epiheveadride (4), acetylaszonalenin (5), (R)-benzodiazepinedione (6), aszonalenin (7), sartorypyrone E (8) and (Z, Z)-N,N’-(1,2-bis[(4-methoxyphenyl)methylene]-1,2-ethanediyl)bis-formamide (9)] from N. spinosa IFM 47025 culture extract using a variety of chromatographic techniques. The structures of these compounds were identified through the analysis of various instrumental data (1D, 2D-NMR, MS, and optical rotation). The NF-κB responsive reporter assay indicated that compounds 2, 3, 5, 7, and 9 exhibited inhibitory activity. We further evaluated the inhibitory activity of these compounds against the expression of endogenous NF-κB responsive genes (CCND1, L1CAM, ICAM1, and TNF) and found that compound 2 showed significant inhibitory activity. Further studies are required to elucidate the mechanism of action of compound 2, which may serve as a lead compound for the development of a novel therapy for ST-EPN-ZFTA.展开更多
Functionally referential signals are a complex form of communication that conveys information about the external environment.Such signals have been found in a range of mammal and bird species and have helped us unders...Functionally referential signals are a complex form of communication that conveys information about the external environment.Such signals have been found in a range of mammal and bird species and have helped us understand the complexities of animal communication.Corvids are well known for their extraordinary cognitive abilities,but relatively little attention has been paid to their vocal function.Here,we investigated the functionally referential signals of a cooperatively breeding corvid species,Azure-winged Magpie(Cyanopica cyanus).Through field observations,we suggest that Azure-winged Magpie uses referential alarm calls to distinguish two types of threats:’rasp’ calls for terrestrial threats and ’chatter’ calls for aerial threats.A playback experiment revealed that Azure-winged Magpies responded to the two call types with qualitatively different behaviors.They sought cover by flying into the bushes in response to the ’chatter’ calls,and flew to or stayed at higher positions in response to ’rasp’ calls,displaying a shorter response time to ’chatter’ calls.Significant differences in acoustic structure were found between the two types of calls.Given the extensive cognitive abilities of corvids and the fact that referential signals were once thought to be unique to primates,these findings are important for expanding our understanding of social communication and language evolution.展开更多
Mitochondrial calcium uniporter(MCU)is a conserved calcium ion(Ca^(2+))transporter in the mitochondrial inner membrane of eukaryotic cells.How MCU proteins regulate Ca^(2+)flow and modulate plant cell development rema...Mitochondrial calcium uniporter(MCU)is a conserved calcium ion(Ca^(2+))transporter in the mitochondrial inner membrane of eukaryotic cells.How MCU proteins regulate Ca^(2+)flow and modulate plant cell development remain largely unclear.Here,we identified the gene GhMCU4 encoding a MCU protein that negatively regulates plant development and fiber elongation in cotton(Gossypium hirsutum).GhMCU4expressed constitutively in various tissues with the higher transcripts in elongating fiber cells.Knockdown of GhMCU4 in cotton significantly elevated the plant height and root length.The calcium signaling pathway was significantly activated and calcium sensor genes,including Ca^(2+)dependent modulator of interactor of constitutively active ROP(GhCMI1),calmodulin like protein(GhCML46),calciumdependent protein kinases(GhCPKs),calcineurin B-like protein(GhCBLs),and CBL-interacting protein kinases(GhCIPKs),were dramatically upregulated in GhMCU4-silenced plants.Metabolic processes were preferentially enriched,and genes related to regulation of transcription were upregulated in GhMCU4-silenced plants.The contents of Ca^(2+)and H_(2)O_(2)were significantly increased in roots and leaves of GhMCU4-silenced plants.Fiber length and Ca^(2+)and H_(2)O_(2)contents in fibers were significantly increased in GhMCU4-silenced plants.This study indicated that GhMCU4 plays a negative role in regulating cell elongation in cotton,thus expanding understanding in the role of MCU proteins in plant growth and development.展开更多
Senescence-induced NAC(senNAC)TFs play a crucial role in senescence during the final stage of leaf development.In this study,we identified a rice senNAC,ONAC016,which functions as a positive regulator of leaf senescen...Senescence-induced NAC(senNAC)TFs play a crucial role in senescence during the final stage of leaf development.In this study,we identified a rice senNAC,ONAC016,which functions as a positive regulator of leaf senescence.The expression of ONAC016 increased rapidly in rice leaves during the progression of dark-induced and natural senescence.The onac016-1 knockout mutant showed a delayed leaf yellowing phenotype,whereas the overexpression of ONAC016 accelerated leaf senescence.Notably,ONAC016 expression was upregulated by abscisic acid(ABA),and thus detached leaves of the onac016-1 mutant remained green much longer under ABA treatment.Quantitative RT-PCR analysis showed that ONAC016 upregulates the genes associated with chlorophyll degradation,senescence,and ABA signaling.Yeast one-hybrid and dual-luciferase assays revealed that ONAC016 binds directly to the promoter regions of OsNAP,a key gene involved in chlorophyll degradation and ABA-induced senescence.Taken together,these results suggest that ONAC016 plays an important role in promoting leaf senescence through the ABA signaling pathway involving OsNAP.展开更多
Plant Homeo Domain(PHD)proteins are involved in diverse biological processes during plant growth.However,the regulation of PHD genes on rice cold stress response remains largely unknown.Here,we reported that PHD17 neg...Plant Homeo Domain(PHD)proteins are involved in diverse biological processes during plant growth.However,the regulation of PHD genes on rice cold stress response remains largely unknown.Here,we reported that PHD17 negatively regulated cold tolerance in rice seedlings as a cleavage target of miR1320.PHD17 expression was greatly induced by cold stress,and was down-regulated by miR1320 overexpression and up-regulated by miR1320 knockdown.Through 5'RACE and dual luciferase assays,we found that miR1320 targeted and cleaved the 3'UTR region of PHD17.PHD17 was a nuclearlocalized protein and acted as a transcriptional activator in yeast.PHD17 overexpression reduced cold tolerance of rice seedlings,while knockout of PHD17 increased cold tolerance,partially via the CBF cold signaling.By combining transcriptomic and physiological analyses,we demonstrated that PHD17 modulated ROS homeostasis and flavonoid accumulation under cold stress.K-means clustering analysis revealed that differentially expressed genes in PHD17 transgenic lines were significantly enriched in the jasmonic acid(JA)biosynthesis pathway,and expression of JA biosynthesis and signaling genes was verified to be affected by PHD17.Cold stress tests applied with MeJA or IBU(JA synthesis inhibitor)further suggested the involvement of PHD17 in JA-mediated cold signaling.Taken together,our results suggest that PHD17 acts downstream of miR1320 and negatively regulates cold tolerance of rice seedlings through JA-mediated signaling pathway.展开更多
Plant calmodulins(CaMs)and calmodulin-like proteins(CMLs)mediate Ca~(2+)signaling in response to abiotic stresses.Manipulation of this signaling in crops could increase stress tolerance.We review methods for detecting...Plant calmodulins(CaMs)and calmodulin-like proteins(CMLs)mediate Ca~(2+)signaling in response to abiotic stresses.Manipulation of this signaling in crops could increase stress tolerance.We review methods for detecting Ca~(2+)signals,regulatory roles of Ca Ms and CMLs,binding targets,and Ca~(2+)networks under abiotic stress in organelles.展开更多
Hepatocellular carcinoma(HCC)is one of the common most malignant tumors.This study aimed to determine the in vitro and in vivo anticancer activity of cordycepin and elucidate its mechanism of action.The results of in ...Hepatocellular carcinoma(HCC)is one of the common most malignant tumors.This study aimed to determine the in vitro and in vivo anticancer activity of cordycepin and elucidate its mechanism of action.The results of in vitro and in vivo studies revealed that cordycepin inhibited proliferation and migration in HepG-2 cells and inhibited the growth of HepG-2 xenograft-bearing nude mice by inducing apoptosis.Transcriptome sequencing analysis revealed a total of 403 differential genes,which revealed that cordycepin may play an anti-HCC role by regulating Hippo signaling pathway.The regulatory effects of cordycepin on the Hippo signaling pathway was further investigated using a YAP1 inhibitor.The results demonstrated that cordycepin upregulated the expression of MST1 and LAST1,and subsequently inhibited YAP1,which activated the Hippo signaling pathway.This in turn downregulated the expression of GBP3 and ETV5,and subsequently inhibited cell proliferation and migration.Additionally,YAP1 regulated the expression of Bax and Bcl-2,regulated the mitochondrial apoptotic pathway,and induced apoptosis by upregulating the expression of the caspase-3 protein.In summary,this study reveals that cordycepin exerts its anti-hepatocarcinoma effect through regulating Hippo signaling pathway,and GBP3 and ETV5 may be potential therapeutic targets for hepatocarcinoma.展开更多
基金supported by the National Key Research and Development Program of China(2022YFF10002020)Sichuan Science and Technology Program,China(2021YFYZ0007 and 2021YFYZ0031).
文摘MicroRNAs(miRNAs)have been demonstrated to control chicken skeletal muscle growth,however,the potential function of the miR-181-5p family in chicken myogenesis remains largely unknown.Here,our study identified the two chicken(Gallus gallus;Gga)miR-181-5p family members widely expressed in various tissues,specifically miR-181a-5p and miR-181b-5p.Besides,the breast muscles of fast-growing broilers expressed higher levels of miR-181a-5p and miR-181b-5p than those of slow-growing layers.Functionally,miR-181a-5p and miR-181b-5p both promote the expression level of myogenic factors including myogenin(MyoG),myogenic differentiation 1(MyoD1),and myosin heavy chain(MyHC),meanwhile accelerating the myotube formation of skeletal muscle satellite cells(SMSCs).Mechanistically,miR-181a-5p and miR-181b-5p directly bind to the 3′untranslated region(UTR)of the transforming growth factor beta receptor 1(TGFBR1)mRNA,further reducing the expression of TGFBR1.TGFBR1 is a key Transforming growth factor beta(TGF-β)signaling transduction receptor and had a negative function in muscle cell differentiation.Furthermore,knockdown of TGFBR1 facilitated the expression of chicken myogenic factors,boosted myotube formation,and decreased the SMAD family member 2/3(SMAD2/3)phosphorylation in chicken SMSCs.SMAD2/3 are downstream of TGF-βsignaling,and miR-181a-5p and miR-181b-5p could reduce the expression of TGFBR1 to further diminish the SMAD2/3 phosphorylation.Our findings revealed that the miR-181-5p family targets TGFBR1 to break the TGF-βsignaling transduction,which resulted in promoting chicken skeletal muscle development.
基金the Japan Society for the Promotion of Science(JSPS),KAKENHI,Grant Number 26350974.
文摘Growing evidence suggests an association between epithelial-mesenchymal transition(EMT),a hallmark of tumor malignancy,and chemoresistance to a number of anti-cancer drugs.However,the mechanism of EMT induction in the process of acquiring anti-cancer drug resistance remains unclear.To address this issue,we obtained a number of cisplatin-resistant clones from LoVo cells and found that almost all of them lost cell-cell contacts.In these clones,the epithelial marker E-cadherin was downregulated,whereas the mesenchymal marker N-cadherin was upregulated.Moreover,the expression of EMT-related transcription factors,including Slug,was elevated.On the other hand,the upregulation of other mesenchymal marker Vimentin was weak,suggesting that the mesenchymal-like phenotypic changes occurred in these cisplatin-resistant clones.These mesenchymal-like features of cisplatin-resistant clones were partially reversed to parental epithelial-like features by treatment with transforming growth factor-β(TGF-β)receptor kinase inhibitors,indicating that TGF-βsignaling is involved in cisplatin-induced the mesenchymallike phenotypic changes.Moreover,cisplatin was observed to enhance the secretion of TGF-βinto the culture media without influencing TGF-βgene transcription.These results suggest that cisplatin may induce the mesenchymal-like phenotypic changes by enhancing TGF-βsecretion,ultimately resulting in drug resistance.
基金partially funded by National Basic Research Program of China(2010CB534909)National Natural Science Foundation of China(30960411 and 81160288)Hainan Provincial Key Scientific Project(061009)
文摘Objective:To investigate possible mechanism of toxicarioside A in HS-5 bone stromal cells.Methods:HS-5 bone stromal cells were cultured in media supplemented with various concentrations of toxicarioside A or control DMSO(not treatment).Endoglin and TGF-βwere detected by Northern and Western blot analysis and quantified in a standard method. Downstream molecules of endoglin and TGF-β(Smad1,Smad2 and their active phosphorylated counterparts,pSmad1 and pSmad2) were also detected and quantified by Western blot analysis. In addition,cell proliferation assay and small interfering RNA(siRNA) against endoglin were used to certificate the function of endolgin in the HS-5 cells.Results:Compared with the not treated(0μg/mL) or DMSO treated control HS-5 cells,HS-5 cells treated with toxicarioside A were found significant attenuation of endolgin and TGF-βexpression.Significant inhibition of cell proliferation was also found in the HS-5 cells treated with toxicarioside A.ALK1-related Smad1 and ALK5-related Smad2 were decreased in HS-5 cells treated with toxicarioside A.In addition,phosphorylated Smad1(pSmad1) and Smad2(pSmad2) were also found attenuation in toxicarioside A-treated HS-5 cells.RNA interference showed that blockage of endoglin by siRNA also decreased Smad1 and Smad2 expression in HS-5 cells.Conclusions:Our results indicate that toxicarioside A can influence bone marrow stromal HS-5’s function and inhibit HS-5 cell proliferation by alteration of endoglin-related ALK1(Smad1) and ALK5(Smad2) signaling.
基金the China’s National Key Research and Development Program Projects(No.2022YFC3500500 and No.2022YFC3500502).
文摘Background: To explore the effects of electroacupuncture on cardiac function and myocardial fibrosis in rat models of heart failure, and to elucidate the underlying mechanism of electroacupuncture in heart failure treatment. Methods: Healthy male Sprague-Dawley rats were allocated into three groups: Sham group, Model group, and electroacupuncture (Model + EA) group, with each group comprising 8 rats. The model underwent a procedure involving the ligation of the left anterior descending coronary artery to induce a model of heart failure. The Model + EA group was used for 7 consecutive days for electroacupuncture of bilateral Shenmen (HT7) and Tongli (HT5), once a day for 30 min each time. Left ventricular parameters in rats were assessed using a small-animal ultrasound machine to analyze changes in left ventricular end-diastolic volume, left ventricular end-systolic volume, left ventricular ejection fraction, and left ventricular fractional shortening. Serum interleukin-1β (IL-1β), cardiac troponin (cTn), and N-terminal brain natriuretic peptide precursor levels were measured using ELISA. Histopathological changes in rat myocardium were observed through HE staining, while collagen deposition in rat myocardial tissue was assessed using the Masson staining method. Picro sirius red staining, immunohistochemical staining, and RT-qPCR were utilized to distinguish between the various types of collagen deposition. The expression level of TGF-β1 and SMAD2/3/4/7 mRNA in rat myocardial tissues was determined using RT-qPCR. Additionally, western blot analysis was conducted to assess the protein expression levels of TGF-β1, SMAD3/7, and p-SMAD3 in rat myocardial tissues. Results: Compared with the Sham group, the left ventricular ejection fraction and left ventricular fractional shortening values of the Model group were significantly decreased (P < 0.01);the left ventricular end-diastolic volume and left ventricular end-systolic volume values were remarkably increased (P < 0.01);serum N-terminal brain natriuretic peptide precursor content was increased (P < 0.01);serum IL-1β and cTn levels were increased (P < 0.01);myocardial collagen volume fraction were increased (P < 0.01);and those of the expression of TGF-β1 and SMAD2/3/4 mRNA was increased (P < 0.01);the expression of SMAD7 mRNA was decreased (P < 0.01);the protein expression levels of TGF-β1, SMAD3, and p-Smad3 were increased (P < 0.01);the protein expression level of SMAD7 was decreased (P < 0.01) in the Model group. Compared to the Model group, the expression levels of the proteins TGF-β1, SMAD3, and p-Smad3 in myocardial tissue were found to be decreased (P < 0.01), and the expression level of the protein SMAD7 was found to be increased (P < 0.01) in the Model + EA group;the collagen volume fraction and deposition of type Ⅰ /Ⅲ collagen were decreased (P < 0.01) in the Model + EA group. Conclusion: Electroacupuncture alleviates myocardial fibrosis in rats with heart failure, and this effect is likely due to attributed to the modulation of the TGF-β1/Smads signaling pathway, which helps reduce collagen deposition in the extracellular matrix.
基金supported by the funds from the National Natural Science Foundation of China(Nos.81830006,82170219,and 81830004)the Science Technology Department of Zhejiang Province(No.2021C03117).
文摘Tumor-derived exosomes (TEXs) enriched in immune suppressive molecules predominantly drive T-cell dysfunction and impair antitumor immunity. Chimeric antigen receptor (CAR) T-cell therapy has emerged as a promising treatment for refractory and relapsed hematological malignancies, but whether lymphoma TEXs have the same impact on CAR T-cell remains unclear. Here, we demonstrated that B-cell lymphoma-derived exosomes induce the initial activation of CD19-CAR T-cells upon stimulation with exosomal CD19. However, lymphoma TEXs might subsequently induce CAR T-cell apoptosis and impair the tumor cytotoxicity of the cells because of the upregulated expression of the inhibitory receptors PD-1, TIM3, and LAG3 upon prolonged exposure. Similar results were observed in the CAR T-cells exposed to plasma exosomes from patients with lymphoma. More importantly, single-cell RNA sequencing revealed that CAR T-cells typically showed differentiated phenotypes and regulatory T-cell (Treg) phenotype conversion. By blocking transforming growth factor β (TGF-β)-Smad3 signaling with TGF-β inhibitor LY2109761, the negative effects of TEXs on Treg conversion, terminal differentiation, and immune checkpoint expression were rescued. Collectively, although TEXs lead to the initial activation of CAR T-cells, the effect of TEXs suppressed CAR T-cells, which can be rescued by LY2109761. A treatment regimen combining CAR T-cell therapy and TGF-β inhibitors might be a novel therapeutic strategy for refractory and relapsed B-cell lymphoma.
基金This research was funded by the National Natural Science Foundation of China(82273919 to Zhang Y)the HMU Marshal Initiative Funding(HMUMIF-21022 to Zhang Y).
文摘Background:Nonalcoholic fatty liver disease(NAFLD)is a chronic condition characterized by a progressive decline in liver function,leading to disruptions in liver integrity and metabolic function,resulting in lipid deposition and excessive accumulation of extracellular matrix(ECM).The pathogenesis of NAFLD is complex and not yet fully understood,contributing to the absence of specific therapeutic strategies.Peroxisome proliferator-activated receptor gamma(PPARγ)is a ligand-activated transcription factor pivotal in regulating lipid and glucose metabolism.However,the impacts of PPARγon NAFLD remains insufficiently explored.Thus,this study aimed to investigate the role of PPARγin NAFLD and its underlying molecular mechanisms.Methods:Chemical detection kits were utilized to quantify collagen content,alanine aminotransferase(ALT),and aspartate aminotransferase(AST)level variations.Quantitative real-time polymerase chain reaction(qRT-PCR)was employed to assess alterations in extracellular matrix-related genes and inflammatory response genes in liver tissue and HepG2 cells,while western blotting was conducted to analyze the levels of both PPARγand the TGF-β/Smad signaling pathway.Results:Our findings unveiled significantly reduced PPARγexpression in a rat model of NAFLD,leading to subsequent activation of the TGF-β/Smad signaling pathway.Furthermore,PPARγactivation effectively mitigated NAFLD progression by inhibiting inflammation and fibrosis-related gene expression and collagen production.On a cellular level,PPARγactivation was found to inhibit the expression of extracellular matrix-related genes such as matrix metalloproteinase 2(MMP2)and matrix metalloproteinase 9(MMP9),along with inflammatory response genes interleukin(IL)-1βand IL-6.Additionally,PPARγactivation led to a significant decrease in the levels of ALT and AST.At the molecular level,PPARγnotably down-regulated the TGF-β/Smad signaling pathway,which is known to promote liver fibrosis.Conclusion:These groundbreaking findings underscore PPARγactivation as a promising therapeutic approach to delay NAFLD progression by targeting the TGF-β/Smad signaling pathway in hepatic cells.This highlights the potential of PPARγas a promising therapeutic target for NAFLD management in clinical settings.
基金supported by the National Natural Science Foundation of China(Grant Nos.82073934,81872937,and 81673513).
文摘The current study aimed to assess the effect of timosaponin AⅢ(T-AⅢ)on drug-metabolizing enzymes during anticancer therapy.The in vivo experiments were conducted on nude and ICR mice.Following a 24-day administration of T-AⅢ,the nude mice exhibited an induction of CYP2B10,MDR1,and CYP3A11 expression in the liver tissues.In the ICR mice,the expression levels of CYP2B10 and MDR1 increased after a three-day T-AⅢ administration.The in vitro assessments with HepG2 cells revealed that T-AⅢ induced the expression of CYP2B6,MDR1,and CYP3A4,along with constitutive androstane receptor(CAR)activation.Treatment with CAR siRNA reversed the T-AⅢ-induced increases in CYP2B6 and CYP3A4 expression.Furthermore,other CAR target genes also showed a significant increase in the expression.The up-regulation of murine CAR was observed in the liver tissues of both nude and ICR mice.Subsequent findings demonstrated that T-AⅢ activated CAR by inhibiting ERK1/2 phosphorylation,with this effect being partially reversed by the ERK activator t-BHQ.Inhibition of the ERK1/2 signaling pathway was also observed in vivo.Additionally,T-AⅢ inhibited the phosphorylation of EGFR at Tyr1173 and Tyr845,and suppressed EGF-induced phosphorylation of EGFR,ERK,and CAR.In the nude mice,T-AⅢ also inhibited EGFR phosphorylation.These results collectively indicate that T-AⅢ is a novel CAR activator through inhibition of the EGFR pathway.
基金supported by Jiangsu Provincial Medical Key Discipline,No.ZDXK202217(to CFL)Jiangsu Planned Projects for Postdoctoral Research Funds,No.1601056C(to SL).
文摘Parkinson’s disease is a neurodegenerative disease characterized by motor and gastrointestinal dysfunction.Gastrointestinal dysfunction can precede the onset of motor symptoms by several years.Gut microbiota dysbiosis is involved in the pathogenesis of Parkinson’s disease,whether it plays a causal role in motor dysfunction,and the mechanism underlying this potential effect,remain unknown.CCAAT/enhancer binding proteinβ/asparagine endopeptidase(C/EBPβ/AEP)signaling,activated by bacterial endotoxin,can promoteα-synuclein transcription,thereby contributing to Parkinson’s disease pathology.In this study,we aimed to investigate the role of the gut microbiota in C/EBPβ/AEP signaling,α-synuclein-related pathology,and motor symptoms using a rotenone-induced mouse model of Parkinson’s disease combined with antibiotic-induced microbiome depletion and fecal microbiota transplantation.We found that rotenone administration resulted in gut microbiota dysbiosis and perturbation of the intestinal barrier,as well as activation of the C/EBP/AEP pathway,α-synuclein aggregation,and tyrosine hydroxylase-positive neuron loss in the substantia nigra in mice with motor deficits.However,treatment with rotenone did not have any of these adverse effects in mice whose gut microbiota was depleted by pretreatment with antibiotics.Importantly,we found that transplanting gut microbiota derived from mice treated with rotenone induced motor deficits,intestinal inflammation,and endotoxemia.Transplantation of fecal microbiota from healthy control mice alleviated rotenone-induced motor deficits,intestinal inflammation,endotoxemia,and intestinal barrier impairment.These results highlight the vital role that gut microbiota dysbiosis plays in inducing motor deficits,C/EBPβ/AEP signaling activation,andα-synuclein-related pathology in a rotenone-induced mouse model of Parkinson’s disease.Additionally,our findings suggest that supplementing with healthy microbiota may be a safe and effective treatment that could help ameliorate the progression of motor deficits in patients with Parkinson’s disease.
基金supported by the Chongqing Science and Technology CommitteeNatural Science Foundation of Chongqing,No.cstc2021jcyj-msxmX0065 (to YL)。
文摘Autism spectrum disorders are a group of neurodevelopmental disorders involving more than 1100 genes,including Ctnnd2 as a candidate gene.Ctnnd2knockout mice,serving as an animal model of autis m,have been demonstrated to exhibit decreased density of dendritic spines.The role of melatonin,as a neuro hormone capable of effectively alleviating social interaction deficits and regulating the development of dendritic spines,in Ctnnd2 deletion-induced nerve injury remains unclea r.In the present study,we discove red that the deletion of exon 2 of the Ctnnd2 gene was linked to social interaction deficits,spine loss,impaired inhibitory neurons,and suppressed phosphatidylinositol-3-kinase(PI3K)/protein kinase B(Akt) signal pathway in the prefrontal cortex.Our findings demonstrated that the long-term oral administration of melatonin for 28 days effectively alleviated the aforementioned abnormalities in Ctnnd2 gene-knockout mice.Furthermore,the administration of melatonin in the prefro ntal cortex was found to improve synaptic function and activate the PI3K/Akt signal pathway in this region.The pharmacological blockade of the PI3K/Akt signal pathway with a PI3K/Akt inhibitor,wo rtmannin,and melatonin receptor antagonists,luzindole and 4-phenyl-2-propionamidotetralin,prevented the melatonin-induced enhancement of GABAergic synaptic function.These findings suggest that melatonin treatment can ameliorate GABAe rgic synaptic function by activating the PI3K/Akt signal pathway,which may contribute to the improvement of dendritic spine abnormalities in autism spectrum disorders.
基金supported by the National Natural Science Foundation of China,No.81971097(to JY)。
文摘Preclinical and clinical studies have shown that microglia and macrophages participate in a multiphasic brain damage repair process following intracerebral hemorrhage.The E26 transformation-specific sequence-related transcription factor Spi1 regulates microglial/macrophage commitment and maturation.However,the effect of Spi1 on intracerebral hemorrhage remains unclear.In this study,we found that Spi1 may regulate recovery from the neuroinflammation and neurofunctional damage caused by intracerebral hemorrhage by modulating the microglial/macrophage transcriptome.We showed that high Spi1expression in microglia/macrophages after intracerebral hemorrhage is associated with the activation of many pathways that promote phagocytosis,glycolysis,and autophagy,as well as debris clearance and sustained remyelination.Notably,microglia with higher levels of Soil expression were chara cterized by activation of pathways associated with a variety of hemorrhage-related cellular processes,such as complement activation,angiogenesis,and coagulation.In conclusion,our results suggest that Spi1 plays a vital role in the microglial/macrophage inflammatory response following intracerebral hemorrhage.This new insight into the regulation of Spi1 and its target genes may advance our understanding of neuroinflammation in intracerebral hemorrhage and provide therapeutic targets for patients with intracerebral hemorrhage.
基金funded by the National Key Research and Development Program of China(2020YFD0900902)Zhejiang Province Public Welfare Technology Application Research Project(LGJ21C20001)Zhejiang Provincial Key Research and Development Project of China(2019C02076 and 2019C02075)。
文摘Type 2 diabetes mellitus(T2DM)is a complex metabolic disease threatening human health.We investigated the effects of Tegillarca granosa polysaccharide(TGP)and determined its potential mechanisms in a mouse model of T2DM established through a high-fat diet and streptozotocin.TGP(5.1×10^(3) Da)was composed of mannose,glucosamine,rhamnose,glucuronic acid,galactosamine,glucose,galactose,xylose,and fucose.It could significantly alleviate weight loss,reduce fasting blood glucose levels,reverse dyslipidemia,reduce liver damage from oxidative stress,and improve insulin sensitivity.RT-PCR and Western blotting indicated that TGP could activate the phosphatidylinositol-3-kinase/protein kinase B signaling pathway to regulate disorders in glucolipid metabolism and improve insulin resistance.TGP increased the abundance of Allobaculum,Akkermansia,and Bifidobacterium,restored the microbiota abundance in the intestinal tracts of mice with T2DM,and promoted short-chain fatty acid production.This study provides new insights into the antidiabetic effects of TGP and highlights its potential as a natural hypoglycemic nutraceutical.
基金Supported by Basic and Applied Basic Research Found of Guangdong Province,No.2022A1515011307。
文摘BACKGROUND Fanlian Huazhuo Formula(FLHZF)has the functions of invigorating spleen and resolving phlegm,clearing heat and purging turbidity.It has been identified to have therapeutic effects on type 2 diabetes mellitus(T2DM)in clinical application.Non-alcoholic fatty liver disease(NAFLD)is frequently diagnosed in patients with T2DM.However,the therapeutic potential of FLHZF on NAFLD and the underlying mechanisms need further investigation.AIM To elucidate the effects of FLHZF on NAFLD and explore the underlying hepatoprotective mechanisms in vivo and in vitro.METHODS HepG2 cells were treated with free fatty acid for 24 hours to induce lipid accumulation cell model.Subsequently,experiments were conducted with the different concentrations of freeze-dried powder of FLHZF for 24 hours.C57BL/6 mice were fed a high-fat diet for 8-week to establish a mouse model of NAFLD,and then treated with the different concentrations of FLHZF for 10 weeks.RESULTS FLHZF had therapeutic potential against lipid accumulation and abnormal changes in biochemical indicators in vivo and in vitro.Further experiments verified that FLHZF alleviated abnormal lipid metabolism might by reducing oxidative stress,regulating the AMPKα/SREBP-1C signaling pathway,activating autophagy,and inhibiting hepatocyte apoptosis.CONCLUSION FLHZF alleviates abnormal lipid metabolism in NAFLD models by regulating reactive oxygen species,autophagy,apoptosis,and lipid synthesis signaling pathways,indicating its potential for clinical application in NAFLD.
基金Supported by the Programa de Apoyo a Proyectos de Investigación e Innovación Tecnológica(PAPIIT)de la Dirección General de Asuntos de Personal Académico,No.IN212722 and No.IA208424Consejo Mexiquense de Ciencia y Tecnología,No.CS000132Consejo Nacional de Humanidades,Ciencia y Tecnología,No.CF-2023-I-563.
文摘Colorectal cancer(CRC)remains one of the most commonly diagnosed and deadliest types of cancer worldwide.CRC displays a desmoplastic reaction(DR)that has been inversely associated with poor prognosis;less DR is associated with a better prognosis.This reaction generates excessive connective tissue,in which cancer-associated fibroblasts(CAFs)are critical cells that form a part of the tumor microenvironment.CAFs are directly involved in tumorigenesis through different mechanisms.However,their role in immunosuppression in CRC is not well understood,and the precise role of signal transducers and activators of transcription(STATs)in mediating CAF activity in CRC remains unclear.Among the myriad chemical and biological factors that affect CAFs,different cytokines mediate their function by activating STAT signaling pathways.Thus,the harmful effects of CAFs in favoring tumor growth and invasion may be modulated using STAT inhibitors.Here,we analyze the impact of different STATs on CAF activity and their immunoregulatory role.
文摘Ependymoma is a rare and chemotherapy-resistant brain tumor, which has resulted in a delay in the development of drugs to treat it. A subclass of supratentorial ependymomas (ST-EPN), designated ST-EPN-zinc finger-translocation-associated (ZFTA, ST-EPN-ZFTA), exhibits the expression of a fusion protein comprising ZFTA and v-rel reticuloendotheliosis viral oncogene homolog A (RELA), an effector transcription factor of the nuclear factor-kappa B (NF-κB) pathway (ZFTA-RELA). The expression of ZFTA-RELA results in the hyperactivation of the oncogenic NF-κB signaling pathway, which ultimately leads to the development of ST-EPN-ZFTA. To identify inhibitors of the NF-κB signaling pathway activated by the expression of ZFTA-RELA, we used a doxycycline-inducible ZFTA-RELA-expressing NF-κB reporter cell line and found that extracts of the fungus Neosartorya spinosa IFM 47025 exhibited NF-κB inhibitory activity. We identified eight compounds [aszonapyrone A (2), sartorypyrone A (3), epiheveadride (4), acetylaszonalenin (5), (R)-benzodiazepinedione (6), aszonalenin (7), sartorypyrone E (8) and (Z, Z)-N,N’-(1,2-bis[(4-methoxyphenyl)methylene]-1,2-ethanediyl)bis-formamide (9)] from N. spinosa IFM 47025 culture extract using a variety of chromatographic techniques. The structures of these compounds were identified through the analysis of various instrumental data (1D, 2D-NMR, MS, and optical rotation). The NF-κB responsive reporter assay indicated that compounds 2, 3, 5, 7, and 9 exhibited inhibitory activity. We further evaluated the inhibitory activity of these compounds against the expression of endogenous NF-κB responsive genes (CCND1, L1CAM, ICAM1, and TNF) and found that compound 2 showed significant inhibitory activity. Further studies are required to elucidate the mechanism of action of compound 2, which may serve as a lead compound for the development of a novel therapy for ST-EPN-ZFTA.
基金funded by the National Natural Science Foundation of China (Grant No. 32170516, 31872243 to Y.Z.)。
文摘Functionally referential signals are a complex form of communication that conveys information about the external environment.Such signals have been found in a range of mammal and bird species and have helped us understand the complexities of animal communication.Corvids are well known for their extraordinary cognitive abilities,but relatively little attention has been paid to their vocal function.Here,we investigated the functionally referential signals of a cooperatively breeding corvid species,Azure-winged Magpie(Cyanopica cyanus).Through field observations,we suggest that Azure-winged Magpie uses referential alarm calls to distinguish two types of threats:’rasp’ calls for terrestrial threats and ’chatter’ calls for aerial threats.A playback experiment revealed that Azure-winged Magpies responded to the two call types with qualitatively different behaviors.They sought cover by flying into the bushes in response to the ’chatter’ calls,and flew to or stayed at higher positions in response to ’rasp’ calls,displaying a shorter response time to ’chatter’ calls.Significant differences in acoustic structure were found between the two types of calls.Given the extensive cognitive abilities of corvids and the fact that referential signals were once thought to be unique to primates,these findings are important for expanding our understanding of social communication and language evolution.
基金supported by National Key Research and Development Program of China(2022YFD1200300)Jiangsu Key R&D Program(BE2022384)the Collaborative Innovation Center for Modern Crop Production co-sponsored by Province and Ministry(CIC-MCP)(No.10)。
文摘Mitochondrial calcium uniporter(MCU)is a conserved calcium ion(Ca^(2+))transporter in the mitochondrial inner membrane of eukaryotic cells.How MCU proteins regulate Ca^(2+)flow and modulate plant cell development remain largely unclear.Here,we identified the gene GhMCU4 encoding a MCU protein that negatively regulates plant development and fiber elongation in cotton(Gossypium hirsutum).GhMCU4expressed constitutively in various tissues with the higher transcripts in elongating fiber cells.Knockdown of GhMCU4 in cotton significantly elevated the plant height and root length.The calcium signaling pathway was significantly activated and calcium sensor genes,including Ca^(2+)dependent modulator of interactor of constitutively active ROP(GhCMI1),calmodulin like protein(GhCML46),calciumdependent protein kinases(GhCPKs),calcineurin B-like protein(GhCBLs),and CBL-interacting protein kinases(GhCIPKs),were dramatically upregulated in GhMCU4-silenced plants.Metabolic processes were preferentially enriched,and genes related to regulation of transcription were upregulated in GhMCU4-silenced plants.The contents of Ca^(2+)and H_(2)O_(2)were significantly increased in roots and leaves of GhMCU4-silenced plants.Fiber length and Ca^(2+)and H_(2)O_(2)contents in fibers were significantly increased in GhMCU4-silenced plants.This study indicated that GhMCU4 plays a negative role in regulating cell elongation in cotton,thus expanding understanding in the role of MCU proteins in plant growth and development.
基金supported by the National Research Foundation of Korea(NRF)grant funded by the Korea government(MSIT)(2022R1A2C1091553 to Nam-Chon Paek and 2022R1F1A1075022 to Kiyoon Kang)。
文摘Senescence-induced NAC(senNAC)TFs play a crucial role in senescence during the final stage of leaf development.In this study,we identified a rice senNAC,ONAC016,which functions as a positive regulator of leaf senescence.The expression of ONAC016 increased rapidly in rice leaves during the progression of dark-induced and natural senescence.The onac016-1 knockout mutant showed a delayed leaf yellowing phenotype,whereas the overexpression of ONAC016 accelerated leaf senescence.Notably,ONAC016 expression was upregulated by abscisic acid(ABA),and thus detached leaves of the onac016-1 mutant remained green much longer under ABA treatment.Quantitative RT-PCR analysis showed that ONAC016 upregulates the genes associated with chlorophyll degradation,senescence,and ABA signaling.Yeast one-hybrid and dual-luciferase assays revealed that ONAC016 binds directly to the promoter regions of OsNAP,a key gene involved in chlorophyll degradation and ABA-induced senescence.Taken together,these results suggest that ONAC016 plays an important role in promoting leaf senescence through the ABA signaling pathway involving OsNAP.
基金supported by the National Natural Science Foundation of China (31971826,U20A2025)Natural Science Foundation of Heilongjiang province (JQ2021C002)the College Student Innovation and Entrepreneurship Program Training Program (202210223055)。
文摘Plant Homeo Domain(PHD)proteins are involved in diverse biological processes during plant growth.However,the regulation of PHD genes on rice cold stress response remains largely unknown.Here,we reported that PHD17 negatively regulated cold tolerance in rice seedlings as a cleavage target of miR1320.PHD17 expression was greatly induced by cold stress,and was down-regulated by miR1320 overexpression and up-regulated by miR1320 knockdown.Through 5'RACE and dual luciferase assays,we found that miR1320 targeted and cleaved the 3'UTR region of PHD17.PHD17 was a nuclearlocalized protein and acted as a transcriptional activator in yeast.PHD17 overexpression reduced cold tolerance of rice seedlings,while knockout of PHD17 increased cold tolerance,partially via the CBF cold signaling.By combining transcriptomic and physiological analyses,we demonstrated that PHD17 modulated ROS homeostasis and flavonoid accumulation under cold stress.K-means clustering analysis revealed that differentially expressed genes in PHD17 transgenic lines were significantly enriched in the jasmonic acid(JA)biosynthesis pathway,and expression of JA biosynthesis and signaling genes was verified to be affected by PHD17.Cold stress tests applied with MeJA or IBU(JA synthesis inhibitor)further suggested the involvement of PHD17 in JA-mediated cold signaling.Taken together,our results suggest that PHD17 acts downstream of miR1320 and negatively regulates cold tolerance of rice seedlings through JA-mediated signaling pathway.
基金supported by the National Science Foundation of China (32171941,31571583)。
文摘Plant calmodulins(CaMs)and calmodulin-like proteins(CMLs)mediate Ca~(2+)signaling in response to abiotic stresses.Manipulation of this signaling in crops could increase stress tolerance.We review methods for detecting Ca~(2+)signals,regulatory roles of Ca Ms and CMLs,binding targets,and Ca~(2+)networks under abiotic stress in organelles.
基金supported by the National Natural Science Foundation of China(81503187)。
文摘Hepatocellular carcinoma(HCC)is one of the common most malignant tumors.This study aimed to determine the in vitro and in vivo anticancer activity of cordycepin and elucidate its mechanism of action.The results of in vitro and in vivo studies revealed that cordycepin inhibited proliferation and migration in HepG-2 cells and inhibited the growth of HepG-2 xenograft-bearing nude mice by inducing apoptosis.Transcriptome sequencing analysis revealed a total of 403 differential genes,which revealed that cordycepin may play an anti-HCC role by regulating Hippo signaling pathway.The regulatory effects of cordycepin on the Hippo signaling pathway was further investigated using a YAP1 inhibitor.The results demonstrated that cordycepin upregulated the expression of MST1 and LAST1,and subsequently inhibited YAP1,which activated the Hippo signaling pathway.This in turn downregulated the expression of GBP3 and ETV5,and subsequently inhibited cell proliferation and migration.Additionally,YAP1 regulated the expression of Bax and Bcl-2,regulated the mitochondrial apoptotic pathway,and induced apoptosis by upregulating the expression of the caspase-3 protein.In summary,this study reveals that cordycepin exerts its anti-hepatocarcinoma effect through regulating Hippo signaling pathway,and GBP3 and ETV5 may be potential therapeutic targets for hepatocarcinoma.
