Low temperature as abiotic stress adversely impacts plant growth and development, and limits the ecological distribution of plants as well. Throughout their long evolutionary history, plants have developed a range of ...Low temperature as abiotic stress adversely impacts plant growth and development, and limits the ecological distribution of plants as well. Throughout their long evolutionary history, plants have developed a range of complicated and precise molecular regulatory mechanisms to deal with low-temperature stress, involving the activation of signal transduction pathways and the regulation of related genes. In this review, we provide a systematic summary of the most recent research findings regarding three hypotheses of cellular perception of low-temperature signals and two major intracellular low-temperature signaling pathways, including CBF-dependent signaling pathways and CBF-independent signaling pathways. Focus is placed on the functions of each component of the ICE-CBF-COR signaling cascade as well as their interrelationships. This review concludes that although some progress has been made in the identification, function, and mechanism of low-temperature response genes, their roles in the low-temperature regulatory network and molecular mechanisms still need to be studied in detail, which will be of great significance for improving the low-temperature tolerance of plants and adapting to climate change.展开更多
BACKGROUND Simulated microgravity environment can lead to gastrointestinal motility disturbance.The pathogenesis of gastrointestinal motility disorders is closely related to the stem cell factor(SCF)/c-kit signaling p...BACKGROUND Simulated microgravity environment can lead to gastrointestinal motility disturbance.The pathogenesis of gastrointestinal motility disorders is closely related to the stem cell factor(SCF)/c-kit signaling pathway associated with intestinal flora and Cajal stromal cells.Moreover,intestinal flora can also affect the regulation of SCF/c-kit signaling pathway,thus affecting the expression of Cajal stromal cells.Cajal cells are the pacemakers of gastrointestinal motility.AIM To investigate the effects of Bifidobacterium lactis(B.lactis)BLa80 on the intestinal flora of rats in simulated microgravity and on the gastrointestinal motility-related SCF/c-kit pathway.METHODS The internationally recognized tail suspension animal model was used to simulate the microgravity environment,and 30 rats were randomly divided into control group,tail suspension group and drug administration tail suspension group with 10 rats in each group for a total of 28 days.The tail group was given B.lactis BLa80 by intragastric administration,and the other two groups were given water intragastric administration,the concentration of intragastric administration was 0.1 g/mL,and each rat was 1 mL/day.Hematoxylin&eosin staining was used to observe the histopathological changes in each segment of the intestine of each group,and the expression levels of SCF,c-kit,extracellular signal-regulated kinase(ERK)and p-ERK in the gastric antrum of each group were detected by Western blotting and PCR.The fecal flora and mucosal flora of rats in each group were detected by 16S rRNA.RESULTS Simulated microgravity resulted in severe exfoliation of villi of duodenum,jejunum and ileum in rats,marked damage,increased space between villi,loose arrangement,shortened columnar epithelium of colon,less folds,narrower mucosal thickness,reduced goblet cell number and crypts,and significant improvement after probiotic intervention.Simulated microgravity reduced the expressions of SCF and c-kit,and increased the expressions of ERK and P-ERK in the gastric antrum of rats.However,after probiotic intervention,the expressions of SCF and ckit were increased,while the expressions of ERK and P-ERK were decreased,with statistical significance(P<0.05).In addition,simulated microgravity can reduce the operational taxonomic unit(OTU)of the overall intestinal flora of rats,B.lactis BLa80 can increase the OTU of rats,simulated microgravity can reduce the overall richness and diversity of stool flora of rats,increase the abundance of firmicutes in stool flora of rats,and reduce the abundance of Bacteroides in stool flora of rats,most of which are mainly beneficial bacteria.Simulated microgravity can increase the overall richness and diversity of mucosal flora,increase the abundance of Bacteroides and Desulphurides in the rat mucosal flora,and decrease the abundance of firmicutes,most of which are proteobacteria.After probiotics intervention,the overall Bacteroidetes trend in simulated microgravity rats was increased.CONCLUSION B.lactis BLa80 can ameliorate intestinal mucosal injury,regulate intestinal flora,inhibit ERK expression,and activate the SCF/c-kit signaling pathway,which may have a facilitating effect on gastrointestinal motility in simulated microgravity rats.展开更多
Pulpitis is a common infective oral disease in clinical situations.The regulatory mechanisms of immune defense in pulpitis are still being investigated.Osteomodulin(OMD)is a small leucine-rich proteoglycan family memb...Pulpitis is a common infective oral disease in clinical situations.The regulatory mechanisms of immune defense in pulpitis are still being investigated.Osteomodulin(OMD)is a small leucine-rich proteoglycan family member distributed in bones and teeth.It is a bioactive protein that promotes osteogenesis and suppresses the apoptosis of human dental pulp stem cells(hDPSCs).In this study,the role of OMD in pulpitis and the OMD-induced regulatory mechanism were investigated.The OMD expression in normal and inflamed human pulp tissues was detected via immunofluorescence staining.Intriguingly,the OMD expression decreased in the inflammatory infiltration area of pulpitis specimens.The cellular experiments demonstrated that recombined human OMD could resist the detrimental effects of lipopolysaccharide(LPS)-induced inflammation.A conditional Omd knockout mouse model with pulpal inflammation was established.LPS-induced inflammatory impairment significantly increased in conditional Omd knockout mice,whereas OMD administration exhibited a protective effect against pulpitis.Mechanistically,the transcriptome alterations of OMD overexpression showed significant enrichment in the nuclear factor-κB(NF-κB)signaling pathway.Interleukin-1 receptor 1(IL1R1),a vital membrane receptor activating the NF-κB pathway,was significantly downregulated in OMD-overexpressing hDPSCs.Additionally,the interaction between OMD and IL1R1 was verified using co-immunoprecipitation and molecular docking.In vivo,excessive pulpal inflammation in Omd-deficient mice was rescued using an IL1R antagonist.Overall,OMD played a protective role in the inflammatory response via the IL1R1/NF-κB signaling pathway.OMD may optimize the immunomodulatory functions of hDPSCs and can be used for regenerative endodontics.展开更多
Epidermal growth factor receptor(EGFR)signaling has become an importanttarget for drug development becauseEGFR signaling enhances tumor cell proliferation,migration,and invasion and inhibits apoptosis.However,theresul...Epidermal growth factor receptor(EGFR)signaling has become an importanttarget for drug development becauseEGFR signaling enhances tumor cell proliferation,migration,and invasion and inhibits apoptosis.However,theresults of clinical trials using EGFR inhibitors in patients with solid tumors have been disappointing.Here,wereport a protective effect of the EGFR inhibitors AG1478 and PD153035 against cell death induced by acute hy-poxia,which contrasts with their proapoptotic effects under normoxia.Under hypoxic conditions,both agents re-展开更多
BACKGROUND Excessive endoplasmic reticulum(ER)stress in intestinal epithelial cells can lead to damage to the intestinal mucosal barrier,activate the signal transducer and activator of transcription 3(STAT3)/nuclear f...BACKGROUND Excessive endoplasmic reticulum(ER)stress in intestinal epithelial cells can lead to damage to the intestinal mucosal barrier,activate the signal transducer and activator of transcription 3(STAT3)/nuclear factor kappa B(NF-κB)signaling pathway,and exacerbate the inflammatory response,thus participating in the pathogenesis of ulcerative colitis(UC).Mesalazine is a commonly used drug in the clinical treatment of UC.However,further studies are needed to determine whether mesalazine regulates the ER stress of intestinal epithelial cells,downregulates the STAT3/NF-κB pathway to play a role in the treatment of UC.AIM To study the therapeutic effects of mesalazine on spontaneous colitis in interleukin-10(IL-10)-/-mice.METHODS The 24-week-old IL-10-/-mice with spontaneous colitis were divided into the model group and the 5-amino salicylic acid group.Littermates of wild-type mice of the same age group served as the control.There were eight mice in each group,four males and four females.The severity of symptoms of spontaneous colitis in IL-10-/-mice was assessed using disease activity index scores.On day 15,the mice were sacrificed.The colon length was measured,and the histopathological changes and ultrastructure of colonic epithelial cells were detected.The protein expressions of STAT3,p-STAT3,NF-κB,IκB,p-IκB,and glucoseregulated protein 78 were identified using Western blotting.The STAT3 and NF-κB mRNA expressions were identified using real-time polymerase chain reaction.The glucose-regulated protein 78 and C/EBP homologous protein expressions in colon sections were detected using immunofluorescence.RESULTS Mesalazine reduced the symptoms of spontaneous colitis in IL-10 knockout mice and the histopathological damage of colonic tissues,and alleviated the ER stress in epithelial cells of colitis mice.Western blotting and quantitative real-time polymerase chain reaction results showed that the STAT3/NF-κB pathway in the colon tissue of model mice was activated,suggesting that this pathway was involved in the pathogenesis of UC and might become a potential therapeutic target.Mesalazine could down-regulate the protein expressions of p-STAT3,NF-κB and p-IκB,and down-regulate the mRNA expression of STAT3 and NF-κB.CONCLUSION Mesalazine may play a protective role in UC by reducing ER stress by regulating the STAT3/NF-κB signaling pathway.展开更多
BACKGROUND Diabetic macular edema(DME)is the most common cause of vision loss in people with diabetes.Tight junction disruption of the retinal pigment epithelium(RPE)cells has been reported to induce DME development.S...BACKGROUND Diabetic macular edema(DME)is the most common cause of vision loss in people with diabetes.Tight junction disruption of the retinal pigment epithelium(RPE)cells has been reported to induce DME development.SMAD-specific E3 ubiquitin protein ligase(SMURF)1 was associated with the tight junctions of cells.However,the mechanism of SMURF1 in the DME process remains unclear.AIM To investigate the role of SMURF1 in RPE cell tight junction during DME.METHODS ARPE-19 cells treated with high glucose(HG)and desferrioxamine mesylate(DFX)for establishment of the DME cell model.DME mice models were constructed by streptozotocin induction.The trans-epithelial electrical resistance and permeability of RPE cells were analyzed.The expressions of tight junction-related and autophagy-related proteins were determined.The interaction between insulin like growth factor 2 mRNA binding protein 2(IGF2BP2)and SMURF1 mRNA was verified by RNA immunoprecipitation(RIP).SMURF1 N6-methyladenosine(m6A)level was detected by methylated RIP.RESULTS SMURF1 and vascular endothelial growth factor(VEGF)were upregulated in DME.SMURF1 knockdown reduced HG/DFX-induced autophagy,which protected RPE cell tight junctions and ameliorated retinal damage in DME mice.SMURF1 activated the Wnt/β-catenin-VEGF signaling pathway by promoting WNT inhibitory factor(WIF)1 ubiquitination and degradation.IGF2BP2 upregulated SMURF1 expression in an m6A modification-dependent manner.CONCLUSION M6A-modified SMURF1 promoted WIF1 ubiquitination and degradation,which activated autophagy to inhibit RPE cell tight junctions,ultimately promoting DME progression.展开更多
We read with great interest the study by Zhang et al on Yiyi Fuzi Baijiang powder(YFB),which exemplifies the power of modern methods to validate traditional Chinese medicine(TCM).The key insight is that YFB doesn’t m...We read with great interest the study by Zhang et al on Yiyi Fuzi Baijiang powder(YFB),which exemplifies the power of modern methods to validate traditional Chinese medicine(TCM).The key insight is that YFB doesn’t merely alter“good”or“bad”bacteria but restores the gut microbiota’s holistic equilibrium.This is powerfully shown by its paradoxical reduction of anaerobic probiotics like Bifidobacterium,rectifying the diseased,hypoxic environment,causing their aberrant overgrowth.This challenges the conventional probiotic paradigm and underscores a core TCM principle:Herbal formulas treat disease by restoring the body’s overall functional balance.Future research should focus on the interplay between herbal components,intestinal oxygen,and microbial metabolites to further unravel this sophisticated dialogue.展开更多
Acute respiratory distress syndrome(ARDS)is a life-threatening condition that is characterized by high mortality rates and limited therapeutic options.Notably,Zhang et al demonstrated that CD146+mesenchymal stromal ce...Acute respiratory distress syndrome(ARDS)is a life-threatening condition that is characterized by high mortality rates and limited therapeutic options.Notably,Zhang et al demonstrated that CD146+mesenchymal stromal cells(MSCs)exhibited greater therapeutic efficacy than CD146-MSCs.These cells enhance epithelial repair through nuclear factor kappa B/cyclooxygenase-2-associated paracrine signaling and secretion of pro-angiogenic factors.We concur that MSCs hold significant promise for ARDS treatment;however,the heterogeneity of cell products is a translational barrier.Phenotype-aware strategies,such as CD146 enrichment,standardized potency assays,and extracellular vesicle profiling,are essential for improving the consistency of these studies.Further-more,advanced preclinical models,such as lung-on-a-chip systems,may provide more predictive insights into the therapeutic mechanisms.This article underscores the importance of CD146+MSCs in ARDS,emphasizes the need for precision in defining cell products,and discusses how integrating subset selection into translational pipelines could enhance the clinical impact of MSC-based therapies.展开更多
AIM:To identify proangiogenic factors engaged in neovascular age-related macular degeneration(AMD)except vascular endothelial growth factor(VEGF)from human retinal pigment epithelial(h RPE)cells and investigate the un...AIM:To identify proangiogenic factors engaged in neovascular age-related macular degeneration(AMD)except vascular endothelial growth factor(VEGF)from human retinal pigment epithelial(h RPE)cells and investigate the underlying mechanisms.METHODS:VEGF receptor 2(VEGFR2)in ARPE-19 cells was depleted by si RNA transfection or overexpressed through adenovirus infection.The m RNA and the protein levels of interleukin-8(IL-8)in ARPE-19 cells were measured by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay respectively.The protein levels of AKT,p-AKT,MEK,p-MEK,ERK1/2,p-ERK1/2,JNK,p-JNK,p38 and p-p38 were detected by Western blotting.A selective chemical inhibitor,LY3214996,was employed to inhibit phosphorylation of ERK1/2.Cell viability was determined by MTT assay.RESULTS:Knockdown of VEGFR2 in ARPE-19 cells robustly augmented IL-8 production at both the m RNA and the protein levels.Silencing VEGFR2 substantially enhanced phosphorylation of MEK and ERK1/2 while exerted no effects on phosphorylation of AKT,JNK and p38.Inhibiting ERK1/2 phosphorylation by LY3214996 reversed changes in VEGFR2 knockdown-induced IL-8 upregulation at the m RNA and the protein levels with no effects on cell viability.VEGFR2 overexpression significantly reduced IL-8 generation at the m RNA and the protein levels.CONCLUSION:Blockade of VEGF signaling augments IL-8 secretion via MEK/ERK1/2 axis and overactivation of VEGF pathway decreases IL-8 production in h RPE cells.Upregulated IL-8 expression after VEGF signaling inhibition in h RPE cells may be responsible for being incompletely responsive to anti-VEGF remedy in neovascular AMD,and IL-8 may serve as an alternative therapeutic target for neovascular AMD.展开更多
BACKGROUND The transforming growth factor β(TGFβ) signaling pathway plays a crucial role in the development of liver fibrosis by activating TGFβ type Ⅱ receptor(TGFβR2), followed by the recruitment of TGFβR1 fin...BACKGROUND The transforming growth factor β(TGFβ) signaling pathway plays a crucial role in the development of liver fibrosis by activating TGFβ type Ⅱ receptor(TGFβR2), followed by the recruitment of TGFβR1 finally triggering downstream signaling pathway.AIM To find drugs targeting TGFβR2 that inhibit TGFβR1/TGFβR2 complex formation, theoretically inhibit TGFβ signaling pathway, and thereby ameliorate liver fibrosis.METHODS Food and Drug Administration-approved drugs were screened for binding affinity with TGFβR2 by virtual molecular docking. We identified 6 candidates and further explored their potential by Cell Counting Kit-8(CCK-8) cell cytotoxic experiment to validate toxicity and titrated the best cellular working concentrations. Next, we further demonstrated the detailed molecular working mechanisms using mutagenesis analysis. Finally, we used a mouse model to investigate its potential anti-liver fibrosis effect.RESULTS We identified 6 drug candidates. Among these 6 drugs, dihydroergotamine(DHE) shows great ability in reducing fibrotic gene expressions such as collagen, p-SMAD3, and α-SMA in TGFβ induced cellular model of liver fibrosis in LX-2 cells. Furthermore, we demonstrated that DHE binds to TGFβR2. Moreover, mutation of Leu27, Phe30, Thr51, Ser52, Ile53, and Glu55 of TGFβR2 disrupted the binding of TGFβR2 with DHE. In addition, DHE significantly improved liver fibrosis, as evidenced by Masson’s trichrome staining of liver sections. This is further supported by the width and the velocity of the portal vein, and serum markers of liver function. In line with those observations, DHE also decreased macrophages infiltration and extracellular matrix deposition in the liver.CONCLUSION DHE alleviates liver fibrosis by binding to TGFβR2 thereby suppressing TGFβ signaling pathway. We show here that as far as drug repurposing, DHE has great potential to treat liver fibrosis.展开更多
Background:This study will be aimed at investigating the effects of Polygonatum sibiricum polysaccharide(PSP)in a rat model of type 2 diabetes mellitus(T2DM).Methods:Thirty Sprague–Dawley male rats were evenly distri...Background:This study will be aimed at investigating the effects of Polygonatum sibiricum polysaccharide(PSP)in a rat model of type 2 diabetes mellitus(T2DM).Methods:Thirty Sprague–Dawley male rats were evenly distributed into three groups:normal,T2DM,and PSP groups,by applying a random sample table method.The typical cluster was served balanced food every day,whereas the others were supplied with a high-fat diet and streptozotocin injections to make T2DM rat models.The changes in humor organic chemistry indicators and liver histopathology were determined following the model institution for every cluster.After PSP intervention,western blotting was applied to research the expression levels of crucial transcription factors concerned within the nuclear factor erythroid 2-related factor 2(Nrf2)signal pathway,as well as Nrf2,glutamate-cysteine ligase chemical process fractional monetary unit,NQO1 and HO-1 within the liver tissues of the rat models,and to seem into the therapeutic edges of PSP and the way it happens in T2DM rats.Results:PSP intervention considerably reduced the concentration levels of aldohexose,lipids,liver-operated indicators,and alternative organic chemistry indicators within the humor of T2DM rat models and improved the histopathological changes within the liver.In addition,the activity of SOD and GSH-Px were increased,and the levels of MDA were decreased in the liver tissues of T2DM rat models following PSP intervention.Western blotting revealed that the expression levels of the Nrf2,HO-1,glutamate-cysteine ligase chemical,and NQO1 proteins were increased in rat liver tissues following PSP intervention.Conclusion:PSP has therapeutic effects in T2DM rat models,and its mechanism of motion might also be related to regulating the Nrf2 signaling pathway in liver tissues and alleviating oxidative stress.展开更多
The mandibular condyle is a critical growth center in craniofacial bone development,especially during postnatal stages.Postnatal condyle osteogenesis requires precise spatiotemporal coordination of growth factor signa...The mandibular condyle is a critical growth center in craniofacial bone development,especially during postnatal stages.Postnatal condyle osteogenesis requires precise spatiotemporal coordination of growth factor signaling cascades and hierarchical gene regulatory networks.Plagl1,which encodes a zinc finger transcription factor,is a paternally expressed gene.We demonstrate that PLAGL1 is highly expressed in cranial neural crest cell(CNCC)-derived lineage cells in mouse condyles.Using the CNCC-derived lineage-specific Plagl1 knockout mouse model,we evaluate the function of PLAGL1 during postnatal mouse condyle development.Our findings show that PLAGL1 contributes significantly to osteoblast differentiation,and its deficiency impairs osteogenic lineage differentiation,which consequently disrupts mandibular condyle development.Mechanistically,insulin-like growth factor 2(IGF2)in complex with IGF-binding proteins(IGFBPs)has been identified as the principal PLAGL1 effector responsible for osteogenic regulation during postnatal condyle morphogenesis.Plagl1 deficiency significantly downregulates the IGF2/IGFBP pathway,leading to disordered glucose metabolism,defective extracellular matrix organization,and impaired ossification.Exogenous IGF2 treatment rescues impaired osteoblast differentiation caused by Plagl1 deficiency.In conclusion,the PLAGL1-IGF2 axis is a critical regulator of osteogenesis during mandibular condyle development.展开更多
Neurodegenerative diseases(NDDs)are characterized primarily by progressive impairments in cognition,behavior,and memory.MicroRNAs(miRNAs)are abundantly expressed in the central nervous system and are vital for the nor...Neurodegenerative diseases(NDDs)are characterized primarily by progressive impairments in cognition,behavior,and memory.MicroRNAs(miRNAs)are abundantly expressed in the central nervous system and are vital for the normal function and survival of neurons.Mature miRNAs are naturally occurring small noncoding single-stranded RNA molecules that are approximately 21–25 nucleotides in length.They regulate gene expression by pairing with target mRNAs and undergo significant alterations in various physiological and pathological processes.miR-146a,a miRNA dependent on nuclear factorκB(NF-κB),is highly expressed in neurons and functions as an anti-inflammatory miRNA via the Toll-like receptor(TLR)pathway,which is an essential regulatory factor for neuroinflammation expression during the development of NDDs.In this review,we summarize and emphasize the pivotal role of miR-146a in NDDs,highlighting the association between miR-146a polymorphisms and the risk of NDDs.We also discuss how alterations in miR-146a expression levels represent a critical event in the pathogenesis of numerous NDDs.Furthermore,the target genes of miR-146a are involved in regulating the pathophysiological processes of these diseases,particularly in the context of neuroinflammatory responses.In conclusion,miR-146a plays a central role in the progression of NDDs,with its primary function in neuroinflammation.These findings suggest that miR-146a holds promise as both a biomarker and a potential therapeutic target.A deeper understanding of how miR-146a influences neuroinflammatory responses across different types of neurological damage,cell types,and even various stages of certain NDDs will pave the way for its use as a therapeutic target in treating these conditions.Therefore,this article reviews the mechanism of miR-146a in NDDs and discusses the future therapeutic prospects for this type of disease.miR-146a regulates the related genes of the inflammatory signaling pathway and its influence on the development of NDDs.(Created in https://BioRender.com).展开更多
Background:VPS37A(VPS37A subunit of ESCRT-I),a component of the ESCRT-I(endosomal sorting complex required for transport I)complex,mediates vesicular trafficking through sorting endocytic ubiquitinated cargos into mul...Background:VPS37A(VPS37A subunit of ESCRT-I),a component of the ESCRT-I(endosomal sorting complex required for transport I)complex,mediates vesicular trafficking through sorting endocytic ubiquitinated cargos into multivesicular bodies(MVBs).Although accumulating evidence indicates that VPS37A deficiency occurs in numerous malignancies and exerts tumor-suppressive effects during cancer progression,its functional significance in colorectal cancer(CRC)pathogenesis remains poorly characterized.Therefore,this study aims to further investigate the functional and molecular mechanisms by which VPS37A downregulation contributes to malignant biological phenotypes in CRC,with a specific focus on how its dysregulation affects cell death pathways.Methods:Multi-omics analysis of TCGA,GEO,and CPTAC cohorts identified VPS37A as a downregulated tumor suppressor gene in CRC.The prognostic relevance of VPS37A was validated in two clinical cohorts(Cohorts 1 and 2)using immunohistochemistry.Functional assays in VPS37A-overexpressing CRC cells and xenografts assessed proliferation,cell cycle progression,and stress-induced cell death.RNA sequencing,nuclear factor kappa-B(NF-κB)luciferase reporter assays,and lysosomal inhibition experiments elucidated the mechanisms underlying tumor necrosis factor receptor 1(TNFR1)degradation.Results:VPS37A is significantly downregulated in advanced-stage CRC and independently predicts poor survival.Functionally,VPS37A overexpression suppresses proliferation and induces G2/M arrest in vitro,while reducing xenograft growth.Under metabolic stress(glucose deprivation/galactose adaptation),VPS37A triggers cell death via apoptosis,necroptosis,and ferroptosis.Mechanistically,VPS37A redirects TNFR1 to lysosomal degradation,suppressing NF-κB nuclear translocation and transcriptional activity.Conclusion:VPS37A deficiency drives CRC progression by sustaining TNFR1/NF-κB signaling under metabolic stress.Restoring VPS37A activity promotes TNFR1 degradation,offering a therapeutic strategy to counteract NF-κB-mediated treatment resistance in CRC.展开更多
Perennial grasses have developed intricate mechanisms to adapt to diverse environments,enabling their resistance to various biotic and abiotic stressors.These mechanisms arise from strong natural selection that contri...Perennial grasses have developed intricate mechanisms to adapt to diverse environments,enabling their resistance to various biotic and abiotic stressors.These mechanisms arise from strong natural selection that contributes to enhancing the adaptation of forage plants to various stress conditions.Methods such as antisense RNA technology,CRISPR/Cas9 screening,virus-induced gene silencing,and transgenic technology,are commonly utilized for investigating the stress response functionalities of grass genes in both warm-season and cool-season varieties.This review focuses on the functional identification of stress-resistance genes and regulatory elements in grasses.It synthesizes recent studies on mining functional genes,regulatory genes,and protein kinase-like signaling factors involved in stress responses in grasses.Additionally,the review outlines future research directions,providing theoretical support and references for further exploration of(i)molecular mechanisms underlying grass stress responses,(ii)cultivation and domestication of herbage,(iii)development of high-yield varieties resistant to stress,and(iv)mechanisms and breeding strategies for stress resistance in grasses.展开更多
Cold temperatures, a major abiotic stress, threaten the growth and development of plants, worldwide. To cope with this adverse environmental cue, plants from temperate climates have evolved an array of sophisticated m...Cold temperatures, a major abiotic stress, threaten the growth and development of plants, worldwide. To cope with this adverse environmental cue, plants from temperate climates have evolved an array of sophisticated mechanisms to acclimate to cold periods, increasing their ability to tolerate freezing stress. Over the last decade, significant progress has been made in determining the molecular mechanisms underpinning cold acclimation, including following the identification of several pivotal components, including candidates for cold sensors, protein kinases, and transcription factors. With these developments, we have a better understanding of the CBF-dependent cold-signaling pathway. In this review, we summarize recent progress made in elucidating the cold-signaling pathways, especially the C-repeat binding factor-dependent pathway, and describe the regulatory function of the crucial components of plant cold signaling. We also discuss the unsolved questions that should be the focus of future work.展开更多
BACKGROUND Regenerating gene 4(REG4)has been proved to be carcinogenic in some cancers,but its manifestation and possible carcinogenic mechanisms in colorectal cancer(CRC)have not yet been elucidated.Our previous stud...BACKGROUND Regenerating gene 4(REG4)has been proved to be carcinogenic in some cancers,but its manifestation and possible carcinogenic mechanisms in colorectal cancer(CRC)have not yet been elucidated.Our previous study found that the drug resistance of CRC cells may be closely linked to their fat metabolism.AIM To explore the role of REG4 in CRC and its association with lipid droplet formation and chemoresistance.METHODS We conducted a meta-analysis and bioinformatics and pathological analyses of REG4 expression in CRC.The effects of REG4 on the phenotypes and related protein expression were also investigated in CRC cells.We detected the impacts of REG4 on the chemoresistance and lipid droplet formation in CRC cells.Finally,we analyzed how REG4 regulated the transcription and proteasomal degradation of lipogenic enzymes in CRC cells.RESULTS Compared to normal mucosa,REG4 mRNA expression was high in CRC(P<0.05)but protein expression was low.An inverse correlation existed between lymph node and distant metastases,tumor-node-metastasis staging or short overall survival and REG4 mRNA overexpression(P<0.05),but vice versa for REG4 protein expression.REG4-related genes included:Chemokine activity;taste receptors;protein-DNA and DNA packing complexes;nucleosomes and chromatin;generation of second messenger molecules;programmed cell death signals;epigenetic regulation and DNA methylation;transcription repression and activation by DNA binding;insulin signaling pathway;sugar metabolism and transfer;and neurotransmitter receptors(P<0.05).REG4 exposure or overexpression promoted proliferation,antiapoptosis,migration,and invasion of DLD-1 cells in an autocrine or paracrine manner by activating the epidermal growth factor receptor-phosphoinositide 3-kinase-Akt-nuclear factor-κB pathway.REG4 was involved in chemoresistance not through de novo lipogenesis,but lipid droplet assembly.REG4 inhibited the transcription of acetyl-CoA carboxylase 1(ACC1)and ATP-citrate lyase(ACLY)by disassociating the complex formation of anti-acetyl(AC)-acetyl-histone 3-AC-histone 4-inhibitor of growth protein-5-si histone deacetylase;-sterol-regulatory element binding protein 1 in their promoters and induced proteasomal degradation of ACC1 or ACLY.CONCLUSION REG4 may be involved in chemoresistance through lipid droplet assembly.REG4 reduces expression of de novo lipid synthesis key enzymes by inhibiting transcription and promoting ubiquitination-mediated proteasomal degradation.展开更多
Background Aberrant epithelial repair has been observed in chronic rhinosinusitis （CRS） patients; however, the mechanism of epithelial cell repair regulation is unclear. Epidermal growth factor （EGF） plays an impo...Background Aberrant epithelial repair has been observed in chronic rhinosinusitis （CRS） patients; however, the mechanism of epithelial cell repair regulation is unclear. Epidermal growth factor （EGF） plays an important role in regulating epithelial cell repair in lower airway and may be a critical factor in the remodeling processes of CRS. The objective of our research is to evaluate the differences between CRS and normal subjects and between chronic rhinosinusitis without nasal poiys （CRSsNP） and chronic rhinosinusitis with nasal polys （CRSwNP） in the regulation of EGF pathways and the regulating proliferative position of classic Ras/Raf/MEK/ERK pathways. Methods We evaluated the proliferation rates of ethmoidal mucosal cells before and after stimulation with EGF, epidermal growth factor receptor （EGFR） kinase inhibitor AG1478, and extracellular signal-regulated kinase 1/2 （ERKI/2）inhibitor PD98059 using MTT assays. We also analyzed the sinonasal epithelial cells collected from control subjects and patients with CRS subtypes CRSsNP and CRSwNP for the expression of ERK1/2, phosphorylated ERK1/2, P21, P15, and P27 using western blotting analyses. Results The proliferation rates of sinonasal epithelial cells before and after EGF stimulation were lower in CRS patients than in the controls. AG1478 or PD98059 inhibitor treatment of control epithelial cells did not result in a significant difference in proliferation. Although, AG1478 and PD98059,inhibited the proliferation of CRS cells, the degree of proliferation inhibition was markedly different in CRSsNP. AG1478 suppressed the proliferation of CRSwNP epithelial cells, whereas PD98059 had no effect. The ratio of ERK1/2 phosphorylation in CRS cells was lower than that of the control cells. Cyclin-dependent kinase inhibitors were highly expressed in CRS cells compared with that of control cells. ERK1/2 and P27 showed differential expression in CRSsNP and CRSwNP. Conclusions Differences existed in EGF pathways in CRS patients and normal subjects as well as in CRSsNP and CRSwNP. Classical Ras/Raf/MEK/ERK pathway may assume absolute superiority in control cells. Ras/Raf/MEK/ERK classical pathway and other pathways might be active at the same time to stimulate epithelial cell proliferation in CRSsNP. The function of Ras/Raf/MEK/ERK classical pathway was weaker in CRSwNP than in CRSsNP and when the classical pathway was blocked in CRSwNP, some other pathway could have completely compensated the proliferation induced by the Ras/Raf/MEK/ERK pathway.展开更多
AIM:To explore the anti-fibrotic effect of Haobie Yangyin Ruanjian Decoction(HYRD)on CCl4-induced hepatic fibrosis in rats and its modulation on the transforming growth factor(TGF)β-Smad signaling pathway.METHODS:Fif...AIM:To explore the anti-fibrotic effect of Haobie Yangyin Ruanjian Decoction(HYRD)on CCl4-induced hepatic fibrosis in rats and its modulation on the transforming growth factor(TGF)β-Smad signaling pathway.METHODS:Fifty-six healthy Wistar rats were randomly divided into five groups:normal control group(n=6),CCl4-induced hepatic fibrosis group(n=14) and three treatment groups(the treated rats received HYRD via oral administration at daily dosages of 8.2,2.5 and 0.82 g/kg,respectively)of HYRD(n=12,respectively).Experimental hepatic fibrosis was induced by subcutaneous injection of carbon tetrachloride solution(CCl4 dissolved in peanut oil,4:6,V/V)with 0.5 mL/100 g body weight for the first time,and then 0.3 mL/100 g body weight twice a week for 8 wk.In the former 2 wk,rats were raised by feedstuffⅠ(80% corn meal,20%lard,0.5%cholesterol).After 2 wk,they were raised by feedstuffⅡ(corn meal and 0.5% cholesterol).Except for the control group,30%alcohol solution was given orally to each rat every other day from the beginning,1 mL for each rat.Liver function parameters and hepatic hydroxyproline content were detected by chromatometry.Serum levels of hyaluronic acid(HA),typeⅣcollagen(CIV),typeⅢprecollagen(PCⅢ)and laminin(LN)were assayed with radioimmunoassay.Deposition of collagen was observed with hematoxylin-eosin staining and collagen staining.Gene expression of TGFβ1 and Smad3 were detected with real-time reverse transcriptase-polymerase chain reaction and Western blotting,respectively.RESULTS:The serum levels of alanine transaminase and aspartate transaminase were increased in the model group compared with the control group(P<0.01),and they were decreased in the three treatment groups compared with the model group.The serum levels of total protein and albumin were decreased in the model group and increased in the three treatment groups.The hepatic hydroxyproline content and serum levels of PCⅢ,HA,LN and CIV were markedly increased in the model group compared with the control group,and decreased in the treatment groups.The gene expression of TGFβ1 and Smad3 was enhanced in the model group compared with the control group,and HYRD could down regulate their expression.CONCLUSION:HYRD can inhibit hepatic fibrosis induced by CCl4 in rats,which is probably associated with its down-regulation on fibrogenic signal transduction of TGFβ-Smad pathway.展开更多
The plant cell wall is an important interface for sensing pathogen attack and activating signaling pathways that promote plant immune responses.THESEUS1(THE1) acts as a sensor of cell wall integrity that controls cell...The plant cell wall is an important interface for sensing pathogen attack and activating signaling pathways that promote plant immune responses.THESEUS1(THE1) acts as a sensor of cell wall integrity that controls cell elongation during plant growth.However, no specific role for THE1 in plant defense responses has been reported. Here, we found that THE1 interacts with GUANINE EXCHANGE FACTOR4(GEF4)and that both proteins play regulatory roles in plant resistance to the necrotrophic fungus Botrytis cinerea.Genetic analysis showed that THE1 and GEF4 function in the same genetic pathway to mediate plant defense responses. In addition, using transcriptome analysis, we identified various genes(such as defense-related,secondary metabolite-related, and transcription factor genes) that are likely downstream targets in the THE1-GEF4 signaling pathway. Our results suggest that THE1 functions as an upstream regulator of GEF4 signaling to positively regulate defense responses against B. cinerea in Arabidopsis.展开更多
文摘Low temperature as abiotic stress adversely impacts plant growth and development, and limits the ecological distribution of plants as well. Throughout their long evolutionary history, plants have developed a range of complicated and precise molecular regulatory mechanisms to deal with low-temperature stress, involving the activation of signal transduction pathways and the regulation of related genes. In this review, we provide a systematic summary of the most recent research findings regarding three hypotheses of cellular perception of low-temperature signals and two major intracellular low-temperature signaling pathways, including CBF-dependent signaling pathways and CBF-independent signaling pathways. Focus is placed on the functions of each component of the ICE-CBF-COR signaling cascade as well as their interrelationships. This review concludes that although some progress has been made in the identification, function, and mechanism of low-temperature response genes, their roles in the low-temperature regulatory network and molecular mechanisms still need to be studied in detail, which will be of great significance for improving the low-temperature tolerance of plants and adapting to climate change.
文摘BACKGROUND Simulated microgravity environment can lead to gastrointestinal motility disturbance.The pathogenesis of gastrointestinal motility disorders is closely related to the stem cell factor(SCF)/c-kit signaling pathway associated with intestinal flora and Cajal stromal cells.Moreover,intestinal flora can also affect the regulation of SCF/c-kit signaling pathway,thus affecting the expression of Cajal stromal cells.Cajal cells are the pacemakers of gastrointestinal motility.AIM To investigate the effects of Bifidobacterium lactis(B.lactis)BLa80 on the intestinal flora of rats in simulated microgravity and on the gastrointestinal motility-related SCF/c-kit pathway.METHODS The internationally recognized tail suspension animal model was used to simulate the microgravity environment,and 30 rats were randomly divided into control group,tail suspension group and drug administration tail suspension group with 10 rats in each group for a total of 28 days.The tail group was given B.lactis BLa80 by intragastric administration,and the other two groups were given water intragastric administration,the concentration of intragastric administration was 0.1 g/mL,and each rat was 1 mL/day.Hematoxylin&eosin staining was used to observe the histopathological changes in each segment of the intestine of each group,and the expression levels of SCF,c-kit,extracellular signal-regulated kinase(ERK)and p-ERK in the gastric antrum of each group were detected by Western blotting and PCR.The fecal flora and mucosal flora of rats in each group were detected by 16S rRNA.RESULTS Simulated microgravity resulted in severe exfoliation of villi of duodenum,jejunum and ileum in rats,marked damage,increased space between villi,loose arrangement,shortened columnar epithelium of colon,less folds,narrower mucosal thickness,reduced goblet cell number and crypts,and significant improvement after probiotic intervention.Simulated microgravity reduced the expressions of SCF and c-kit,and increased the expressions of ERK and P-ERK in the gastric antrum of rats.However,after probiotic intervention,the expressions of SCF and ckit were increased,while the expressions of ERK and P-ERK were decreased,with statistical significance(P<0.05).In addition,simulated microgravity can reduce the operational taxonomic unit(OTU)of the overall intestinal flora of rats,B.lactis BLa80 can increase the OTU of rats,simulated microgravity can reduce the overall richness and diversity of stool flora of rats,increase the abundance of firmicutes in stool flora of rats,and reduce the abundance of Bacteroides in stool flora of rats,most of which are mainly beneficial bacteria.Simulated microgravity can increase the overall richness and diversity of mucosal flora,increase the abundance of Bacteroides and Desulphurides in the rat mucosal flora,and decrease the abundance of firmicutes,most of which are proteobacteria.After probiotics intervention,the overall Bacteroidetes trend in simulated microgravity rats was increased.CONCLUSION B.lactis BLa80 can ameliorate intestinal mucosal injury,regulate intestinal flora,inhibit ERK expression,and activate the SCF/c-kit signaling pathway,which may have a facilitating effect on gastrointestinal motility in simulated microgravity rats.
基金supported by grants from the National Natural Science Foundation of China (82071104)Science and Technology Commission of Shanghai Municipality (23XD1434200/22Y21901000)+9 种基金Shanghai Hospital Development Center(SHDC12022120)National Clinical Research Center for Oral Diseases (NCRCO2021-omics-07)Shanghai Clinical Research Center for Oral Diseases (19MC1910600)Major and Key Cultivation Projects of Ninth People’s Hospital affiliated to Shanghai Jiao Tong University School of Medicine (JYZP006)Shanghai’s Top Priority Research Center (2022ZZ01017)CAMS Innovation Fund for Medical Sciences (2019-I2M-5-037)Fundamental research program funding of Ninth People’s Hospital affiliated to Shanghai Jiao Tong University School of Medicine(JYZZ237)Eastern Talent Plan Leading Project (BJZH2024001)partly supported by the Shanghai Ninth People’s Hospital affiliated with Shanghai Jiao Tong University,School of Medicine(JYJC202223)Shanghai Key Laboratory of Translational Medicine on Ear and Nose diseases (14DZ2260300)
文摘Pulpitis is a common infective oral disease in clinical situations.The regulatory mechanisms of immune defense in pulpitis are still being investigated.Osteomodulin(OMD)is a small leucine-rich proteoglycan family member distributed in bones and teeth.It is a bioactive protein that promotes osteogenesis and suppresses the apoptosis of human dental pulp stem cells(hDPSCs).In this study,the role of OMD in pulpitis and the OMD-induced regulatory mechanism were investigated.The OMD expression in normal and inflamed human pulp tissues was detected via immunofluorescence staining.Intriguingly,the OMD expression decreased in the inflammatory infiltration area of pulpitis specimens.The cellular experiments demonstrated that recombined human OMD could resist the detrimental effects of lipopolysaccharide(LPS)-induced inflammation.A conditional Omd knockout mouse model with pulpal inflammation was established.LPS-induced inflammatory impairment significantly increased in conditional Omd knockout mice,whereas OMD administration exhibited a protective effect against pulpitis.Mechanistically,the transcriptome alterations of OMD overexpression showed significant enrichment in the nuclear factor-κB(NF-κB)signaling pathway.Interleukin-1 receptor 1(IL1R1),a vital membrane receptor activating the NF-κB pathway,was significantly downregulated in OMD-overexpressing hDPSCs.Additionally,the interaction between OMD and IL1R1 was verified using co-immunoprecipitation and molecular docking.In vivo,excessive pulpal inflammation in Omd-deficient mice was rescued using an IL1R antagonist.Overall,OMD played a protective role in the inflammatory response via the IL1R1/NF-κB signaling pathway.OMD may optimize the immunomodulatory functions of hDPSCs and can be used for regenerative endodontics.
文摘Epidermal growth factor receptor(EGFR)signaling has become an importanttarget for drug development becauseEGFR signaling enhances tumor cell proliferation,migration,and invasion and inhibits apoptosis.However,theresults of clinical trials using EGFR inhibitors in patients with solid tumors have been disappointing.Here,wereport a protective effect of the EGFR inhibitors AG1478 and PD153035 against cell death induced by acute hy-poxia,which contrasts with their proapoptotic effects under normoxia.Under hypoxic conditions,both agents re-
基金Supported by Xi’an Science and Technology Plan Project,No.23YXYJ0162Shaanxi Province Traditional Chinese Medicine Research and Innovation Talent Plan Project,No.TZKN-CXRC-16+2 种基金Project of Shaanxi Administration of Traditional Chinese Medicine,No.SZYKJCYC-2025-JC-010Shaanxi Province Key Research and Development Plan Project-Social Development Field,No.S2025-YF-YBSF-0391the Science and Technology Innovation Cultivation Program of Longhua Hospital affiliated to Shanghai University of Chinese Medicine,No.YD202220。
文摘BACKGROUND Excessive endoplasmic reticulum(ER)stress in intestinal epithelial cells can lead to damage to the intestinal mucosal barrier,activate the signal transducer and activator of transcription 3(STAT3)/nuclear factor kappa B(NF-κB)signaling pathway,and exacerbate the inflammatory response,thus participating in the pathogenesis of ulcerative colitis(UC).Mesalazine is a commonly used drug in the clinical treatment of UC.However,further studies are needed to determine whether mesalazine regulates the ER stress of intestinal epithelial cells,downregulates the STAT3/NF-κB pathway to play a role in the treatment of UC.AIM To study the therapeutic effects of mesalazine on spontaneous colitis in interleukin-10(IL-10)-/-mice.METHODS The 24-week-old IL-10-/-mice with spontaneous colitis were divided into the model group and the 5-amino salicylic acid group.Littermates of wild-type mice of the same age group served as the control.There were eight mice in each group,four males and four females.The severity of symptoms of spontaneous colitis in IL-10-/-mice was assessed using disease activity index scores.On day 15,the mice were sacrificed.The colon length was measured,and the histopathological changes and ultrastructure of colonic epithelial cells were detected.The protein expressions of STAT3,p-STAT3,NF-κB,IκB,p-IκB,and glucoseregulated protein 78 were identified using Western blotting.The STAT3 and NF-κB mRNA expressions were identified using real-time polymerase chain reaction.The glucose-regulated protein 78 and C/EBP homologous protein expressions in colon sections were detected using immunofluorescence.RESULTS Mesalazine reduced the symptoms of spontaneous colitis in IL-10 knockout mice and the histopathological damage of colonic tissues,and alleviated the ER stress in epithelial cells of colitis mice.Western blotting and quantitative real-time polymerase chain reaction results showed that the STAT3/NF-κB pathway in the colon tissue of model mice was activated,suggesting that this pathway was involved in the pathogenesis of UC and might become a potential therapeutic target.Mesalazine could down-regulate the protein expressions of p-STAT3,NF-κB and p-IκB,and down-regulate the mRNA expression of STAT3 and NF-κB.CONCLUSION Mesalazine may play a protective role in UC by reducing ER stress by regulating the STAT3/NF-κB signaling pathway.
基金Supported by Natural Science Foundation of Guangdong Province,No.2022A1515012346.
文摘BACKGROUND Diabetic macular edema(DME)is the most common cause of vision loss in people with diabetes.Tight junction disruption of the retinal pigment epithelium(RPE)cells has been reported to induce DME development.SMAD-specific E3 ubiquitin protein ligase(SMURF)1 was associated with the tight junctions of cells.However,the mechanism of SMURF1 in the DME process remains unclear.AIM To investigate the role of SMURF1 in RPE cell tight junction during DME.METHODS ARPE-19 cells treated with high glucose(HG)and desferrioxamine mesylate(DFX)for establishment of the DME cell model.DME mice models were constructed by streptozotocin induction.The trans-epithelial electrical resistance and permeability of RPE cells were analyzed.The expressions of tight junction-related and autophagy-related proteins were determined.The interaction between insulin like growth factor 2 mRNA binding protein 2(IGF2BP2)and SMURF1 mRNA was verified by RNA immunoprecipitation(RIP).SMURF1 N6-methyladenosine(m6A)level was detected by methylated RIP.RESULTS SMURF1 and vascular endothelial growth factor(VEGF)were upregulated in DME.SMURF1 knockdown reduced HG/DFX-induced autophagy,which protected RPE cell tight junctions and ameliorated retinal damage in DME mice.SMURF1 activated the Wnt/β-catenin-VEGF signaling pathway by promoting WNT inhibitory factor(WIF)1 ubiquitination and degradation.IGF2BP2 upregulated SMURF1 expression in an m6A modification-dependent manner.CONCLUSION M6A-modified SMURF1 promoted WIF1 ubiquitination and degradation,which activated autophagy to inhibit RPE cell tight junctions,ultimately promoting DME progression.
文摘We read with great interest the study by Zhang et al on Yiyi Fuzi Baijiang powder(YFB),which exemplifies the power of modern methods to validate traditional Chinese medicine(TCM).The key insight is that YFB doesn’t merely alter“good”or“bad”bacteria but restores the gut microbiota’s holistic equilibrium.This is powerfully shown by its paradoxical reduction of anaerobic probiotics like Bifidobacterium,rectifying the diseased,hypoxic environment,causing their aberrant overgrowth.This challenges the conventional probiotic paradigm and underscores a core TCM principle:Herbal formulas treat disease by restoring the body’s overall functional balance.Future research should focus on the interplay between herbal components,intestinal oxygen,and microbial metabolites to further unravel this sophisticated dialogue.
基金the Scientific and Technological Research Council of Türkiye(TÜBİTAK)Under the International Postdoctoral Research Fellowship Program(2219),No.1059B192400980the National Postdoctoral Research Fellowship Program(2218),No.122C158.
文摘Acute respiratory distress syndrome(ARDS)is a life-threatening condition that is characterized by high mortality rates and limited therapeutic options.Notably,Zhang et al demonstrated that CD146+mesenchymal stromal cells(MSCs)exhibited greater therapeutic efficacy than CD146-MSCs.These cells enhance epithelial repair through nuclear factor kappa B/cyclooxygenase-2-associated paracrine signaling and secretion of pro-angiogenic factors.We concur that MSCs hold significant promise for ARDS treatment;however,the heterogeneity of cell products is a translational barrier.Phenotype-aware strategies,such as CD146 enrichment,standardized potency assays,and extracellular vesicle profiling,are essential for improving the consistency of these studies.Further-more,advanced preclinical models,such as lung-on-a-chip systems,may provide more predictive insights into the therapeutic mechanisms.This article underscores the importance of CD146+MSCs in ARDS,emphasizes the need for precision in defining cell products,and discusses how integrating subset selection into translational pipelines could enhance the clinical impact of MSC-based therapies.
基金Supported by the National Natural Science Foundation of China(No.81200670)。
文摘AIM:To identify proangiogenic factors engaged in neovascular age-related macular degeneration(AMD)except vascular endothelial growth factor(VEGF)from human retinal pigment epithelial(h RPE)cells and investigate the underlying mechanisms.METHODS:VEGF receptor 2(VEGFR2)in ARPE-19 cells was depleted by si RNA transfection or overexpressed through adenovirus infection.The m RNA and the protein levels of interleukin-8(IL-8)in ARPE-19 cells were measured by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay respectively.The protein levels of AKT,p-AKT,MEK,p-MEK,ERK1/2,p-ERK1/2,JNK,p-JNK,p38 and p-p38 were detected by Western blotting.A selective chemical inhibitor,LY3214996,was employed to inhibit phosphorylation of ERK1/2.Cell viability was determined by MTT assay.RESULTS:Knockdown of VEGFR2 in ARPE-19 cells robustly augmented IL-8 production at both the m RNA and the protein levels.Silencing VEGFR2 substantially enhanced phosphorylation of MEK and ERK1/2 while exerted no effects on phosphorylation of AKT,JNK and p38.Inhibiting ERK1/2 phosphorylation by LY3214996 reversed changes in VEGFR2 knockdown-induced IL-8 upregulation at the m RNA and the protein levels with no effects on cell viability.VEGFR2 overexpression significantly reduced IL-8 generation at the m RNA and the protein levels.CONCLUSION:Blockade of VEGF signaling augments IL-8 secretion via MEK/ERK1/2 axis and overactivation of VEGF pathway decreases IL-8 production in h RPE cells.Upregulated IL-8 expression after VEGF signaling inhibition in h RPE cells may be responsible for being incompletely responsive to anti-VEGF remedy in neovascular AMD,and IL-8 may serve as an alternative therapeutic target for neovascular AMD.
基金Supported by the Special Research Project for Capital Health Development,No.2022-2-2174the Beijing Municipal Science and Technology Commission,No.Z191100007619037.
文摘BACKGROUND The transforming growth factor β(TGFβ) signaling pathway plays a crucial role in the development of liver fibrosis by activating TGFβ type Ⅱ receptor(TGFβR2), followed by the recruitment of TGFβR1 finally triggering downstream signaling pathway.AIM To find drugs targeting TGFβR2 that inhibit TGFβR1/TGFβR2 complex formation, theoretically inhibit TGFβ signaling pathway, and thereby ameliorate liver fibrosis.METHODS Food and Drug Administration-approved drugs were screened for binding affinity with TGFβR2 by virtual molecular docking. We identified 6 candidates and further explored their potential by Cell Counting Kit-8(CCK-8) cell cytotoxic experiment to validate toxicity and titrated the best cellular working concentrations. Next, we further demonstrated the detailed molecular working mechanisms using mutagenesis analysis. Finally, we used a mouse model to investigate its potential anti-liver fibrosis effect.RESULTS We identified 6 drug candidates. Among these 6 drugs, dihydroergotamine(DHE) shows great ability in reducing fibrotic gene expressions such as collagen, p-SMAD3, and α-SMA in TGFβ induced cellular model of liver fibrosis in LX-2 cells. Furthermore, we demonstrated that DHE binds to TGFβR2. Moreover, mutation of Leu27, Phe30, Thr51, Ser52, Ile53, and Glu55 of TGFβR2 disrupted the binding of TGFβR2 with DHE. In addition, DHE significantly improved liver fibrosis, as evidenced by Masson’s trichrome staining of liver sections. This is further supported by the width and the velocity of the portal vein, and serum markers of liver function. In line with those observations, DHE also decreased macrophages infiltration and extracellular matrix deposition in the liver.CONCLUSION DHE alleviates liver fibrosis by binding to TGFβR2 thereby suppressing TGFβ signaling pathway. We show here that as far as drug repurposing, DHE has great potential to treat liver fibrosis.
基金Su Xiuhai National Traditional Chinese Medicine Expert Heritage Workplace,project number:National Traditional Chinese Medicine project[2022]75.
文摘Background:This study will be aimed at investigating the effects of Polygonatum sibiricum polysaccharide(PSP)in a rat model of type 2 diabetes mellitus(T2DM).Methods:Thirty Sprague–Dawley male rats were evenly distributed into three groups:normal,T2DM,and PSP groups,by applying a random sample table method.The typical cluster was served balanced food every day,whereas the others were supplied with a high-fat diet and streptozotocin injections to make T2DM rat models.The changes in humor organic chemistry indicators and liver histopathology were determined following the model institution for every cluster.After PSP intervention,western blotting was applied to research the expression levels of crucial transcription factors concerned within the nuclear factor erythroid 2-related factor 2(Nrf2)signal pathway,as well as Nrf2,glutamate-cysteine ligase chemical process fractional monetary unit,NQO1 and HO-1 within the liver tissues of the rat models,and to seem into the therapeutic edges of PSP and the way it happens in T2DM rats.Results:PSP intervention considerably reduced the concentration levels of aldohexose,lipids,liver-operated indicators,and alternative organic chemistry indicators within the humor of T2DM rat models and improved the histopathological changes within the liver.In addition,the activity of SOD and GSH-Px were increased,and the levels of MDA were decreased in the liver tissues of T2DM rat models following PSP intervention.Western blotting revealed that the expression levels of the Nrf2,HO-1,glutamate-cysteine ligase chemical,and NQO1 proteins were increased in rat liver tissues following PSP intervention.Conclusion:PSP has therapeutic effects in T2DM rat models,and its mechanism of motion might also be related to regulating the Nrf2 signaling pathway in liver tissues and alleviating oxidative stress.
基金sponsored by funding from the National Natural Science Foundation of China(82201004 to J.D.,81921002 to X.J.,82130027 to X.J.)the Young Elite Scientists Sponsorship Program by CAST(YESS20230102 to J.D.)the innovative research team of high-level local universities in Shanghai(SHSMU-ZLCX20212400 to X.J.).
文摘The mandibular condyle is a critical growth center in craniofacial bone development,especially during postnatal stages.Postnatal condyle osteogenesis requires precise spatiotemporal coordination of growth factor signaling cascades and hierarchical gene regulatory networks.Plagl1,which encodes a zinc finger transcription factor,is a paternally expressed gene.We demonstrate that PLAGL1 is highly expressed in cranial neural crest cell(CNCC)-derived lineage cells in mouse condyles.Using the CNCC-derived lineage-specific Plagl1 knockout mouse model,we evaluate the function of PLAGL1 during postnatal mouse condyle development.Our findings show that PLAGL1 contributes significantly to osteoblast differentiation,and its deficiency impairs osteogenic lineage differentiation,which consequently disrupts mandibular condyle development.Mechanistically,insulin-like growth factor 2(IGF2)in complex with IGF-binding proteins(IGFBPs)has been identified as the principal PLAGL1 effector responsible for osteogenic regulation during postnatal condyle morphogenesis.Plagl1 deficiency significantly downregulates the IGF2/IGFBP pathway,leading to disordered glucose metabolism,defective extracellular matrix organization,and impaired ossification.Exogenous IGF2 treatment rescues impaired osteoblast differentiation caused by Plagl1 deficiency.In conclusion,the PLAGL1-IGF2 axis is a critical regulator of osteogenesis during mandibular condyle development.
基金supported by Zhejiang Basic Public Welfare Research Program(No.LGF21H090002)Zhejiang Medical and Health Science and Technology Plan Project(No.2022497454)+5 种基金Research Foundation of Yichang City Science and Technology Bureau(A21-2-044.No.A18-302-a2)Open Foundation of Hubei Key Laboratory of Wudang characteristic traditional Chinese medicine research(No.WDCM2022010)Hubei Provincial Department of Science and Technology Key Research and Development Big Health Plan Project(No.2022BCE017)Natural Science Foundation Project of Hubei Provincial Department of Science and Technology(No.2023AFB600,No.2022CFB357,No.2022CFB427)Open Fund of Traditional Chinese Medicine Clinical Research Center for Functional Digestive System Diseases in Hubei Province(No.SXZ202308,No.SXZ202311)Key Traditional Chinese Medicine Project of Hubei Provincial Health Commission(No.ZY2023Z015).
文摘Neurodegenerative diseases(NDDs)are characterized primarily by progressive impairments in cognition,behavior,and memory.MicroRNAs(miRNAs)are abundantly expressed in the central nervous system and are vital for the normal function and survival of neurons.Mature miRNAs are naturally occurring small noncoding single-stranded RNA molecules that are approximately 21–25 nucleotides in length.They regulate gene expression by pairing with target mRNAs and undergo significant alterations in various physiological and pathological processes.miR-146a,a miRNA dependent on nuclear factorκB(NF-κB),is highly expressed in neurons and functions as an anti-inflammatory miRNA via the Toll-like receptor(TLR)pathway,which is an essential regulatory factor for neuroinflammation expression during the development of NDDs.In this review,we summarize and emphasize the pivotal role of miR-146a in NDDs,highlighting the association between miR-146a polymorphisms and the risk of NDDs.We also discuss how alterations in miR-146a expression levels represent a critical event in the pathogenesis of numerous NDDs.Furthermore,the target genes of miR-146a are involved in regulating the pathophysiological processes of these diseases,particularly in the context of neuroinflammatory responses.In conclusion,miR-146a plays a central role in the progression of NDDs,with its primary function in neuroinflammation.These findings suggest that miR-146a holds promise as both a biomarker and a potential therapeutic target.A deeper understanding of how miR-146a influences neuroinflammatory responses across different types of neurological damage,cell types,and even various stages of certain NDDs will pave the way for its use as a therapeutic target in treating these conditions.Therefore,this article reviews the mechanism of miR-146a in NDDs and discusses the future therapeutic prospects for this type of disease.miR-146a regulates the related genes of the inflammatory signaling pathway and its influence on the development of NDDs.(Created in https://BioRender.com).
基金funded by the National Natural Science Foundation of China(81902815,81802786)the Natural Science Foundation of Shandong Province(ZR2023MH011,ZR2019BH044,ZR2018BH025).
文摘Background:VPS37A(VPS37A subunit of ESCRT-I),a component of the ESCRT-I(endosomal sorting complex required for transport I)complex,mediates vesicular trafficking through sorting endocytic ubiquitinated cargos into multivesicular bodies(MVBs).Although accumulating evidence indicates that VPS37A deficiency occurs in numerous malignancies and exerts tumor-suppressive effects during cancer progression,its functional significance in colorectal cancer(CRC)pathogenesis remains poorly characterized.Therefore,this study aims to further investigate the functional and molecular mechanisms by which VPS37A downregulation contributes to malignant biological phenotypes in CRC,with a specific focus on how its dysregulation affects cell death pathways.Methods:Multi-omics analysis of TCGA,GEO,and CPTAC cohorts identified VPS37A as a downregulated tumor suppressor gene in CRC.The prognostic relevance of VPS37A was validated in two clinical cohorts(Cohorts 1 and 2)using immunohistochemistry.Functional assays in VPS37A-overexpressing CRC cells and xenografts assessed proliferation,cell cycle progression,and stress-induced cell death.RNA sequencing,nuclear factor kappa-B(NF-κB)luciferase reporter assays,and lysosomal inhibition experiments elucidated the mechanisms underlying tumor necrosis factor receptor 1(TNFR1)degradation.Results:VPS37A is significantly downregulated in advanced-stage CRC and independently predicts poor survival.Functionally,VPS37A overexpression suppresses proliferation and induces G2/M arrest in vitro,while reducing xenograft growth.Under metabolic stress(glucose deprivation/galactose adaptation),VPS37A triggers cell death via apoptosis,necroptosis,and ferroptosis.Mechanistically,VPS37A redirects TNFR1 to lysosomal degradation,suppressing NF-κB nuclear translocation and transcriptional activity.Conclusion:VPS37A deficiency drives CRC progression by sustaining TNFR1/NF-κB signaling under metabolic stress.Restoring VPS37A activity promotes TNFR1 degradation,offering a therapeutic strategy to counteract NF-κB-mediated treatment resistance in CRC.
基金supported by the Chief Scientist Program of Qinghai Province(2024-SF-101).
文摘Perennial grasses have developed intricate mechanisms to adapt to diverse environments,enabling their resistance to various biotic and abiotic stressors.These mechanisms arise from strong natural selection that contributes to enhancing the adaptation of forage plants to various stress conditions.Methods such as antisense RNA technology,CRISPR/Cas9 screening,virus-induced gene silencing,and transgenic technology,are commonly utilized for investigating the stress response functionalities of grass genes in both warm-season and cool-season varieties.This review focuses on the functional identification of stress-resistance genes and regulatory elements in grasses.It synthesizes recent studies on mining functional genes,regulatory genes,and protein kinase-like signaling factors involved in stress responses in grasses.Additionally,the review outlines future research directions,providing theoretical support and references for further exploration of(i)molecular mechanisms underlying grass stress responses,(ii)cultivation and domestication of herbage,(iii)development of high-yield varieties resistant to stress,and(iv)mechanisms and breeding strategies for stress resistance in grasses.
基金supported by grants from the National Natural Science Foundation of China(31730011 and 31700214)
文摘Cold temperatures, a major abiotic stress, threaten the growth and development of plants, worldwide. To cope with this adverse environmental cue, plants from temperate climates have evolved an array of sophisticated mechanisms to acclimate to cold periods, increasing their ability to tolerate freezing stress. Over the last decade, significant progress has been made in determining the molecular mechanisms underpinning cold acclimation, including following the identification of several pivotal components, including candidates for cold sensors, protein kinases, and transcription factors. With these developments, we have a better understanding of the CBF-dependent cold-signaling pathway. In this review, we summarize recent progress made in elucidating the cold-signaling pathways, especially the C-repeat binding factor-dependent pathway, and describe the regulatory function of the crucial components of plant cold signaling. We also discuss the unsolved questions that should be the focus of future work.
基金Natural Science Foundation of Hebei Province,No.21377772DNo.H2022406034National Natural Scientific Foundation of China,No.81672700.
文摘BACKGROUND Regenerating gene 4(REG4)has been proved to be carcinogenic in some cancers,but its manifestation and possible carcinogenic mechanisms in colorectal cancer(CRC)have not yet been elucidated.Our previous study found that the drug resistance of CRC cells may be closely linked to their fat metabolism.AIM To explore the role of REG4 in CRC and its association with lipid droplet formation and chemoresistance.METHODS We conducted a meta-analysis and bioinformatics and pathological analyses of REG4 expression in CRC.The effects of REG4 on the phenotypes and related protein expression were also investigated in CRC cells.We detected the impacts of REG4 on the chemoresistance and lipid droplet formation in CRC cells.Finally,we analyzed how REG4 regulated the transcription and proteasomal degradation of lipogenic enzymes in CRC cells.RESULTS Compared to normal mucosa,REG4 mRNA expression was high in CRC(P<0.05)but protein expression was low.An inverse correlation existed between lymph node and distant metastases,tumor-node-metastasis staging or short overall survival and REG4 mRNA overexpression(P<0.05),but vice versa for REG4 protein expression.REG4-related genes included:Chemokine activity;taste receptors;protein-DNA and DNA packing complexes;nucleosomes and chromatin;generation of second messenger molecules;programmed cell death signals;epigenetic regulation and DNA methylation;transcription repression and activation by DNA binding;insulin signaling pathway;sugar metabolism and transfer;and neurotransmitter receptors(P<0.05).REG4 exposure or overexpression promoted proliferation,antiapoptosis,migration,and invasion of DLD-1 cells in an autocrine or paracrine manner by activating the epidermal growth factor receptor-phosphoinositide 3-kinase-Akt-nuclear factor-κB pathway.REG4 was involved in chemoresistance not through de novo lipogenesis,but lipid droplet assembly.REG4 inhibited the transcription of acetyl-CoA carboxylase 1(ACC1)and ATP-citrate lyase(ACLY)by disassociating the complex formation of anti-acetyl(AC)-acetyl-histone 3-AC-histone 4-inhibitor of growth protein-5-si histone deacetylase;-sterol-regulatory element binding protein 1 in their promoters and induced proteasomal degradation of ACC1 or ACLY.CONCLUSION REG4 may be involved in chemoresistance through lipid droplet assembly.REG4 reduces expression of de novo lipid synthesis key enzymes by inhibiting transcription and promoting ubiquitination-mediated proteasomal degradation.
文摘Background Aberrant epithelial repair has been observed in chronic rhinosinusitis （CRS） patients; however, the mechanism of epithelial cell repair regulation is unclear. Epidermal growth factor （EGF） plays an important role in regulating epithelial cell repair in lower airway and may be a critical factor in the remodeling processes of CRS. The objective of our research is to evaluate the differences between CRS and normal subjects and between chronic rhinosinusitis without nasal poiys （CRSsNP） and chronic rhinosinusitis with nasal polys （CRSwNP） in the regulation of EGF pathways and the regulating proliferative position of classic Ras/Raf/MEK/ERK pathways. Methods We evaluated the proliferation rates of ethmoidal mucosal cells before and after stimulation with EGF, epidermal growth factor receptor （EGFR） kinase inhibitor AG1478, and extracellular signal-regulated kinase 1/2 （ERKI/2）inhibitor PD98059 using MTT assays. We also analyzed the sinonasal epithelial cells collected from control subjects and patients with CRS subtypes CRSsNP and CRSwNP for the expression of ERK1/2, phosphorylated ERK1/2, P21, P15, and P27 using western blotting analyses. Results The proliferation rates of sinonasal epithelial cells before and after EGF stimulation were lower in CRS patients than in the controls. AG1478 or PD98059 inhibitor treatment of control epithelial cells did not result in a significant difference in proliferation. Although, AG1478 and PD98059,inhibited the proliferation of CRS cells, the degree of proliferation inhibition was markedly different in CRSsNP. AG1478 suppressed the proliferation of CRSwNP epithelial cells, whereas PD98059 had no effect. The ratio of ERK1/2 phosphorylation in CRS cells was lower than that of the control cells. Cyclin-dependent kinase inhibitors were highly expressed in CRS cells compared with that of control cells. ERK1/2 and P27 showed differential expression in CRSsNP and CRSwNP. Conclusions Differences existed in EGF pathways in CRS patients and normal subjects as well as in CRSsNP and CRSwNP. Classical Ras/Raf/MEK/ERK pathway may assume absolute superiority in control cells. Ras/Raf/MEK/ERK classical pathway and other pathways might be active at the same time to stimulate epithelial cell proliferation in CRSsNP. The function of Ras/Raf/MEK/ERK classical pathway was weaker in CRSwNP than in CRSsNP and when the classical pathway was blocked in CRSwNP, some other pathway could have completely compensated the proliferation induced by the Ras/Raf/MEK/ERK pathway.
基金Supported by The Major Project of Applied Basic Research Plan of the Scientific and Technological Department of Tianjin,No.06YFJZJC02900
文摘AIM:To explore the anti-fibrotic effect of Haobie Yangyin Ruanjian Decoction(HYRD)on CCl4-induced hepatic fibrosis in rats and its modulation on the transforming growth factor(TGF)β-Smad signaling pathway.METHODS:Fifty-six healthy Wistar rats were randomly divided into five groups:normal control group(n=6),CCl4-induced hepatic fibrosis group(n=14) and three treatment groups(the treated rats received HYRD via oral administration at daily dosages of 8.2,2.5 and 0.82 g/kg,respectively)of HYRD(n=12,respectively).Experimental hepatic fibrosis was induced by subcutaneous injection of carbon tetrachloride solution(CCl4 dissolved in peanut oil,4:6,V/V)with 0.5 mL/100 g body weight for the first time,and then 0.3 mL/100 g body weight twice a week for 8 wk.In the former 2 wk,rats were raised by feedstuffⅠ(80% corn meal,20%lard,0.5%cholesterol).After 2 wk,they were raised by feedstuffⅡ(corn meal and 0.5% cholesterol).Except for the control group,30%alcohol solution was given orally to each rat every other day from the beginning,1 mL for each rat.Liver function parameters and hepatic hydroxyproline content were detected by chromatometry.Serum levels of hyaluronic acid(HA),typeⅣcollagen(CIV),typeⅢprecollagen(PCⅢ)and laminin(LN)were assayed with radioimmunoassay.Deposition of collagen was observed with hematoxylin-eosin staining and collagen staining.Gene expression of TGFβ1 and Smad3 were detected with real-time reverse transcriptase-polymerase chain reaction and Western blotting,respectively.RESULTS:The serum levels of alanine transaminase and aspartate transaminase were increased in the model group compared with the control group(P<0.01),and they were decreased in the three treatment groups compared with the model group.The serum levels of total protein and albumin were decreased in the model group and increased in the three treatment groups.The hepatic hydroxyproline content and serum levels of PCⅢ,HA,LN and CIV were markedly increased in the model group compared with the control group,and decreased in the treatment groups.The gene expression of TGFβ1 and Smad3 was enhanced in the model group compared with the control group,and HYRD could down regulate their expression.CONCLUSION:HYRD can inhibit hepatic fibrosis induced by CCl4 in rats,which is probably associated with its down-regulation on fibrogenic signal transduction of TGFβ-Smad pathway.
基金supported by the National Natural Science Foundation of China(31400221)the Beijing Advanced Innovation Center for Tree Breeding by Molecular Design+1 种基金the Program for Changjiang Scholars and Innovative Research Team in University(IRT13047)the Fundamental Research Funds for the Central Universities(BLX2012038)
文摘The plant cell wall is an important interface for sensing pathogen attack and activating signaling pathways that promote plant immune responses.THESEUS1(THE1) acts as a sensor of cell wall integrity that controls cell elongation during plant growth.However, no specific role for THE1 in plant defense responses has been reported. Here, we found that THE1 interacts with GUANINE EXCHANGE FACTOR4(GEF4)and that both proteins play regulatory roles in plant resistance to the necrotrophic fungus Botrytis cinerea.Genetic analysis showed that THE1 and GEF4 function in the same genetic pathway to mediate plant defense responses. In addition, using transcriptome analysis, we identified various genes(such as defense-related,secondary metabolite-related, and transcription factor genes) that are likely downstream targets in the THE1-GEF4 signaling pathway. Our results suggest that THE1 functions as an upstream regulator of GEF4 signaling to positively regulate defense responses against B. cinerea in Arabidopsis.
