Most plant cells contain a large central vacuole that is essential to maintain cellular turgor. We report a new mutant allele of VTI11 that implicates the SNARE protein VTI11 in homotypic fusion of protein storage and...Most plant cells contain a large central vacuole that is essential to maintain cellular turgor. We report a new mutant allele of VTI11 that implicates the SNARE protein VTI11 in homotypic fusion of protein storage and lytic vacuoles. Fusion of the multiple vacuoles present in vtill mutants could be induced by treatment with Wortmannin and LY294002, which are inhibitors of Phosphatidylinositol 3-Kinase （PI3K）. We provide evidence that Phosphatidylinositol 3-Phosphate （Ptdlns（3）P） regulates vacuole fusion in vtill mutants, and that fusion of these vacuoles requires intact microtubules and actin filaments. Finally, we show that Wortmannin also induced the fusion of guard cell vacuoles in fava beans, where vacuoles are naturally fragmented after ABA-induced stomata closure. These results suggest a ubiquitous role of phosphoinositides in vacuole fusion, both during the development of the large central vacuole and during the dynamic vacuole remodeling that occurs as part of stomata movements.展开更多
Phosphoinositides are important regulatory membrane lipids,with a role in plant development and cellular function.Emerging evidence indicates that phosphoinositides play crucial roles in plant defence and are also uti...Phosphoinositides are important regulatory membrane lipids,with a role in plant development and cellular function.Emerging evidence indicates that phosphoinositides play crucial roles in plant defence and are also utilized by pathogens for infection.In this review,we highlight the role of phosphoinositides in plant-pathogen interaction and the implication of this remarkable convergence in the battle against plant diseases.展开更多
Recent studies have found that the suppression of phosphatase and tensin homolog is one of the most effective single-gene approaches for promoting optic nerve regeneration.This effect is primarily mediated through the...Recent studies have found that the suppression of phosphatase and tensin homolog is one of the most effective single-gene approaches for promoting optic nerve regeneration.This effect is primarily mediated through the activation of the protein kinase B/phosphoinositide 3-kinase/mammalian target of rapamycin signaling pathway.The purpose of this article is to elucidate how the downregulation of phosphatase and tensin homolog is involved in each key phase of optic nerve regeneration and to summarize the potential targets for therapeutic interventions in this process.Optic nerve regeneration progresses through five phases:stress response,growth navigation,nerve regeneration,synaptic reconstruction,and remyelination.During the stress response phase,the suppression of phosphatase and tensin homolog enhances the survival of retinal ganglion cells and promotes the proliferation of microglia.In the nerve regeneration phase,reduced levels of phosphatase and tensin homolog facilitate mitochondrial transport,while inhibition of the phosphatase and tensin homolog-L isoform specifically promotes mitophagy.During the synaptic reconstruction phase,the deletion of phosphatase and tensin homolog modulates the synthesis of axon extension-related proteins and stabilizes microglial microtubules,thereby accele rating the clearance of damaged synapses and the fo rmation of new ones.During the remyelination phase,the knockout of phosphatase and tensin homolog promotes the proliferation of oligodendrocyte progenitor cells and the diffe rentiation of oligodendrocytes,relieving myelination obstruction.This paper also discusses current strategies and translational challenges for neuron-specific inhibition of phosphatase and tensin homolog,including off-ta rget effects,delive ry precisio n,and long-term safety.By integrating molecular insights with emerging bioengineering approaches,this paper provides a framework for develo ping targeted therapies for optic nerve regeneration and broader applications in the field of central nervous system regeneration.展开更多
OBJECTIVE:To elucidate the therapeutic efficacy and mechanism of action of Chaihu Guizhi Ganjiang decoction(柴胡桂枝干姜汤,CGGD)in autoimmune hepatitis.METHODS:CGGD components and potential target genes were extracted...OBJECTIVE:To elucidate the therapeutic efficacy and mechanism of action of Chaihu Guizhi Ganjiang decoction(柴胡桂枝干姜汤,CGGD)in autoimmune hepatitis.METHODS:CGGD components and potential target genes were extracted from previously published databases.The autoimmune hepatitis(AIH)-related regulatory genes were obtained from the Dis Ge NET database.Intersections were taken,and enrichment analyses were performed on the extracted data.Concanavalin A(Con A)-induced AIH model mice were treated with CGGD via gavage.The results of network pharmacological analysis were experimentally validated.RESULTS:Network pharmacology revealed 228 genes at the intersection of AIH and CGGD.Kyoto Encyclopedia of Genes and Genomes analysis revealed that CGGD primarily regulates the phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)signaling pathway and cellular metabolism in AIH.Gene Ontology enrichment analysis revealed that CGGD modulates inflammation through transcription factor-mediated signaling pathways.As predicted,CGGD attenuated Con A-induced AIH in a dose-dependent manner by activating the PI3K/AKT signaling pathway.Histopathological assessment confirmed the protective effects of CGGD against Con Ainduced AIH.Further investigation revealed that CGGD regulated the T helper cell 17(Th17)/regulatory T cell(Treg)balance by modulating the PI3K/Akt/nuclear factor kappa-B(NF-κB)pathway.CONCLUSIONS:This study demonstrated the therapeutic effect of CGGD on AIH through a combination of network pharmacological prediction and experimental validation.Its mechanism of action involves PI3K/Akt/NF-κB-mediated regulation of Th17/Treg cells.展开更多
Recombinant tissue plasminogen activator is commonly used for hematoma evacuation in minimally invasive surgery following intracerebral hemorrhage.However,during minimally invasive surgery,recombinant tissue plasminog...Recombinant tissue plasminogen activator is commonly used for hematoma evacuation in minimally invasive surgery following intracerebral hemorrhage.However,during minimally invasive surgery,recombinant tissue plasminogen activator may come into contact with brain tissue.Therefore,a thorough assessment of its safety is required.In this study,we established a mouse model of intracerebral hemorrhage induced by type VII collagenase.We observed that the administration of recombinant tissue plasminogen activator without hematoma aspiration significantly improved the neurological function of mice with intracerebral hemorrhage,reduced pathological damage,and lowered the levels of apoptosis and autophagy in the tissue surrounding the hematoma.In an in vitro model of intracerebral hemorrhage using primary cortical neurons induced by hemin,the administration of recombinant tissue plasminogen activator suppressed neuronal apoptosis,autophagy,and endoplasmic reticulum stress.Transcriptome sequencing analysis revealed that recombinant tissue plasminogen activator upregulated the phosphoinositide 3-kinase/RAC-alpha serine/threonine-protein kinase/mammalian target of rapamycin pathway in neurons.Moreover,the phosphoinositide 3-kinase inhibitor LY294002 abrogated the neuroprotective effects of recombinant tissue plasminogen activator in inhibiting excessive apoptosis,autophagy,and endoplasmic reticulum stress.Furthermore,to specify the domain of recombinant tissue plasminogen activator responsible for its neuroprotective effects,various inhibitors were used to target distinct domains.It has been revealed that the epidermal growth factor receptor inhibitor AG-1478 reversed the effect of recombinant tissue plasminogen activator on the phosphoinositide 3-kinase/RAC-alpha serine/threonineprotein kinase/mammalian target of rapamycin pathway.These findings suggest that recombinant tissue plasminogen activator exerts a direct neuroprotective effect on neurons following intracerebral hemorrhage,possibly through activation of the phosphoinositide 3-kinase/RAC-alpha serine/threonine-protein kinase/mammalian target of rapamycin pathway.展开更多
In the early stages of traumatic spinal cord injury,extensive accumulation of autophagosomes creates a neurotoxic microenvironment,exacerbating neuronal cell death and worsening tissue damage,ultimately hindering neur...In the early stages of traumatic spinal cord injury,extensive accumulation of autophagosomes creates a neurotoxic microenvironment,exacerbating neuronal cell death and worsening tissue damage,ultimately hindering neurofunctional recovery.Activin A is a critical growth factor necessary for the development of the embryonic nervous system and for maintaining neuronal function in the adult cerebral cortex.It can inhibit excessive autophagy in ischemic stroke to reduce neuronal damage.However,the specific mechanism through which Activin A functions in the spinal cord remains poorly understood.In this study,we administered different concentrations of Activin A to neural stem cells from the spinal cord and found that Activin A stimulated the proliferation and neuronal differentiation of neural stem cells.Then,we established an in vitro oxidative stress model by using hydrogen peroxide to stimulate the neural stem cells-induced neurons.We found that Activin A could reduce apoptosis caused by oxidative stress.Subsequently,we treated a mouse model of spinal cord contusion with intrathecal injection of Activin A.Behavioral and electrophysiological results showed that Activin A promoted recovery of motor function and reconstruction of neural circuits in the model mice.Finally,RNA sequencing indicated that Activin A inhibited autophagy by activating the PI3K/AKT/mTOR pathway and upregulating the expression of synaptogenesis-related factor Sema3A in the spinal cord.These results suggest that Activin A may mediate the excessive autophagic response after spinal cord injury,promote the reconstruction of damaged neural circuits,and restore neurological function in the injured spinal cord.展开更多
Human neural stem cell-derived extracellular vesicles exhibit analogous functions to their parental cells,and can thus be used as substitutes for stem cells in stem cell therapy,thereby mitigating the risks of stem ce...Human neural stem cell-derived extracellular vesicles exhibit analogous functions to their parental cells,and can thus be used as substitutes for stem cells in stem cell therapy,thereby mitigating the risks of stem cell therapy and advancing the frontiers of stem cell-derived treatments.This lays a foundation for the development of potentially potent new treatment modalities for ischemic stroke.However,the precise mechanisms underlying the efficacy and safety of human neural stem cell-derived extracellular vesicles remain unclear,presenting challenges for clinical translation.To promote the translation of therapy based on human neural stem cell-derived extracellular vesicles from the bench to the bedside,we conducted a comprehensive preclinical study to evaluate the efficacy and safety of human neural stem cell-derived extracellular vesicles in the treatment of ischemic stroke.We found that administration of human neural stem cell-derived extracellular vesicles to an ischemic stroke rat model reduced the volume of cerebral infarction and promoted functional recovery by alleviating neuronal apoptosis.The human neural stem cell-derived extracellular vesicles reduced neuronal apoptosis by enhancing phosphorylation of phosphoinositide 3-kinase,mammalian target of rapamycin,and protein kinase B,and these effects were reversed by treatment with a phosphoinositide 3-kinase inhibitor.These findings suggest that human neural stem cell-derived extracellular vesicles play a neuroprotective role in ischemic stroke through activation of phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin signaling pathway.Finally,we showed that human neural stem cell-derived extracellular vesicles have a good in vivo safety profile.Therefore,human neural stem cell-derived extracellular vesicles are a promising potential agent for the treatment of ischemic stroke.展开更多
Vitex negundo(V.negundo),an Indian herb with a rich historical background for the handling of various complaints,is a member of the Verbenaceae family and is characterized by small trees with pale gray bark.This herb ...Vitex negundo(V.negundo),an Indian herb with a rich historical background for the handling of various complaints,is a member of the Verbenaceae family and is characterized by small trees with pale gray bark.This herb is widely used and has been recognized in traditional medicine for its pharmacological effects on a wide range of diseases.All sections of the plant,but particularly the leaves,contain a variety of secondary metabolites,including alkaloids,phenols,flavonoids,glycoside iridoids,tannins,and terpenes.The system is included in a number of store-bought herbal preparations and has the potential to function as an efficient bio-committee.Cancer continues to be a major cause of death and morbidity in spite of the intervention.One of the leading causes of death is cancer,and current therapies can have unpleasant side effects.Unhindered reactions,resistance to traditional cancer medications,radiation therapy,chemotherapy,and restricted access to tumor tissue are some of the reasons why treatment frequently fails.To reduce side effects,increase chemotherapy sensitivity,and slow the spread of cancer,new approaches are required.Small food molecules have been suggested in numerous research as supplemental therapies for cancer patients.The effectiveness of the flavonoid-rich V.negundo extract in treating cancer was assessed mechanically in this investigation.Total flavonoids have been isolated for qualitative phytochemical investigation using V.negundo ethanolic extract.This article highlights significant developments in this field and explores how flavonoids contribute to the targeted suppression of the phosphoinositide 3-kinase-protein kinase B-mammalian target of rapamycin pathway in different cancer types.展开更多
BACKGROUND Uric acid(UA),a key antioxidant metabolite,demonstrates dual roles in cancer.Unfortunately,studies on its role in colon cancer risk are uncommon,and the limited results are inconsistent.AIM To elucidate the...BACKGROUND Uric acid(UA),a key antioxidant metabolite,demonstrates dual roles in cancer.Unfortunately,studies on its role in colon cancer risk are uncommon,and the limited results are inconsistent.AIM To elucidate the association between UA and colon cancer risk and its me-chanisms.METHODS Multivariate logistic regression analysis evaluated the association between UA levels and colon cancer risk.Non-linear relationships were illustrated using restricted cubic splines.The threshold effect was performed to identify cut-off points.Human colon cancer cell lines(HCT-116 and HT29)were exposed to UA for 48 hours.Cell viability was assessed via the cell counting kit-8 assay.The evaluation of cell migration involved wound healing and transwell migration assays.HCT-116 cells were exposed to 4 mg/dL UA for 48 hours.The impact of the subsequent treatment with a phosphoinositide 3-kinases(PI3K)agonist and UA was assessed.RESULTS After adjusting for potential confounders,an inverse association was observed between UA and colon cancer risk(odds ratio=0.65,P<0.05).A non-linear relationship was identified,with a 4.79 mg/dL cut-off point(P<0.05).UA inhibited colon cancer cell proliferation and migration.These effects were mediated by the induction of reactive oxygen species and the suppression of the PI3K/protein kinase B/mammalian target of rapamycin pathway.CONCLUSION UA acts as a protective agent against colon cancer by inhibiting cell proliferation and migration through increased reactive oxygen species production and modulation of the PI3K/protein kinase B/mammalian target of rapamycin pathway.展开更多
Triple negative breast cancer(TNBC)is an exceptionally aggressive subtype of breast cancer with a poor prognosis.TNBC patients have limited treatment options beyond conventional chemotherapy,and they face significant ...Triple negative breast cancer(TNBC)is an exceptionally aggressive subtype of breast cancer with a poor prognosis.TNBC patients have limited treatment options beyond conventional chemotherapy,and they face significant challenges associated with disease recurrence and resistance to chemotherapy.The phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)/mechanistic target of rapamycin(mTOR)signaling pathway plays a pivotal role in cell proliferation,growth,metabolism,and survival.Its aberrant activation is closely linked to the development and progression of TNBC,as well as treatment response and drug resistance.Currently,numerous targeted drugs specifically inhibiting this signaling pathway are being developed and undergoing clinical trials.These include inhibitors targeting PI3K,AKT,or mTOR individually,as well as dual-target or multi-target inhibitors simultaneously targeting different components of this pathway.Encouragingly,some inhibitors have demonstrated promising potential in clinical trials.This review delves into the therapeutic potential of the PI3K/AKT/mTOR signaling pathway for TNBC and explores prospects for drug discovery.展开更多
BACKGROUND Macrophages are central to the orchestration of immune responses,inflammatory processes,and the pathogenesis of diabetic complications.The dynamic polarization of macrophages into M1 and M2 phenotypes criti...BACKGROUND Macrophages are central to the orchestration of immune responses,inflammatory processes,and the pathogenesis of diabetic complications.The dynamic polarization of macrophages into M1 and M2 phenotypes critically modulates inflammation and contributes to the progression of diabetic nephropathy.Sodiumglucose cotransporter 2 inhibitors such as dapagliflozin,which are acclaimed for their efficacy in diabetes management,may influence macrophage polarization,thereby ameliorating diabetic nephropathy.This investigation delves into these mechanistic pathways,aiming to elucidate novel therapeutic strategies for diabetes.AIM To investigate the inhibitory effect of dapagliflozin on macrophage M1 polarization and apoptosis and to explore its mechanism of action.METHODS We established a murine model of type 2 diabetes mellitus and harvested peritoneal macrophages following treatment with dapagliflozin.Concurrently,the human monocyte cell line cells were used for in vitro studies.Macrophage viability was assessed in a cell counting kit 8 assay,whereas apoptosis was evaluated by Annexin V/propidium iodide staining.Protein expression was examined through western blotting,and the expression levels of macrophage M1 surface immunosorbent assay,and quantitative real-time polymerase chain reaction analyses.RESULTS Dapagliflozin attenuated M1 macrophage polarization and mitigated apoptosis in the abdominal macrophages of diabetic mice,evidenced by the downregulation of proapoptotic genes(Caspase 3),inflammatory cytokines[interleukin(IL)-6,tumor necrosis factor-α,and IL-1β],and M1 surface markers(inducible nitric oxide synthase,and cluster of differentiation 86),as well as the upregulation of the antiapoptotic gene BCL2.Moreover,dapagliflozin suppressed the expression of proteins associated with the phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)signaling pathway(PI3K,AKT,phosphorylated protein kinase B).These observations were corroborated in vitro,where we found that the modulatory effects of dapagliflozin were abrogated by 740Y-P,an activator of the PI3K/AKT signaling pathway.CONCLUSION Dapagliflozin attenuates the polarization of macrophages toward the M1 phenotype,thereby mitigating inflammation and promoting macrophage apoptosis.These effects are likely mediated through the inhibition of the PI3K/AKT signaling pathway.展开更多
BACKGROUND Hepatocellular carcinoma(HCC)ranks among the most prevalent and deadly malignancies,characterized by a high recurrence rate.Regulator of chromosome condensation 1(RCC1)serves as a principal guanine nucleoti...BACKGROUND Hepatocellular carcinoma(HCC)ranks among the most prevalent and deadly malignancies,characterized by a high recurrence rate.Regulator of chromosome condensation 1(RCC1)serves as a principal guanine nucleotide exchange factor for ras-related nuclear protein guanosine triphosphatase(GTPase)and is implicated in various cancers.However,the role of RCC1 in HCC remains unex-plored.AIM To elucidate the functional significance and molecular mechanisms of RCC1 in HCC.METHODS Bioinformatics were to examine the expression levels of RCC1 in HCC and to assess its impact on the prognosis of this malignancy.The cell counting kit-8 assay and flow cytometry were utilized to evaluate the cell viability and cell cycle of HCC cells.Furthermore,quantitative reverse transcription and immunoblotting were to investigate the influence of RCC1 on cyclin associated proteins.RESULTS Bioinformatics analysis revealed that RCC1 was highly expressed in HCC and correlated with poor prognosis in HCC patients.Functional studies showed that RCC1 overexpression promoted the malignant phenotype of HCC cells,especially the proliferation of HCC cells,whereas RCC1 knockdown had the opposite effect.Mechanistically,we identied cell division cycle-associated(CDCA)8 as a downstream target of RCC1 in HCC.RCC1 overexpression markedly increased CDCA8 levels,consequently enhancing cell proliferation and survival in HCC cells.Additionally,we discovered that RCC1 contributed to the development and progression of HCC by activating the phosphoinositide 3-kinase/protein kinase B/cyclin-dependent kinase inhibitor 1a pathway through CDCA8.CONCLUSION Our study provides profound insights into the pivotal role of RCC1 in HCC and its potential as a therapeutic target.展开更多
BACKGROUND Uterine injury can cause uterine scarring,leading to a series of complications that threaten women’s health.Uterine healing is a complex process,and there are currently no effective treatments.Although our...BACKGROUND Uterine injury can cause uterine scarring,leading to a series of complications that threaten women’s health.Uterine healing is a complex process,and there are currently no effective treatments.Although our previous studies have shown that bone marrow mesenchymal stem cells(BMSCs)promote uterine damage repair,the underlying mechanisms remain unclear.However,exploring the specific regulatory roles of BMSCs in uterine injury treatment is crucial for further understanding their functions and enhancing therapeutic efficacy.AIM To investigate the underlying mechanism by which BMSCs promote the process of uterine healing.METHODS In in vivo experiments,we established a model of full-thickness uterine injury and injected BMSCs into the uterine wound.Transcriptome sequencing was per-formed to determine the enrichment of differentially expressed genes at the wound site.In in vitro experiments,we isolated rat uterine smooth muscle cells(USMCs)and cocultured them with BMSCs to observe the interaction between BMSCs and USMCs in the microenvironment.RESULTS We found that the differentially expressed genes were mainly related to cell growth,tissue repair,and angiogenesis,while the phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)pathway was highly enriched.Quantitative reverse-transcription polymerase chain reaction was used to validate differentially expressed genes,and the results demonstrated that BMSCs can upregulate genes related to regeneration and downregulate genes related to inflammation.Coculturing BMSCs promoted the migration and proliferation of USMCs,and the USMC microenvironment promoted the myogenic differentiation of BMSCs.Finally,we validated the PI3K/AKT pathway in tissues and cells and showed that BMSCs activate the PI3K/AKT pathway to promote the regeneration of uterine smooth muscle both in vivo and in vitro.CONCLUSION BMSCs upregulated uterine wound regeneration and anti-inflammatory factors and enhanced uterine smooth muscle proliferation through the PI3K/AKT pathway both in vivo and in vitro.展开更多
Objective Endothelial dysfunction is a central contributor to the vascular complications observed in individuals with diabetes.cAMP response element-binding protein(CREB)plays a crucial role in mediating hyperglycemia...Objective Endothelial dysfunction is a central contributor to the vascular complications observed in individuals with diabetes.cAMP response element-binding protein(CREB)plays a crucial role in mediating hyperglycemia-induced endothelial dysfunction.Phosphatase and tensin homolog(PTEN)has been implicated in the regulation of endothelial inflammation,yet the precise mechanism by which CREB modulates PTEN to protect endothelial cells under high glucose conditions remains unknown.This study aims to elucidate this potential mechanism.Methods Human umbilical vein endothelial cells(HUVECs)were exposed to high glucose(30 mM)or normal glucose(5.5 mM)for 6 days.Cell viability and apoptosis were assessed via the Cell Counting Kit-8 and flow cytometry.To evaluate oxidative stress,the levels of reactive oxygen species(ROS),lactate dehydrogenase(LDH),and malondialdehyde(MDA)were measured via commercial assay kits.The interaction between CREB and endothelial specific molecule 1(ESE-1)was assessed via coimmunoprecipitation.Chromatin immunoprecipitation and luciferase reporter assays were used to investigate the transcriptional regulation of PTEN by ESE-1 and CREB.Western blotting was performed to analyze the expression of intercellular adhesion molecule-1 and E-selectin.The adhesion of HUVECs was evaluated via monocyte‒endothelial cell adhesion assays.Results Our findings revealed a direct interaction between CREB and ESE-1,which together regulate PTEN expression to activate the phosphoinositide 3-kinase/protein kinase B pathway.Under high-glucose conditions,we observed significant increases in oxidative stress,inflammatory responses,and adhesion in HUVECs.ESE-1 knockdown reversed these effects,restoring endothelial cell function.Moreover,the overexpression of PTEN in high glucose–treated HUVECs rescued the endothelial injury induced by ESE-1 knockdown,suggesting that PTEN plays a pivotal role in mediating the protective effects.Conclusion ESE-1,through the regulation of CREB-mediated PTEN expression,activates the PI3K/AKT pathway and modulates key processes such as oxidative stress,inflammation,and adhesion in endothelial cells under high-glucose stress.展开更多
The most striking morphological feature of eukaryotic cells is the presence of various membrane-enclosed compartments. These compartments, including organelles and transient transport intermediates, are not static. Ra...The most striking morphological feature of eukaryotic cells is the presence of various membrane-enclosed compartments. These compartments, including organelles and transient transport intermediates, are not static. Rather, dynamic exchange of proteins and membrane is needed to maintain cellular homeostasis. One of the most dramatic examples of membrane mobilization is seen during the process ofmacroautophagy. Macroautophagy is the primary cellular pathway for degradation of long-lived proteins and organelles. In response to environmental cues, such as starvation or other types of stress, the cell produces a unique membrane structure, the phagophore. The phagophore sequesters cytoplasm as it forms a double-membrane cytosolic vesicle, an autophagosome. Upon completion, the autophagosome fuses with a lysosome or a vacuole in yeast, which delivers hydrolases that break down the inner autophagosome membrane along with its cargo, and the resulting macromolecules are released back into the cytosol for reuse. Autophagy is therefore a recycling process, allowing cells to survive periods of nutrient limitation; however, it has a wider physiological role, participating in development and aging, and also in protection against pathogen invasion, cancer and certain neurodegenerative diseases. In many cases, the role ofautophagy is identified through studies of an autophagy-related protein, Atg6/Beclin 1. This protein is part of a lipid kinase complex, and recent studies suggest that it plays a central role in coordinating the cytoprotective function ofautophagy and in opposing the cellular death process of apoptosis. Here, we summarize our current knowledge ofAtg6/Beclin 1 in different model organisms and its unique function in the cell.展开更多
The brain is,after the adipose tissue,the organ with the greatest amount of lipids and diversity in their composition in the human body.In neurons,lipids are involved in signaling pathways controlling autophagy,a lyso...The brain is,after the adipose tissue,the organ with the greatest amount of lipids and diversity in their composition in the human body.In neurons,lipids are involved in signaling pathways controlling autophagy,a lysosome-dependent catabolic process essential for the maintenance of neuronal homeostasis and the function of the primary cilium,a cellular antenna that acts as a communication hub that transfers extracellular signals into intracellular responses required for neurogenesis and brain development.A crosstalk between primary cilia and autophagy has been established;however,its role in the control of neuronal activity and homeostasis is barely known.In this review,we briefly discuss the current knowledge regarding the role of autophagy and the primary cilium in neurons.Then we review the recent literature about specific lipid subclasses in the regulation of autophagy,in the control of primary cilium structure and its dependent cellular signaling in physiological and pathological conditions,specifically focusing on neurons,an area of research that could have major implications in neurodevelopment,energy homeostasis,and neurodegeneration.展开更多
Eukaryotic cells are confined by membranes that create hydrophobic barriers for substance and information exchange between the inside and outside of the cell.These barriers are formed by assembly of lipids and protein...Eukaryotic cells are confined by membranes that create hydrophobic barriers for substance and information exchange between the inside and outside of the cell.These barriers are formed by assembly of lipids and protein in aqueous environments.Lipids not only serve as building blocks for membrane construction,but also possess regulatory functions in cellular activities.These regulatory lipids are non-uniformly distributed in membrane systems;their temporal and spatial accumulation in specific membranes decodes environmental cues and changes cellular activity accordingly.Phosphoinositides(PIs)are phospholipids that exert regulatory effects.In recent years,research on PIs roles in regulating plant growth,development,and responses to environmental stress is increasing.Several reviews have been published on the composition of PIs,intermolecular transferring of PIs by lipid kinases(phosphatases)or PI-PLCs,subcellular localization,and specially their functions in plant developments.Herein,we review the crucial regulatory functions of PIs in plant stress responses,with a particular focus on PIs involved in membrane trafficking.展开更多
Hepatitis C virus(HCV) infects hepatocytes, polarized cells in the liver. Chronic HCV infection often leads to steatosis, fibrosis, cirrhosis and hepatocellular carcinoma, and it has been identified as the leading cau...Hepatitis C virus(HCV) infects hepatocytes, polarized cells in the liver. Chronic HCV infection often leads to steatosis, fibrosis, cirrhosis and hepatocellular carcinoma, and it has been identified as the leading cause of liver transplantation worldwide. The HCV replication cycle is dependent on lipid metabolism and particularly an accumulation of lipid droplets in host cells. Phosphoinositides(PIs) are minor phospholipids enriched in different membranes and their levels are tightly regulated by specific PI kinases and phosphatases. PIs are implicated in a vast array of cellular responses that are central to morphogenesis, such as cytoskeletal changes, cytokinesis and the recruitment of downstream effectors to govern mechanisms involved in polarization and lumen formation. Important reviews of the literature identified phosphatidylinositol(Ptd Ins) 4-kinases, and their lipid products Ptd Ins(4)P, as critical regulators of the HCV life cycle. SH2-containing inositol polyphosphate 5-phosphatase(SHIP2), phosphoinositide 3-kinase(PI3K) and their lipid products Ptd Ins(3,4)P2 and Ptd Ins(3,4,5)P3, respectively, play an important role in the cell membrane and are key to the establishment of apicobasal polarity and lumen formation. In this review, we will focus on these new functions of PI3 K and SHIP2, and their deregulation by HCV, causing a disruption of apicobasal polarity, actin organization and extracellular matrix assembly. Finally we will highlight the involvement of this pathway in the event of insulin resistance and nonalcoholic fatty liver disease related to HCV infection.展开更多
The recent COVID-19 pandemic poses a global health emergency.Cellular entry of the causative agent SARS-CoV-2 is mediated by its spike protein interacting with cellular receptor-human angiotensin converting enzyme 2(A...The recent COVID-19 pandemic poses a global health emergency.Cellular entry of the causative agent SARS-CoV-2 is mediated by its spike protein interacting with cellular receptor-human angiotensin converting enzyme 2(ACE2).Here,by using lentivirus based pseudotypes bearing spike protein,we demonstrated that entry of SARS-CoV-2 into host cells was dependent on clathrin-mediated endocytosis,and phosphoinositides played essential roles during this process.In addition,we showed that the intracellular domain and the catalytic activity of ACE2 were not required for efficient virus entry.Finally,we showed that the current predominant Delta variant,although with high infectivity and high syncytium formation,also entered cells through clathrin-mediated endocytosis.These results provide new insights into SARS-CoV-2 cellular entry and present proof of principle that targeting viral entry could be an effective way to treat different variant infections.展开更多
文摘Most plant cells contain a large central vacuole that is essential to maintain cellular turgor. We report a new mutant allele of VTI11 that implicates the SNARE protein VTI11 in homotypic fusion of protein storage and lytic vacuoles. Fusion of the multiple vacuoles present in vtill mutants could be induced by treatment with Wortmannin and LY294002, which are inhibitors of Phosphatidylinositol 3-Kinase （PI3K）. We provide evidence that Phosphatidylinositol 3-Phosphate （Ptdlns（3）P） regulates vacuole fusion in vtill mutants, and that fusion of these vacuoles requires intact microtubules and actin filaments. Finally, we show that Wortmannin also induced the fusion of guard cell vacuoles in fava beans, where vacuoles are naturally fragmented after ABA-induced stomata closure. These results suggest a ubiquitous role of phosphoinositides in vacuole fusion, both during the development of the large central vacuole and during the dynamic vacuole remodeling that occurs as part of stomata movements.
基金Financial support from DST FIST Ⅱ and DBT BUILDER to SC(SC/DBT-BUILDER/2022)is gratefully acknowledgedSERB and CSIR for providing National Post-doctoral fellowship and Ph.D.scholarship,respectively.
文摘Phosphoinositides are important regulatory membrane lipids,with a role in plant development and cellular function.Emerging evidence indicates that phosphoinositides play crucial roles in plant defence and are also utilized by pathogens for infection.In this review,we highlight the role of phosphoinositides in plant-pathogen interaction and the implication of this remarkable convergence in the battle against plant diseases.
基金National Natural Science Foundation of China,Nos.82260279,31960169the Natural Science Foundation of Jiangxi Province,Nos.20202ACB206002,20213BCJ22057a grant from School of Basic Medical Sciences,Nanchang University。
文摘Recent studies have found that the suppression of phosphatase and tensin homolog is one of the most effective single-gene approaches for promoting optic nerve regeneration.This effect is primarily mediated through the activation of the protein kinase B/phosphoinositide 3-kinase/mammalian target of rapamycin signaling pathway.The purpose of this article is to elucidate how the downregulation of phosphatase and tensin homolog is involved in each key phase of optic nerve regeneration and to summarize the potential targets for therapeutic interventions in this process.Optic nerve regeneration progresses through five phases:stress response,growth navigation,nerve regeneration,synaptic reconstruction,and remyelination.During the stress response phase,the suppression of phosphatase and tensin homolog enhances the survival of retinal ganglion cells and promotes the proliferation of microglia.In the nerve regeneration phase,reduced levels of phosphatase and tensin homolog facilitate mitochondrial transport,while inhibition of the phosphatase and tensin homolog-L isoform specifically promotes mitophagy.During the synaptic reconstruction phase,the deletion of phosphatase and tensin homolog modulates the synthesis of axon extension-related proteins and stabilizes microglial microtubules,thereby accele rating the clearance of damaged synapses and the fo rmation of new ones.During the remyelination phase,the knockout of phosphatase and tensin homolog promotes the proliferation of oligodendrocyte progenitor cells and the diffe rentiation of oligodendrocytes,relieving myelination obstruction.This paper also discusses current strategies and translational challenges for neuron-specific inhibition of phosphatase and tensin homolog,including off-ta rget effects,delive ry precisio n,and long-term safety.By integrating molecular insights with emerging bioengineering approaches,this paper provides a framework for develo ping targeted therapies for optic nerve regeneration and broader applications in the field of central nervous system regeneration.
基金Supported by the Nanjing Health Science and Technology Key Medical Science and Technology Development Program:Mechanism of Action of the Modified Si-Miao Powder with Sanguisorba Carbonisata in Regulating Microbiota and Microecology for the Treatment of Recurrent Vulvovaginal Candidiasis(ZKX22039)。
文摘OBJECTIVE:To elucidate the therapeutic efficacy and mechanism of action of Chaihu Guizhi Ganjiang decoction(柴胡桂枝干姜汤,CGGD)in autoimmune hepatitis.METHODS:CGGD components and potential target genes were extracted from previously published databases.The autoimmune hepatitis(AIH)-related regulatory genes were obtained from the Dis Ge NET database.Intersections were taken,and enrichment analyses were performed on the extracted data.Concanavalin A(Con A)-induced AIH model mice were treated with CGGD via gavage.The results of network pharmacological analysis were experimentally validated.RESULTS:Network pharmacology revealed 228 genes at the intersection of AIH and CGGD.Kyoto Encyclopedia of Genes and Genomes analysis revealed that CGGD primarily regulates the phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)signaling pathway and cellular metabolism in AIH.Gene Ontology enrichment analysis revealed that CGGD modulates inflammation through transcription factor-mediated signaling pathways.As predicted,CGGD attenuated Con A-induced AIH in a dose-dependent manner by activating the PI3K/AKT signaling pathway.Histopathological assessment confirmed the protective effects of CGGD against Con Ainduced AIH.Further investigation revealed that CGGD regulated the T helper cell 17(Th17)/regulatory T cell(Treg)balance by modulating the PI3K/Akt/nuclear factor kappa-B(NF-κB)pathway.CONCLUSIONS:This study demonstrated the therapeutic effect of CGGD on AIH through a combination of network pharmacological prediction and experimental validation.Its mechanism of action involves PI3K/Akt/NF-κB-mediated regulation of Th17/Treg cells.
基金supported by the National Natural Science Foundation of China,Nos.92148206,82071330(both to ZT)a grant from the Major Program of Hubei Province,No.2023BAA005(to ZT)+1 种基金a grant from the Key Research and Discovery Program of Hubei Province,No.2021BCA109(to ZT)the Research Foundation of Tongji Hospital,No.2022B37(to PZ)。
文摘Recombinant tissue plasminogen activator is commonly used for hematoma evacuation in minimally invasive surgery following intracerebral hemorrhage.However,during minimally invasive surgery,recombinant tissue plasminogen activator may come into contact with brain tissue.Therefore,a thorough assessment of its safety is required.In this study,we established a mouse model of intracerebral hemorrhage induced by type VII collagenase.We observed that the administration of recombinant tissue plasminogen activator without hematoma aspiration significantly improved the neurological function of mice with intracerebral hemorrhage,reduced pathological damage,and lowered the levels of apoptosis and autophagy in the tissue surrounding the hematoma.In an in vitro model of intracerebral hemorrhage using primary cortical neurons induced by hemin,the administration of recombinant tissue plasminogen activator suppressed neuronal apoptosis,autophagy,and endoplasmic reticulum stress.Transcriptome sequencing analysis revealed that recombinant tissue plasminogen activator upregulated the phosphoinositide 3-kinase/RAC-alpha serine/threonine-protein kinase/mammalian target of rapamycin pathway in neurons.Moreover,the phosphoinositide 3-kinase inhibitor LY294002 abrogated the neuroprotective effects of recombinant tissue plasminogen activator in inhibiting excessive apoptosis,autophagy,and endoplasmic reticulum stress.Furthermore,to specify the domain of recombinant tissue plasminogen activator responsible for its neuroprotective effects,various inhibitors were used to target distinct domains.It has been revealed that the epidermal growth factor receptor inhibitor AG-1478 reversed the effect of recombinant tissue plasminogen activator on the phosphoinositide 3-kinase/RAC-alpha serine/threonineprotein kinase/mammalian target of rapamycin pathway.These findings suggest that recombinant tissue plasminogen activator exerts a direct neuroprotective effect on neurons following intracerebral hemorrhage,possibly through activation of the phosphoinositide 3-kinase/RAC-alpha serine/threonine-protein kinase/mammalian target of rapamycin pathway.
基金supported by the National Natural Science Foundation of China,Nos.82271419,81901902(to YZ),82202702(to ZW),82202351(to XH),82301550(to LYang),82271418(to XX)the Shanghai Rising-Star Program,No.22QA1408200(to YZ)the Fundamental Research Fundsfor the Central Universities,No.22120220555(to YZ).
文摘In the early stages of traumatic spinal cord injury,extensive accumulation of autophagosomes creates a neurotoxic microenvironment,exacerbating neuronal cell death and worsening tissue damage,ultimately hindering neurofunctional recovery.Activin A is a critical growth factor necessary for the development of the embryonic nervous system and for maintaining neuronal function in the adult cerebral cortex.It can inhibit excessive autophagy in ischemic stroke to reduce neuronal damage.However,the specific mechanism through which Activin A functions in the spinal cord remains poorly understood.In this study,we administered different concentrations of Activin A to neural stem cells from the spinal cord and found that Activin A stimulated the proliferation and neuronal differentiation of neural stem cells.Then,we established an in vitro oxidative stress model by using hydrogen peroxide to stimulate the neural stem cells-induced neurons.We found that Activin A could reduce apoptosis caused by oxidative stress.Subsequently,we treated a mouse model of spinal cord contusion with intrathecal injection of Activin A.Behavioral and electrophysiological results showed that Activin A promoted recovery of motor function and reconstruction of neural circuits in the model mice.Finally,RNA sequencing indicated that Activin A inhibited autophagy by activating the PI3K/AKT/mTOR pathway and upregulating the expression of synaptogenesis-related factor Sema3A in the spinal cord.These results suggest that Activin A may mediate the excessive autophagic response after spinal cord injury,promote the reconstruction of damaged neural circuits,and restore neurological function in the injured spinal cord.
基金supported by the National Nature Science Foundation of China,No.81471308(to JL)the Innovative Leading Talents of Liaoning Province,No.XLYC1902031(to JL)+2 种基金Science and Technology Projects in Liaoning Province,No.2022-BS-238(to CH)Young Top Talents of Liaoning Province,No.XLYC1907009(to LW)Dalian Science and Technology Innovation Fund,No.2018J11CY025(to JL)。
文摘Human neural stem cell-derived extracellular vesicles exhibit analogous functions to their parental cells,and can thus be used as substitutes for stem cells in stem cell therapy,thereby mitigating the risks of stem cell therapy and advancing the frontiers of stem cell-derived treatments.This lays a foundation for the development of potentially potent new treatment modalities for ischemic stroke.However,the precise mechanisms underlying the efficacy and safety of human neural stem cell-derived extracellular vesicles remain unclear,presenting challenges for clinical translation.To promote the translation of therapy based on human neural stem cell-derived extracellular vesicles from the bench to the bedside,we conducted a comprehensive preclinical study to evaluate the efficacy and safety of human neural stem cell-derived extracellular vesicles in the treatment of ischemic stroke.We found that administration of human neural stem cell-derived extracellular vesicles to an ischemic stroke rat model reduced the volume of cerebral infarction and promoted functional recovery by alleviating neuronal apoptosis.The human neural stem cell-derived extracellular vesicles reduced neuronal apoptosis by enhancing phosphorylation of phosphoinositide 3-kinase,mammalian target of rapamycin,and protein kinase B,and these effects were reversed by treatment with a phosphoinositide 3-kinase inhibitor.These findings suggest that human neural stem cell-derived extracellular vesicles play a neuroprotective role in ischemic stroke through activation of phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin signaling pathway.Finally,we showed that human neural stem cell-derived extracellular vesicles have a good in vivo safety profile.Therefore,human neural stem cell-derived extracellular vesicles are a promising potential agent for the treatment of ischemic stroke.
文摘Vitex negundo(V.negundo),an Indian herb with a rich historical background for the handling of various complaints,is a member of the Verbenaceae family and is characterized by small trees with pale gray bark.This herb is widely used and has been recognized in traditional medicine for its pharmacological effects on a wide range of diseases.All sections of the plant,but particularly the leaves,contain a variety of secondary metabolites,including alkaloids,phenols,flavonoids,glycoside iridoids,tannins,and terpenes.The system is included in a number of store-bought herbal preparations and has the potential to function as an efficient bio-committee.Cancer continues to be a major cause of death and morbidity in spite of the intervention.One of the leading causes of death is cancer,and current therapies can have unpleasant side effects.Unhindered reactions,resistance to traditional cancer medications,radiation therapy,chemotherapy,and restricted access to tumor tissue are some of the reasons why treatment frequently fails.To reduce side effects,increase chemotherapy sensitivity,and slow the spread of cancer,new approaches are required.Small food molecules have been suggested in numerous research as supplemental therapies for cancer patients.The effectiveness of the flavonoid-rich V.negundo extract in treating cancer was assessed mechanically in this investigation.Total flavonoids have been isolated for qualitative phytochemical investigation using V.negundo ethanolic extract.This article highlights significant developments in this field and explores how flavonoids contribute to the targeted suppression of the phosphoinositide 3-kinase-protein kinase B-mammalian target of rapamycin pathway in different cancer types.
文摘BACKGROUND Uric acid(UA),a key antioxidant metabolite,demonstrates dual roles in cancer.Unfortunately,studies on its role in colon cancer risk are uncommon,and the limited results are inconsistent.AIM To elucidate the association between UA and colon cancer risk and its me-chanisms.METHODS Multivariate logistic regression analysis evaluated the association between UA levels and colon cancer risk.Non-linear relationships were illustrated using restricted cubic splines.The threshold effect was performed to identify cut-off points.Human colon cancer cell lines(HCT-116 and HT29)were exposed to UA for 48 hours.Cell viability was assessed via the cell counting kit-8 assay.The evaluation of cell migration involved wound healing and transwell migration assays.HCT-116 cells were exposed to 4 mg/dL UA for 48 hours.The impact of the subsequent treatment with a phosphoinositide 3-kinases(PI3K)agonist and UA was assessed.RESULTS After adjusting for potential confounders,an inverse association was observed between UA and colon cancer risk(odds ratio=0.65,P<0.05).A non-linear relationship was identified,with a 4.79 mg/dL cut-off point(P<0.05).UA inhibited colon cancer cell proliferation and migration.These effects were mediated by the induction of reactive oxygen species and the suppression of the PI3K/protein kinase B/mammalian target of rapamycin pathway.CONCLUSION UA acts as a protective agent against colon cancer by inhibiting cell proliferation and migration through increased reactive oxygen species production and modulation of the PI3K/protein kinase B/mammalian target of rapamycin pathway.
基金Supported by the Scientific Research Fund of Tai’an Science and Technology Agency,No.2019NS180.
文摘Triple negative breast cancer(TNBC)is an exceptionally aggressive subtype of breast cancer with a poor prognosis.TNBC patients have limited treatment options beyond conventional chemotherapy,and they face significant challenges associated with disease recurrence and resistance to chemotherapy.The phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)/mechanistic target of rapamycin(mTOR)signaling pathway plays a pivotal role in cell proliferation,growth,metabolism,and survival.Its aberrant activation is closely linked to the development and progression of TNBC,as well as treatment response and drug resistance.Currently,numerous targeted drugs specifically inhibiting this signaling pathway are being developed and undergoing clinical trials.These include inhibitors targeting PI3K,AKT,or mTOR individually,as well as dual-target or multi-target inhibitors simultaneously targeting different components of this pathway.Encouragingly,some inhibitors have demonstrated promising potential in clinical trials.This review delves into the therapeutic potential of the PI3K/AKT/mTOR signaling pathway for TNBC and explores prospects for drug discovery.
基金Natural Science Foundation of Anhui Province,No.2208085MH216Major Natural Science and Technology Project of Bengbu Medical College,No.2020byfy004Scientific Research Program of Anhui Provincial Health Commission,No.AHWJ2023BAc10028.
文摘BACKGROUND Macrophages are central to the orchestration of immune responses,inflammatory processes,and the pathogenesis of diabetic complications.The dynamic polarization of macrophages into M1 and M2 phenotypes critically modulates inflammation and contributes to the progression of diabetic nephropathy.Sodiumglucose cotransporter 2 inhibitors such as dapagliflozin,which are acclaimed for their efficacy in diabetes management,may influence macrophage polarization,thereby ameliorating diabetic nephropathy.This investigation delves into these mechanistic pathways,aiming to elucidate novel therapeutic strategies for diabetes.AIM To investigate the inhibitory effect of dapagliflozin on macrophage M1 polarization and apoptosis and to explore its mechanism of action.METHODS We established a murine model of type 2 diabetes mellitus and harvested peritoneal macrophages following treatment with dapagliflozin.Concurrently,the human monocyte cell line cells were used for in vitro studies.Macrophage viability was assessed in a cell counting kit 8 assay,whereas apoptosis was evaluated by Annexin V/propidium iodide staining.Protein expression was examined through western blotting,and the expression levels of macrophage M1 surface immunosorbent assay,and quantitative real-time polymerase chain reaction analyses.RESULTS Dapagliflozin attenuated M1 macrophage polarization and mitigated apoptosis in the abdominal macrophages of diabetic mice,evidenced by the downregulation of proapoptotic genes(Caspase 3),inflammatory cytokines[interleukin(IL)-6,tumor necrosis factor-α,and IL-1β],and M1 surface markers(inducible nitric oxide synthase,and cluster of differentiation 86),as well as the upregulation of the antiapoptotic gene BCL2.Moreover,dapagliflozin suppressed the expression of proteins associated with the phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)signaling pathway(PI3K,AKT,phosphorylated protein kinase B).These observations were corroborated in vitro,where we found that the modulatory effects of dapagliflozin were abrogated by 740Y-P,an activator of the PI3K/AKT signaling pathway.CONCLUSION Dapagliflozin attenuates the polarization of macrophages toward the M1 phenotype,thereby mitigating inflammation and promoting macrophage apoptosis.These effects are likely mediated through the inhibition of the PI3K/AKT signaling pathway.
基金Supported by the National Natural Science Foundation of China,No.82002940 and No.82203336Shaanxi Natural Science Foundation,No.2023-JC-YB-166.
文摘BACKGROUND Hepatocellular carcinoma(HCC)ranks among the most prevalent and deadly malignancies,characterized by a high recurrence rate.Regulator of chromosome condensation 1(RCC1)serves as a principal guanine nucleotide exchange factor for ras-related nuclear protein guanosine triphosphatase(GTPase)and is implicated in various cancers.However,the role of RCC1 in HCC remains unex-plored.AIM To elucidate the functional significance and molecular mechanisms of RCC1 in HCC.METHODS Bioinformatics were to examine the expression levels of RCC1 in HCC and to assess its impact on the prognosis of this malignancy.The cell counting kit-8 assay and flow cytometry were utilized to evaluate the cell viability and cell cycle of HCC cells.Furthermore,quantitative reverse transcription and immunoblotting were to investigate the influence of RCC1 on cyclin associated proteins.RESULTS Bioinformatics analysis revealed that RCC1 was highly expressed in HCC and correlated with poor prognosis in HCC patients.Functional studies showed that RCC1 overexpression promoted the malignant phenotype of HCC cells,especially the proliferation of HCC cells,whereas RCC1 knockdown had the opposite effect.Mechanistically,we identied cell division cycle-associated(CDCA)8 as a downstream target of RCC1 in HCC.RCC1 overexpression markedly increased CDCA8 levels,consequently enhancing cell proliferation and survival in HCC cells.Additionally,we discovered that RCC1 contributed to the development and progression of HCC by activating the phosphoinositide 3-kinase/protein kinase B/cyclin-dependent kinase inhibitor 1a pathway through CDCA8.CONCLUSION Our study provides profound insights into the pivotal role of RCC1 in HCC and its potential as a therapeutic target.
基金support from the“111 program”of Ministry of Education of China and State Administration of Foreign Experts Affairs of China.
文摘BACKGROUND Uterine injury can cause uterine scarring,leading to a series of complications that threaten women’s health.Uterine healing is a complex process,and there are currently no effective treatments.Although our previous studies have shown that bone marrow mesenchymal stem cells(BMSCs)promote uterine damage repair,the underlying mechanisms remain unclear.However,exploring the specific regulatory roles of BMSCs in uterine injury treatment is crucial for further understanding their functions and enhancing therapeutic efficacy.AIM To investigate the underlying mechanism by which BMSCs promote the process of uterine healing.METHODS In in vivo experiments,we established a model of full-thickness uterine injury and injected BMSCs into the uterine wound.Transcriptome sequencing was per-formed to determine the enrichment of differentially expressed genes at the wound site.In in vitro experiments,we isolated rat uterine smooth muscle cells(USMCs)and cocultured them with BMSCs to observe the interaction between BMSCs and USMCs in the microenvironment.RESULTS We found that the differentially expressed genes were mainly related to cell growth,tissue repair,and angiogenesis,while the phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)pathway was highly enriched.Quantitative reverse-transcription polymerase chain reaction was used to validate differentially expressed genes,and the results demonstrated that BMSCs can upregulate genes related to regeneration and downregulate genes related to inflammation.Coculturing BMSCs promoted the migration and proliferation of USMCs,and the USMC microenvironment promoted the myogenic differentiation of BMSCs.Finally,we validated the PI3K/AKT pathway in tissues and cells and showed that BMSCs activate the PI3K/AKT pathway to promote the regeneration of uterine smooth muscle both in vivo and in vitro.CONCLUSION BMSCs upregulated uterine wound regeneration and anti-inflammatory factors and enhanced uterine smooth muscle proliferation through the PI3K/AKT pathway both in vivo and in vitro.
基金supported by the Natural Science Foundation of Xinjiang Uygur Autonomous Region(No.2020D01C210).
文摘Objective Endothelial dysfunction is a central contributor to the vascular complications observed in individuals with diabetes.cAMP response element-binding protein(CREB)plays a crucial role in mediating hyperglycemia-induced endothelial dysfunction.Phosphatase and tensin homolog(PTEN)has been implicated in the regulation of endothelial inflammation,yet the precise mechanism by which CREB modulates PTEN to protect endothelial cells under high glucose conditions remains unknown.This study aims to elucidate this potential mechanism.Methods Human umbilical vein endothelial cells(HUVECs)were exposed to high glucose(30 mM)or normal glucose(5.5 mM)for 6 days.Cell viability and apoptosis were assessed via the Cell Counting Kit-8 and flow cytometry.To evaluate oxidative stress,the levels of reactive oxygen species(ROS),lactate dehydrogenase(LDH),and malondialdehyde(MDA)were measured via commercial assay kits.The interaction between CREB and endothelial specific molecule 1(ESE-1)was assessed via coimmunoprecipitation.Chromatin immunoprecipitation and luciferase reporter assays were used to investigate the transcriptional regulation of PTEN by ESE-1 and CREB.Western blotting was performed to analyze the expression of intercellular adhesion molecule-1 and E-selectin.The adhesion of HUVECs was evaluated via monocyte‒endothelial cell adhesion assays.Results Our findings revealed a direct interaction between CREB and ESE-1,which together regulate PTEN expression to activate the phosphoinositide 3-kinase/protein kinase B pathway.Under high-glucose conditions,we observed significant increases in oxidative stress,inflammatory responses,and adhesion in HUVECs.ESE-1 knockdown reversed these effects,restoring endothelial cell function.Moreover,the overexpression of PTEN in high glucose–treated HUVECs rescued the endothelial injury induced by ESE-1 knockdown,suggesting that PTEN plays a pivotal role in mediating the protective effects.Conclusion ESE-1,through the regulation of CREB-mediated PTEN expression,activates the PI3K/AKT pathway and modulates key processes such as oxidative stress,inflammation,and adhesion in endothelial cells under high-glucose stress.
文摘The most striking morphological feature of eukaryotic cells is the presence of various membrane-enclosed compartments. These compartments, including organelles and transient transport intermediates, are not static. Rather, dynamic exchange of proteins and membrane is needed to maintain cellular homeostasis. One of the most dramatic examples of membrane mobilization is seen during the process ofmacroautophagy. Macroautophagy is the primary cellular pathway for degradation of long-lived proteins and organelles. In response to environmental cues, such as starvation or other types of stress, the cell produces a unique membrane structure, the phagophore. The phagophore sequesters cytoplasm as it forms a double-membrane cytosolic vesicle, an autophagosome. Upon completion, the autophagosome fuses with a lysosome or a vacuole in yeast, which delivers hydrolases that break down the inner autophagosome membrane along with its cargo, and the resulting macromolecules are released back into the cytosol for reuse. Autophagy is therefore a recycling process, allowing cells to survive periods of nutrient limitation; however, it has a wider physiological role, participating in development and aging, and also in protection against pathogen invasion, cancer and certain neurodegenerative diseases. In many cases, the role ofautophagy is identified through studies of an autophagy-related protein, Atg6/Beclin 1. This protein is part of a lipid kinase complex, and recent studies suggest that it plays a central role in coordinating the cytoprotective function ofautophagy and in opposing the cellular death process of apoptosis. Here, we summarize our current knowledge ofAtg6/Beclin 1 in different model organisms and its unique function in the cell.
基金funded by grants from Fondo Nacional de Desarrollo Científico y Tecnológico,FONDECYT 1200499 to EM,11200592 to MJY,1211329 to ACby the ANID PIA ACT172066 to EM and AC+3 种基金by the ANID postdoctoral fellowship 3210630 to MPHCby the ANID doctoral fellowship 21230122 to DPNby the ANID doctoral fellowship 21211189 to PRby the ANID doctoral fellowship by the ANID doctoral fellowship 21210611 to FDC。
文摘The brain is,after the adipose tissue,the organ with the greatest amount of lipids and diversity in their composition in the human body.In neurons,lipids are involved in signaling pathways controlling autophagy,a lysosome-dependent catabolic process essential for the maintenance of neuronal homeostasis and the function of the primary cilium,a cellular antenna that acts as a communication hub that transfers extracellular signals into intracellular responses required for neurogenesis and brain development.A crosstalk between primary cilia and autophagy has been established;however,its role in the control of neuronal activity and homeostasis is barely known.In this review,we briefly discuss the current knowledge regarding the role of autophagy and the primary cilium in neurons.Then we review the recent literature about specific lipid subclasses in the regulation of autophagy,in the control of primary cilium structure and its dependent cellular signaling in physiological and pathological conditions,specifically focusing on neurons,an area of research that could have major implications in neurodevelopment,energy homeostasis,and neurodegeneration.
基金the National Natural Science Foundation of China (32100553, 32171956, and 31770294)Natural Science Foundation of Jiangsu Province (BK20200555)the Fundamental Research Funds for the Central Universities, and a start-up fund for advanced talents from Nanjing Agricultural University (680-804016 to F.L.)
文摘Eukaryotic cells are confined by membranes that create hydrophobic barriers for substance and information exchange between the inside and outside of the cell.These barriers are formed by assembly of lipids and protein in aqueous environments.Lipids not only serve as building blocks for membrane construction,but also possess regulatory functions in cellular activities.These regulatory lipids are non-uniformly distributed in membrane systems;their temporal and spatial accumulation in specific membranes decodes environmental cues and changes cellular activity accordingly.Phosphoinositides(PIs)are phospholipids that exert regulatory effects.In recent years,research on PIs roles in regulating plant growth,development,and responses to environmental stress is increasing.Several reviews have been published on the composition of PIs,intermolecular transferring of PIs by lipid kinases(phosphatases)or PI-PLCs,subcellular localization,and specially their functions in plant developments.Herein,we review the crucial regulatory functions of PIs in plant stress responses,with a particular focus on PIs involved in membrane trafficking.
基金Supported by Agence Nationale de Recherche sur le Sida et les hépatites(ANRS,France),Ligue contre le cancer,France
文摘Hepatitis C virus(HCV) infects hepatocytes, polarized cells in the liver. Chronic HCV infection often leads to steatosis, fibrosis, cirrhosis and hepatocellular carcinoma, and it has been identified as the leading cause of liver transplantation worldwide. The HCV replication cycle is dependent on lipid metabolism and particularly an accumulation of lipid droplets in host cells. Phosphoinositides(PIs) are minor phospholipids enriched in different membranes and their levels are tightly regulated by specific PI kinases and phosphatases. PIs are implicated in a vast array of cellular responses that are central to morphogenesis, such as cytoskeletal changes, cytokinesis and the recruitment of downstream effectors to govern mechanisms involved in polarization and lumen formation. Important reviews of the literature identified phosphatidylinositol(Ptd Ins) 4-kinases, and their lipid products Ptd Ins(4)P, as critical regulators of the HCV life cycle. SH2-containing inositol polyphosphate 5-phosphatase(SHIP2), phosphoinositide 3-kinase(PI3K) and their lipid products Ptd Ins(3,4)P2 and Ptd Ins(3,4,5)P3, respectively, play an important role in the cell membrane and are key to the establishment of apicobasal polarity and lumen formation. In this review, we will focus on these new functions of PI3 K and SHIP2, and their deregulation by HCV, causing a disruption of apicobasal polarity, actin organization and extracellular matrix assembly. Finally we will highlight the involvement of this pathway in the event of insulin resistance and nonalcoholic fatty liver disease related to HCV infection.
基金supported by the National Natural Science Foundation of China(81871662,82150201)Xi’an Jiaotong University Fund(xzy012019066 and xzy032020037)Xi’an Jiaotong University Health Science Center-Qinnong Bank Fund(QNXJTU-04&QNXJTU-07)。
文摘The recent COVID-19 pandemic poses a global health emergency.Cellular entry of the causative agent SARS-CoV-2 is mediated by its spike protein interacting with cellular receptor-human angiotensin converting enzyme 2(ACE2).Here,by using lentivirus based pseudotypes bearing spike protein,we demonstrated that entry of SARS-CoV-2 into host cells was dependent on clathrin-mediated endocytosis,and phosphoinositides played essential roles during this process.In addition,we showed that the intracellular domain and the catalytic activity of ACE2 were not required for efficient virus entry.Finally,we showed that the current predominant Delta variant,although with high infectivity and high syncytium formation,also entered cells through clathrin-mediated endocytosis.These results provide new insights into SARS-CoV-2 cellular entry and present proof of principle that targeting viral entry could be an effective way to treat different variant infections.
