Epidermal growth factor receptor(EGFR)is one of the most important tyrosine kinase receptor families,which plays a pivotal role in cell signaling transduction and physiological processes.Studies on the EGFR gene in hu...Epidermal growth factor receptor(EGFR)is one of the most important tyrosine kinase receptor families,which plays a pivotal role in cell signaling transduction and physiological processes.Studies on the EGFR gene in humans and other species have demonstrated its pivotal role in regulating the sodium ion balance and mediating sodium and water reabsorption in the kidney's proximal tubules.However,the impact of EGFR gene in how the Yarkand hare(Lepus yarkandensis)adapts to extreme environmental habitat remains unclear,The Yarkand hare is a desert-dwelling animal with multiple adaptations to cope with drought.Given the important physiological function of EGFR gene,we strived to understand its role in arid environment and explore the molecular mechanism of drought tolerance in the Yarkand hare.We first performed segmental cloning of the CDS of the Yarkand hare EGFR gene.Then,We constructed the phylogenetic tree of the Yarkand hare's EGFR gene and compared it with that of other species.The results showed that the Yarkand hare was most closely related to the Tolai hare(Lepus tolai).Through quantitative reverse transcription polymerase chain reaction(RT-qPCR),we discovered that EGFR expression in the kidneys of the Yarkand hare was higher than in the allopatric Tolai hare from non-arid areas.Therefore,we hypothesized that EGFR gene overexpression in the kidney of the Yarkand hare may play a crucial role in drought adaptability.Subsequently,we inserted CDS of EGFR gene into a pcDNA3.1-EGFP expression vector to construct recombinant plasmid,which was transfected into HeLa cells and overexpressed.RT-qPCR demonstrated a notable and statistically significant increase in EGFR mRNA expression and western blot proved stable expression of this protein in HeLa cells.Through cell experiments,EGFR gene overexpression markedly enhanced the survival of Hela cells subjected to NaCl,H_(2)O_(2),and heat stresses,increased superoxide dismutase activity,and decreased malondialdehyde content.In conclusion,these findings preliminarily suggest that EGFR might help the Yarkand hare adapt to extreme environmental conditions.EGFR manipulation in vivo could be a promising strategy to enhance the resilience of animals to extreme conditions.展开更多
Fibroblast growth factor(FGF)signaling encompasses a multitude of functions,including regulation of cell proliferation,differentiation,morphogenesis,and patterning.FGFs and their receptors(FGFR)are crucial for adult t...Fibroblast growth factor(FGF)signaling encompasses a multitude of functions,including regulation of cell proliferation,differentiation,morphogenesis,and patterning.FGFs and their receptors(FGFR)are crucial for adult tissue repair processes.Aberrant FGF signal transduction is associated with various pathological conditions such as cartilage damage,bone loss,muscle reduction,and other core pathological changes observed in orthopedic degenerative diseases like osteoarthritis(OA),intervertebral disc degeneration(IVDD),osteoporosis(OP),and sarcopenia.In OA and IVDD pathologies specifically,FGF1,FGF2,FGF8,FGF9,FGF18,FGF21,and FGF23 regulate the synthesis,catabolism,and ossification of cartilage tissue.Additionally,the dysregulation of FGFR expression(FGFR1 and FGFR3)promotes the pathological process of cartilage degradation.In OP and sarcopenia,endocrine-derived FGFs(FGF19,FGF21,and FGF23)modulate bone mineral synthesis and decomposition as well as muscle tissues.FGF2 and other FGFs also exert regulatory roles.A growing body of research has focused on understanding the implications of FGF signaling in orthopedic degeneration.Moreover,an increasing number of potential targets within the FGF signaling have been identified,such as FGF9,FGF18,and FGF23.However,it should be noted that most of these discoveries are still in the experimental stage,and further studies are needed before clinical application can be considered.Presently,this review aims to document the association between the FGF signaling pathway and the development and progression of orthopedic diseases.Besides,current therapeutic strategies targeting the FGF signaling pathway to prevent and treat orthopedic degeneration will be evaluated.展开更多
AIM:To assess the relationship between serological parameters and the prognosis of young patients with retinal vein occlusion(RVO)after intravitreal conbercept injection(IVC).METHODS:This study enrolled 100 young pati...AIM:To assess the relationship between serological parameters and the prognosis of young patients with retinal vein occlusion(RVO)after intravitreal conbercept injection(IVC).METHODS:This study enrolled 100 young patients(≤50 years old)diagnosed with RVO-related macular edema(RVO-ME)who had been undergoing IVC at the 474 Hospital in Xinjiang between January 2022 and October 2023.Patients were categorized into two groups:70 eyes in the effective group and 30 eyes in the ineffective group.The effective group comprised patients exhibiting a visual acuity improvement of≥2 lines at the last follow-up,with resolved ME and central macular thickness(CMT)<300μm.Conversely,the ineffective group included patients with visual acuity improvement of<1 line,persistent ME,and CMT≥300μm at the last follow-up.Serological parameters,including white blood cell count,neutrophil count,lymphocyte count,monocyte count,and mean platelet volume were assessed before treatment.The correlation between bestcorrected visual acuity(BCVA)and neutrophil-to-lymphocyte ratio(NLR),platelet-to-lymphocyte ratio(PLR),systemic immune inflammation index(SII),and systemic immune response index(SIRI)was analyzed.Additionally,the association between these serological parameters and the efficacy of IVC was explored.RESULTS:Three months after treatment,the effective group demonstrated a significant improvement in BCVA from 0.82±0.20 to 0.36±0.10,with a concurrent decrease in CMT from 661.28±163.90 to 200.61±82.45μm(P<0.001).Conversely,the ineffective group exhibited minimal changes in BCVA(0.86±0.25 to 0.82±0.14)and CMT(669.84±164.95 to 492.13±138.67μm,P<0.001).The differences in BCVA and CMT between the two groups were statistically significant(P<0.001).According to subgroup analysis,in patients with central RVO(CRVO),BCVA improved from 0.82±0.23 to 0.49±0.12 in the effective group and from 0.80±0.18 to 0.76±0.22 in the ineffective group(P<0.001).The CMT changes followed a similar pattern.In patients with branch RVO(BRVO),comparable trends in BCVA and CMT changes were observed between the effective and ineffective groups(P<0.001).Additionally,the effective group exhibited higher PLR and SII values than the ineffective group(P<0.05).Further CRVO and BRVO subgroups analysis exhibited consistent PLR and SII value trends.CONCLUSION:Compared to other inflammatory factors,elevated PLR and SII levels before treatment are better predictors of outcomes in young RVO-ME patients undergoing IVC treatment.展开更多
After brain damage,regenerative angiogenesis and neurogenesis have been shown to occur simultaneously in mammals,suggesting a close link between these processes.However,the mechanisms by which these processes interact...After brain damage,regenerative angiogenesis and neurogenesis have been shown to occur simultaneously in mammals,suggesting a close link between these processes.However,the mechanisms by which these processes interact are not well understood.In this work,we aimed to study the correlation between angiogenesis and neurogenesis after a telencephalic stab wound injury.To this end,we used zebrafish as a relevant model of neuroplasticity and brain repair mechanisms.First,using the Tg(fli1:EGFP×mpeg1.1:mCherry)zebrafish line,which enables visualization of blood vessels and microglia respectively,we analyzed regenerative angiogenesis from 1 to 21 days post-lesion.In parallel,we monitored brain cell proliferation in neurogenic niches localized in the ventricular zone by using immunohistochemistry.We found that after brain damage,the blood vessel area and width as well as expression of the fli1 transgene and vascular endothelial growth factor(vegfaa and vegfbb)were increased.At the same time,neural stem cell proliferation was also increased,peaking between 3 and 5 days post-lesion in a manner similar to angiogenesis,along with the recruitment of microglia.Then,through pharmacological manipulation by injecting an anti-angiogenic drug(Tivozanib)or Vegf at the lesion site,we demonstrated that blocking or activating Vegf signaling modulated both angiogenic and neurogenic processes,as well as microglial recruitment.Finally,we showed that inhibition of microglia by clodronate-containing liposome injection or dexamethasone treatment impairs regenerative neurogenesis,as previously described,as well as injury-induced angiogenesis.In conclusion,we have described regenerative angiogenesis in zebrafish for the first time and have highlighted the role of inflammation in this process.In addition,we have shown that both angiogenesis and neurogenesis are involved in brain repair and that microglia and inflammation-dependent mechanisms activated by Vegf signaling are important contributors to these processes.This study paves the way for a better understanding of the effect of Vegf on microglia and for studies aimed at promoting angiogenesis to improve brain plasticity after brain injury.展开更多
BACKGROUND Liver cirrhosis and portal hypertension(PHT)can lead to lymphatic abnormalities and coagulation dysfunction.Because lymphangiogenesis may relieve liver cirrhosis and PHT,the present study investigated the g...BACKGROUND Liver cirrhosis and portal hypertension(PHT)can lead to lymphatic abnormalities and coagulation dysfunction.Because lymphangiogenesis may relieve liver cirrhosis and PHT,the present study investigated the gene expression alterations in the lymphatic system and the effectiveness of platelet-mediated lymphangiogenesis in improving liver cirrhosis and PHT.AIM To investigate the role of lymphangiogenesis in preclinical PHT models.METHODS Immunohistochemistry and transcriptome sequencing of bile duct ligation(BDL)and control lymphatic samples were conducted to reveal the indicated signaling pathways.Functional enrichment analyses were performed on the differentially expressed genes and hub genes.Adenoviral infection of vascular endothelial growth factor C(VEGF-C),plateletrich plasma(PRP),and VEGF3 receptor(VEGFR)inhibitor MAZ-51 was used as an intervention for the lymphatic system in PHT models.Histology,hemodynamic tests and western blot analyses were performed to demonstrate the effects of lymphatic intervention in PHT patients.RESULTS Lymphangiogenesis was increased in the BDL rat model.Transcriptome sequencing analysis of the extrahepatic lymphatic system revealed its close association with platelet adherence,aggregation,and activation.The role of PHT in the rat model was investigated by activating(PRP)and inhibiting(MAZ-51)the lymphatic system.PRP promoted lymphangiogenesis,which increased lymphatic drainage,alleviated portal pressure,reduced liver fibrosis,inhibited inflammation,inhibited angiogenesis,and suppressed mesenteric artery remodeling.MAZ-51 reversed the above improvements.CONCLUSION Via VEGF-C/VEGFR-3,platelets impede fibrosis,angiogenesis,and mesenteric artery remodeling,ultimately alleviating PHT.Thus,platelet intervention is a therapeutic approach for cirrhosis and PHT.展开更多
BACKGROUND In patients with colorectal cancer(CRC),tumour metastasis is the leading cause of death.The search for key genes involved in metastasis of CRC is imperative for improved prognoses and treatments.SPDL1 has b...BACKGROUND In patients with colorectal cancer(CRC),tumour metastasis is the leading cause of death.The search for key genes involved in metastasis of CRC is imperative for improved prognoses and treatments.SPDL1 has been implicated in the deve-lopment of CRC,however,its mechanism of action remains unclear.AIM To investigate the role and mechanism of action by which SPDL1 inhibits the development and metastasis of CRC.METHODS In this study,we examined the relationship between SPDL1 expression and CRC prognosis using immunohistochemistry.Survival analyses were performed using Kaplan-Meier analysis and log-rank test.After knocking down SPDL1 in the HCT116 cancer cell line changes in cell viability,migration,invasion,and gene expression were examined using a cell counting kit 8 assay,Transwell assay,and Western blot.The effect of SPDL1 on the cell cycle was assessed using flow cy-tometry.RNA sequencing was used to analyse the effect of SPDL1 on gene expression of CRC cells.The mechanism of action of SPDL1 in CRC was further clarified using U0126,an inhibitor of the mitogen-activated protein kinase signaling pathway.RESULTS SPDL1 is expressed at low levels in tissues of patients with CRC,and this reduced expression is associated with poor prognosis.Functionally,low expression of SPDL1 in CRC promotes cell proliferation,migration,invasion,and affects the cell cycle.Mechanistically,SPDL1 affects the progression of CRC through its regulation of the process of epithelial-mesenchymal transition(EMT)and of the epidermal growth factor receptor(EGFR)/extracellular signal-regulated kinase(ERK)signaling pathways.CONCLUSION This study showed that the loss of SPDL1 may induce EMT and promote cell migration and invasion in CRC through the EGFR/ERK pathway.展开更多
BACKGROUND Interleukin-22(IL-22)belongs to the IL-10 cytokine family,recognized for its ability to modulate diverse immune responses.Previous studies have indicated that IL-22 promotes cancer advancement and metastasi...BACKGROUND Interleukin-22(IL-22)belongs to the IL-10 cytokine family,recognized for its ability to modulate diverse immune responses.Previous studies have indicated that IL-22 promotes cancer advancement and metastasis.However,the precise function of IL-22 in colorectal cancer(CRC)remains unclear.AIM To investigate the role of IL-22 in promoting stem cell-like characteristics and chemotherapy resistance in CRC cells,as well as to elucidate the mechanisms underlying these effects.METHODS HCT116 cells were treated with IL-22(50 ng/mL)and oxaliplatin(L-OHP,5μg/mL).A series of functional assays-including cell counting kit-8 assay,tumor sphere formation assay,and cell apoptosis assay-were conducted to assess the effects of IL-22 on cell viability and stem cell-like characteristics.The expression of stemness-related markers(SOX2,Oct4,NANOG,and Bmi-1)was examined using Western blot analysis.Additionally,the total and phosphorylated levels of epidermal growth factor receptor(EGFR),protein kinase B(AKT),and extracellular signal-regulated kinase(ERK)were evaluated by Western blot.An EGFR inhibitor,osimertinib(Osi),was used to assess the pathway's functional relevance.RESULTS IL-22 treatment promotes CRC cell proliferation,enhances sphere formation,and elevates the expression of stem cell markers,including SOX2,Oct4,NANOG,and Bmi-1.IL-22 treatment increases the phosphorylation of EGFR,AKT,and ERK.Additionally,IL-22 treatment mitigates the cytotoxic effects and the ability to induce apoptosis of L-OHP.Furthermore,IL-22 treatment activated the EGFR/ERK signaling pathway by increasing the phosphorylation of EGFR,AKT,and ERK.Importantly,the use of the EGFR inhibitor Osi significantly counteracted the chemoresistance induced by IL-22 in CRC cells.CONCLUSION IL-22 promotes tumor growth and induces chemotherapy resistance in CRC cells by activating the EGFR/ERK signaling pathway.These findings suggest that targeting IL-22 or its downstream signaling may offer novel therapeutic strategies in CRC.展开更多
BACKGROUND Although targeted therapy provides survival benefits for patients with metastatic colorectal cancer,some patients develop resistance to these treatments.Human epidermal growth factor receptor 2(HER2)is over...BACKGROUND Although targeted therapy provides survival benefits for patients with metastatic colorectal cancer,some patients develop resistance to these treatments.Human epidermal growth factor receptor 2(HER2)is overexpressed in a subset of pa-tients with colorectal cancer and has been established as a therapeutic target.CASE SUMMARY This case report describes a Chinese patient with HER2-amplified advanced rectal cancer who showed no response to chemotherapy and targeted therapies against epidermal growth factor receptor and vascular endothelial growth factor but achieved a remarkable response following treatment with immune checkpoint inhibitors(ICIs)in combination with pyrotinib.The combination of oxaliplatin and ICIs with pyrotinib demonstrates synergistic effects after late-stage disease progression.CONCLUSION ICIs and pyrotinib may be effective in treating HER2-amplified advanced rectal cancer.Chemotherapy following disease progression could enhance efficacy synergistically.展开更多
Prenatal caffeine exposure(PCE)leads to intrauterine growth retardation and altered glucose homeostasis after birth,but the underlying mechanism remains unclear.This study aims to investigate the alteration of pancrea...Prenatal caffeine exposure(PCE)leads to intrauterine growth retardation and altered glucose homeostasis after birth,but the underlying mechanism remains unclear.This study aims to investigate the alteration of pancreatic development and insulin biosynthesis in the PCE female offspring and explore the intrauterine programming mechanism.Pregnant rats were orally treated with 120 mg/(kg·day)of caffeine from gestational day(GD)9 to 20.Results showed that fetal pancreaticβ-cells in the PCE group exhibited reduced mass and impaired insulin synthesis function,as evidenced by decreased expression of developmental and functional genes and reduced pancreatic insulin content.At postnatal week(PW)12,the PCE offspring exhibited glucose intolerance,diminishedβ-cell mass,and lower blood insulin levels.However,by PW28,glucose tolerance showed some improvement.Both in vivo and in vitro findings collectively indicated that excessive serum corticosterone(CORT)levels of the PCE fetuses may act through the activation of the pancreatic glucocorticoid receptor(GR)and recruitment of histone deacetylase 9(HDAC9),leading to H3K9 deacetylation in promoter and downregulation of insulin-like growth factor 1(IGF1),thereby inhibiting pancreatic islet morphogenesis and insulin synthesis in fetal rats.Furthermore,the PCE offspring after birth exhibited decreased blood CORT levels,increased H3K9 acetylation in promoter and upregulated gene expression of the pancreatic IGF1 promoter region,accompanied by elevated insulin biosynthesis.However,when exposed to chronic stress,the above changes were totally reversed.Conclusively,“glucocorticoid-insulin like growth factor 1(GC-IGF1)axis”programming may be involved in pancreaticβ-cell dysplasia and dysfunction in the PCE female offspring.展开更多
BACKGROUND Human epidermal growth factor receptor 2(HER2)-positive gastric cancer(GC)represents a distinct molecular cancer subtype that is often associated with a poor prognosis.While perioperative chemotherapy regim...BACKGROUND Human epidermal growth factor receptor 2(HER2)-positive gastric cancer(GC)represents a distinct molecular cancer subtype that is often associated with a poor prognosis.While perioperative chemotherapy regimens are currently the primary recommendation for locally advanced HER2-positive GC,combination therapies incorporating immune checkpoint inhibitors are under active investigation.CASE SUMMARY The present case describes a patient with locally advanced HER2-positive GC who underwent perioperative treatment with chemotherapy combined with trastuzumab.Although significant tumor shrinkage was observed,surgical pathology results did not confirm the achievement of a pathological complete response.The current treatment strategies for advanced GC were also reviewed.Relevant case reports,retrospective studies,and prospective clinical trials were retrieved for analysis after searching the PubMed/MEDLINE,EMBASE,Cochrane Library,Web of Science,and American Society of Clinical Oncology/European Society for Medical Oncology conference abstracts between 2014 and 2024.CONCLUSION Large-scale phase III clinical trials are needed to verify the efficacy of combined neoadjuvant treatment application for GC.展开更多
BACKGROUND Yinchenhao decoction(YCHD)is a traditional Chinese medicine widely used to treat liver damage caused by obstructive jaundice(OJ).Although YCHD has demonstrated protective effects against liver damage,reduce...BACKGROUND Yinchenhao decoction(YCHD)is a traditional Chinese medicine widely used to treat liver damage caused by obstructive jaundice(OJ).Although YCHD has demonstrated protective effects against liver damage,reduced apoptosis,and mitigated oxidative stress in OJ,the precise molecular mechanisms involved remain poorly understood.AIM To investigate the beneficial effects of YCHD on OJ and elucidate the underlying mechanisms.METHODS The active constituents of YCHD were identified using liquid chromatography tandem mass spectrometry,and their potential targets for OJ treatment were predicted through network pharmacology.Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed.An OJ rat model was established by common bile duct ligation.Rats were divided into three groups:Sham surgery(S Group),model(O Group),and YCHD(Y Group).YCHD was administered to Group Y for one week.Bilirubin levels,liver function parameters,and bile acid concentrations in blood and urine were measured by enzyme-linked immunosorbent assay.The bile acid renal clearance rate(Clr)was calculated.Histopathological evaluation of liver and kidney tissues was performed using hematoxylin-eosin staining.Western blotting was utilized to assess the expression of key bile acid metabolism and transport proteins in both liver and kidney tissues.The expression of the constitutive androstane receptor(CAR)and its nuclear localization were evaluated by immunohistochemistry.Molecular docking studies identified the epidermal growth factor receptor(EGFR)as a potential target of YCHD's active components.An OJ cell model was created using human liver(L02)and renal tubular epithelial(HK-2)cells,which were treated with YCHD-containing serum.Western blotting and immunofluorescence assays were employed to evaluate CAR expression and its nuclear localization in relation to EGFR activation.RESULTS Network analysis identified the EGFR signaling pathway as a key mechanism through which YCHD exerts its effects on OJ.In vivo experiments showed that YCHD improved liver function,reduced OJ-induced pathology in liver and kidney tissues,and decreased serum bile acid content by enhancing bile acid Clr and urine output.YCHD also increased CAR expression and nuclear heterotopy,upregulating proteins involved in bile acid metabolism and transport,including CYP3A4,UGT1A1,MRP3,and MRP4 in the liver,and MRP2 and MRP4 in the kidneys.In vitro,YCHD increased CAR expression and nuclear heterotopy in L02 and HK-2 cells,an effect that was reversed by EGFR agonists.CONCLUSION YCHD enhances bile acid metabolism in the liver and promotes bile acid excretion in the kidneys,ameliorating liver damage caused by OJ.These effects are likely mediated by the upregulation of CAR and its nuclear translocation.展开更多
The onset of pregnancy is marked by the formation of a zygote,while the culmination of gestation is manifested by the delivery of a fetus.Meanwhile,a successful pregnancy entails a meticulously coordinated sequence of...The onset of pregnancy is marked by the formation of a zygote,while the culmination of gestation is manifested by the delivery of a fetus.Meanwhile,a successful pregnancy entails a meticulously coordinated sequence of events from embryo implantation to sustained decidualization of the uterus to placental development and childbirth.The decidual reaction,a pivotal process occurring within the endometrium during pregnancy,is finely regulated by sex steroids and cytokines.Notably,fibroblast growth factors(FGFs),particularly FGF2,play a critical role in this physiological cascade.Dysregulated FGF expression may trigger inadequate decidualization,precipitating a spectrum of adverse pregnancy outcomes,including preeclampsia,recurrent implantation failure,and miscarriage.Furthermore,the human decidua,distinct from most mammalian species and similar to great apes,undergoes regular cycles of formation and shedding,independent of the presence of the embryo in the endometrium.This process is also tightly controlled by various FGFs.In this review,we comprehensively compare diverse research decidualization models,delineate the trend of endometrial FGFs during the menstrual cycle,and provide a synopsis of endometrial diseases triggered by FGF dysregulation.展开更多
BACKGROUND Gastric cancer is one of the most common malignant tumors worldwide,with its incidence and mortality rates ranking among the highest in gastrointestinal cancers.The overexpression or gene amplification of h...BACKGROUND Gastric cancer is one of the most common malignant tumors worldwide,with its incidence and mortality rates ranking among the highest in gastrointestinal cancers.The overexpression or gene amplification of human epidermal growth factor receptor 2(HER-2)occurs in approximately 15%-20%of gastric cancers and serves as a critical molecular target influencing prognosis and treatment out-comes.For patients with HER-2-positive gastric cancer,trastuzumab combined with platinum-based chemotherapy has been established as the standard first-line treatment.However,despite the demonstrated clinical benefits in prolonging survival,the overall efficacy remains limited.In recent years,with the successful application of immune checkpoint inhibitors(ICIs)in various malignant tumors,combining ICIs with existing standard treatment regimens has emerged as a promising approach to enhance the therapeutic efficacy of HER-2-positive gastric cancer.Nevertheless,the efficacy and prognostic factors of ICIs combined with trastuzumab and chemotherapy in HER-2-positive gastric cancer remain unclear.AIM To analyze the efficacy of ICIs combined with standard treatment regimens and the prognostic factors in patients with advanced HER-2-positive gastric cancer.METHODS Clinical data from 104 patients with advanced HER-2-positive gastric cancer who were treated at our hospital between March 2021 and May 2023 were retrospectively analyzed.Patients were divided into a control group(n=54,treated with trastuzumab combined with platinum-based chemotherapy as the standard regimen)and an observation group(n=50,treated with ICIs in addition to the standard regimen).The therapeutic efficacy,survival outcomes,and adverse reactions were compared between the two groups.Univariate and Cox multivariate analyses were performed to identify factors influencing patient prognosis.RESULTS With a median follow-up time of 14.6 months,there were no significant differences between the two groups in terms of objective response rate or disease control rate(P>0.05).The median progression-free survival(mPFS)and mPFS for patients with immunohistochemistry 3+in the observation group were significantly higher than those in the control group(P<0.05).Among patients in the observation group,those with positive programmed death-ligand 1(PD-L1)expression had a significantly higher mPFS than those with negative PD-L1 expression(P<0.05).Regarding adverse events,significant differences were observed between the two groups in hypothyroidism and neutropenia(P<0.05).Cox multivariate analysis showed that Eastern Cooperative Oncology Group(ECOG)performance status,peritoneal metastasis,positive programmed death-1 expression,and treatment regimen were independent factors influencing PFS(hazard ratio>1,P<0.05).CONCLUSION ICIs combined with standard treatment regimens for patients with advanced HER-2-positive gastric cancer demonstrate favorable clinical efficacy,significantly prolonging PFS with manageable safety.ECOG performance status,peritoneal metastasis,positive PD-L1 expression,and treatment regimen are independent factors influ-encing PFS,warranting increased clinical attention to patients exhibiting these factors.展开更多
OBJECTIVES:To investigate the effect of Bushen Tongluo recipe(BSTLR, 补肾通络方) on rats with diabetic kidney disease(DKD) and to explore the underlying mechanism of action. METHODS:The rat model of DKD was establishe...OBJECTIVES:To investigate the effect of Bushen Tongluo recipe(BSTLR, 补肾通络方) on rats with diabetic kidney disease(DKD) and to explore the underlying mechanism of action. METHODS:The rat model of DKD was established, and rats were treated with different doses of BSTLR. Body weight and the levels of urinary protein, α1-microglobulin, glucose, blood urea nitrogen, creatinine, Cystatin C, superoxide dismutase, malondialdehyde, and catalase were analyzed biochemically or by enzyme-linked immunosorbent assay. The pathological damage to renal tissues was assessed by hematoxylin-eosin staining. Immunohistochemical staining was carried out to detect the expression levels of fibronectin, E-cadherin, α-smooth muscle actin, laminin, vimentin, collagen type Ⅳ in kidney tissues. Western blot analysis was conducted to analyze the expression levels of Nephrin, Desmin, Podocin, transforming growth factor-β1, mothers against decapentaplegic homolog 3(Smad3), Notch1, jagged, hairy and enhancer of split 1(Hes1) in kidney tissues, and the expression levels of maternally expressed gene 3(MEG3) and mi R-145 were measured by quantitative reverse transcription-polymerase chain reaction. Moreover, dual-luciferase reporter assay was employed to verify the binding of mi R-145 to MEG3. RESULTS:BSTLR increased the body weight of DKD rats, effectively ameliorated the renal function and pathological injury in DKD, regulated the balance of renal oxidative stress, inhibited the TGF/Notch signaling pathway, and affected the variations in the lnc RNA MEG3/mi R-145 axis. CONCLUSION:BSTLR improved oxidative stress homeostasis, inhibited the TGF/Notch signaling pathway, and regulated the lnc RNA MEG3/mi R-145 axis, effectively delaying the progression of DKD.展开更多
OBJECTIVE:To explore the role and mechanism of Qufeng Jiejing(祛风解痉,QFJJ)formula in the asthma progression.METHODS:The Bagg Albino/c mice treated with Ovalbumin and AL(OH)3,and airway smooth muscle cells(ASMCs)trea...OBJECTIVE:To explore the role and mechanism of Qufeng Jiejing(祛风解痉,QFJJ)formula in the asthma progression.METHODS:The Bagg Albino/c mice treated with Ovalbumin and AL(OH)3,and airway smooth muscle cells(ASMCs)treated with platelet-derived growth factor(PDGF)-BB to establish a asthma model in vivo and in vitro.The cell morphology was observed with microscope and immunofluorescence staining.The cell viability was assessed with methyl thiazolyl tetrazolium assay.The tumor necrosis factor-αlpha(TNF-α),interleukin-1beta(IL-1β),laminin,fibronectin and collagen IV levels in the ASMCs were detected with corresponding enzyme linked immunosorbent assay kits.Transwell and wound healing assays were conducted to test the cell migration.The TGF-β1,Smad2 and Smad3 levels were measured with Western blot.RESULTS:We found that QFJJ formula treatment dramatically decreased the cell viability,TNF-α,IL-1β,laminin,fibronectin and collagen IV levels in the PDGFBB stimulated ASMCs.Additionally,the protein levels of TGF-β1,Smad2 and Smad3 in the PDGF-BB stimulated ASMCs were prominently depleted after QFJJ formula treatment.Besides,SRI treatment neutralized the role of QFJJ formula in the PDGF-BB stimulated ASMCs.CONCLUSION:QFJJ formula effectively relieved the asthma progression through ameliorate the ASMCs function,which was achieved through suppressing the TGF-β1/Smads signaling pathway.展开更多
Adipose-derived stem cell,one type of mesenchymal stem cells,is a promising approach in treating ischemia-reperfusion injury caused by occlusion of the middle cerebral artery.However,its application has been limited b...Adipose-derived stem cell,one type of mesenchymal stem cells,is a promising approach in treating ischemia-reperfusion injury caused by occlusion of the middle cerebral artery.However,its application has been limited by the complexities of the ischemic microenvironment.Hydrogel scaffolds,which are composed of hyaluronic acid and chitosan,exhibit excellent biocompatibility and biodegradability,making them promising candidates as cell carriers.Vascular endothelial growth factor is a crucial regulatory factor for stem cells.Both hyaluronic acid and chitosan have the potential to make the microenvironment more hospitable to transplanted stem cells,thereby enhancing the therapeutic effect of mesenchymal stem cell transplantation in the context of stroke.Here,we found that vascular endothelial growth factor significantly improved the activity and paracrine function of adipose-derived stem cells.Subsequently,we developed a chitosan-hyaluronic acid hydrogel scaffold that incorporated vascular endothelial growth factor and first injected the scaffold into an animal model of cerebral ischemiareperfusion injury.When loaded with adipose-derived stem cells,this vascular endothelial growth factor–loaded scaffold markedly reduced neuronal apoptosis caused by oxygen-glucose deprivation/reoxygenation and substantially restored mitochondrial membrane potential and axon morphology.Further in vivo experiments revealed that this vascular endothelial growth factor–loaded hydrogel scaffold facilitated the transplantation of adipose-derived stem cells,leading to a reduction in infarct volume and neuronal apoptosis in a rat model of stroke induced by transient middle cerebral artery occlusion.It also helped maintain mitochondrial integrity and axonal morphology,greatly improving rat motor function and angiogenesis.Therefore,utilizing a hydrogel scaffold loaded with vascular endothelial growth factor as a stem cell delivery system can mitigate the adverse effects of ischemic microenvironment on transplanted stem cells and enhance the therapeutic effect of stem cells in the context of stroke.展开更多
The aging process is an inexorable fact throughout our lives and is considered a major factor in develo ping neurological dysfunctions associated with cognitive,emotional,and motor impairments.Aging-associated neurode...The aging process is an inexorable fact throughout our lives and is considered a major factor in develo ping neurological dysfunctions associated with cognitive,emotional,and motor impairments.Aging-associated neurodegenerative diseases are characterized by the progressive loss of neuronal structure and function.展开更多
BACKGROUND Diabetes is characterized by insulin resistance as well as impaired insulin production,withβ-cell dysfunction playing a critical role in disease progression.Exercise is known to improve insulin sensitivity...BACKGROUND Diabetes is characterized by insulin resistance as well as impaired insulin production,withβ-cell dysfunction playing a critical role in disease progression.Exercise is known to improve insulin sensitivity,but its effects on pancreatic islet quality and function remain poorly understood.This work hypothesized that swimming training enhances glycemic control and insulin secretion by upregulating the insulin-like growth factor 1(IGF-1)/phosphatidylinositol 3-kinase/protein kinase B(PI3K/AKT)pathway in streptozotocin(STZ)-induced diabetic rats.AIM To investigate the effects of swimming on pancreatic islet quality and function in STZ-induced diabetic rats via the IGF-1/PI3K/AKT pathway.METHODS Twenty-six Sprague-Dawley rats were grouped into diabetic and control groups,with each group further split into exercise and sedentary subgroups.Diabetic rats were induced with STZ.The exercise groups underwent swimming training for 60 minutes/day,5 days/week,for 8 weeks.Body weight,food intake,blood glucose,insulin,lipids,and muscle glycogen were measured.Pancreatic islet morphology and the protein expression levels of IGF-1,PI3K,and AKT were analyzed.Data were analyzed using two-way repeated-measure ANOVA,followed by Tukey’s post-hoc test.RESULTS Exercise training significantly improved body weight[diabetic exercise group(D-Ex):390.66±50.14 g vs diabetic sedentary group(D-Sed):315.89±50.12 g,P<0.05],reduced blood glucose(D-Ex:12.21±4.43 mmol/L vs D-Sed:17.79±2.05 mmol/L,P<0.05),and increased insulin levels(D-Ex:53.50±15.31 pmol/L vs D-Sed:25.31±10.23 pmol/L,P<0.05)in diabetic rats.It also enhanced islet morphology,increased IGF-1 expression,and activated the PI3K/AKT pathway(P<0.05).In-vitro experiments confirmed that IGF-1 positively regulated insulin expression and inhibitedβ-cell apoptosis via the PI3K/AKT pathway.CONCLUSION Exercise training improves pancreatic islet quality and function in diabetic rats by modulating the IGF-1/PI3K/AKT pathway,highlighting its therapeutic potential for diabetes management.展开更多
The epidermal growth factor receptor(EGFR)is a transmembrane glycoprotein that plays a crucial role in signal transduction and cellular responses.This review explores the function of EGFR in kidney physiology and its ...The epidermal growth factor receptor(EGFR)is a transmembrane glycoprotein that plays a crucial role in signal transduction and cellular responses.This review explores the function of EGFR in kidney physiology and its implications for various kidney diseases.EGFR signaling is essential for kidney function and repair mechanisms,and its dysregulation significantly impacts both acute and chronic kidney conditions.The review discusses the normal distribution of EGFR in kidney tubular segments,the mechanism of its activation and inhibition,and the therapeutic potential of EGFR-targeting antagonists and ligands.Additionally,it explores the pathophysiological characteristics observed in rodent models of kidney diseases through pharmacological and genetic inhibition of EGFR,highlighting therapeutic challenges and limitations such as species differences,variability in disease models,and potential adverse effects.Overall,the findings underscore the multifaceted role of EGFR in kidney diseases,influencing inflammation,fibrosis,and tissue injury.This complex involvement suggests that targeting EGFR may be a beneficial therapeutic strategy for managing these conditions,potentially mitigating inflammation and fibrosis while promoting tissue repair.展开更多
BACKGROUND Diabetic retinopathy(DR)is the leading cause of vision loss in patients with diabetes.The vascular endothelial growth factor(VEGF)pathway plays a critical role in the pathogenesis of DR,and ranibizumab,an a...BACKGROUND Diabetic retinopathy(DR)is the leading cause of vision loss in patients with diabetes.The vascular endothelial growth factor(VEGF)pathway plays a critical role in the pathogenesis of DR,and ranibizumab,an anti-VEGF agent,has shown promise in its treatment.Signal transducer and activator of transcription 3(STAT3)is involved in inflammatory processes and cellular signaling,while glial fibrillary acidic protein(GFAP)is a marker of glial cell activation,both contributing to retinal damage in DR.However,the mechanisms by which ranibizumab affect early-stage DR through the VEGF/STAT3/GFAP pathway are not fully understood.AIM To investigate the role of ranibizumab in early DR via the VEGF/STAT3/GFAP pathway.METHODS Adult retinal pigment epithelial 19(ARPE-19)cells and human retinal microvascular endothelial cells(HRMECs)were cultured under high-glucose conditions to simulate a diabetic environment.The effects of ranibizumab on cytokine mRNA and protein expression were analyzed by quantitative polymerase chain reaction and Western blot analysis.A diabetic rat model was induced with streptozotocin(60 mg/kg).Retinal changes,including retinal ganglion cell(RGC)apoptosis,vascular alterations,and cytokine expression,were evaluated using fundus fluorescein angiography,hematoxylin and eosin and periodic acid Schiff staining,immunofluorescence,confocal imaging,and Western blot analysis.RESULTS High-glucose conditions significantly increased the mRNA and protein levels of VEGF,STAT3,GFAP,and other cytokines in ARPE-19 and HRMECs.However,these levels were partially suppressed by ranibizumab.RGC apoptosis,vascular leakage,and elevated cytokine expression were observed during early-stage DR in diabetic rats.Ranibizumab treatment in diabetic rats reduced cytokine expression,restored RGCs,and repaired vascular networks.CONCLUSION Intravitreal ranibizumab modulates the VEGF/STAT3/GFAP pathway,suppresses cytokine expression,and promotes retinal repair,effectively delaying or preventing early DR progression.展开更多
基金supported by the Central Guidance for Local Projects of Xinjiang(ZYYD2024ZY04)the National Natural Science Foundation of China(32260116).
文摘Epidermal growth factor receptor(EGFR)is one of the most important tyrosine kinase receptor families,which plays a pivotal role in cell signaling transduction and physiological processes.Studies on the EGFR gene in humans and other species have demonstrated its pivotal role in regulating the sodium ion balance and mediating sodium and water reabsorption in the kidney's proximal tubules.However,the impact of EGFR gene in how the Yarkand hare(Lepus yarkandensis)adapts to extreme environmental habitat remains unclear,The Yarkand hare is a desert-dwelling animal with multiple adaptations to cope with drought.Given the important physiological function of EGFR gene,we strived to understand its role in arid environment and explore the molecular mechanism of drought tolerance in the Yarkand hare.We first performed segmental cloning of the CDS of the Yarkand hare EGFR gene.Then,We constructed the phylogenetic tree of the Yarkand hare's EGFR gene and compared it with that of other species.The results showed that the Yarkand hare was most closely related to the Tolai hare(Lepus tolai).Through quantitative reverse transcription polymerase chain reaction(RT-qPCR),we discovered that EGFR expression in the kidneys of the Yarkand hare was higher than in the allopatric Tolai hare from non-arid areas.Therefore,we hypothesized that EGFR gene overexpression in the kidney of the Yarkand hare may play a crucial role in drought adaptability.Subsequently,we inserted CDS of EGFR gene into a pcDNA3.1-EGFP expression vector to construct recombinant plasmid,which was transfected into HeLa cells and overexpressed.RT-qPCR demonstrated a notable and statistically significant increase in EGFR mRNA expression and western blot proved stable expression of this protein in HeLa cells.Through cell experiments,EGFR gene overexpression markedly enhanced the survival of Hela cells subjected to NaCl,H_(2)O_(2),and heat stresses,increased superoxide dismutase activity,and decreased malondialdehyde content.In conclusion,these findings preliminarily suggest that EGFR might help the Yarkand hare adapt to extreme environmental conditions.EGFR manipulation in vivo could be a promising strategy to enhance the resilience of animals to extreme conditions.
基金supported by the National Key R&D Program of China(2023YFC3603400)the National Natural Science Foundation of China(82072506,92268115)+2 种基金the Hunan Provincial Science Fund for Distinguished Young Scholars(2024JJ2089)the Science and Technology Innovation Program of Hunan Province(2021RC3025)the National Clinical Research Center for Geriatric Disorders(Xiangya Hospital,2021KF02).
文摘Fibroblast growth factor(FGF)signaling encompasses a multitude of functions,including regulation of cell proliferation,differentiation,morphogenesis,and patterning.FGFs and their receptors(FGFR)are crucial for adult tissue repair processes.Aberrant FGF signal transduction is associated with various pathological conditions such as cartilage damage,bone loss,muscle reduction,and other core pathological changes observed in orthopedic degenerative diseases like osteoarthritis(OA),intervertebral disc degeneration(IVDD),osteoporosis(OP),and sarcopenia.In OA and IVDD pathologies specifically,FGF1,FGF2,FGF8,FGF9,FGF18,FGF21,and FGF23 regulate the synthesis,catabolism,and ossification of cartilage tissue.Additionally,the dysregulation of FGFR expression(FGFR1 and FGFR3)promotes the pathological process of cartilage degradation.In OP and sarcopenia,endocrine-derived FGFs(FGF19,FGF21,and FGF23)modulate bone mineral synthesis and decomposition as well as muscle tissues.FGF2 and other FGFs also exert regulatory roles.A growing body of research has focused on understanding the implications of FGF signaling in orthopedic degeneration.Moreover,an increasing number of potential targets within the FGF signaling have been identified,such as FGF9,FGF18,and FGF23.However,it should be noted that most of these discoveries are still in the experimental stage,and further studies are needed before clinical application can be considered.Presently,this review aims to document the association between the FGF signaling pathway and the development and progression of orthopedic diseases.Besides,current therapeutic strategies targeting the FGF signaling pathway to prevent and treat orthopedic degeneration will be evaluated.
基金Supported by Youth Cultivation Research Program of Beijing Road Medical Area,Xinjiang Military Region General Hospital,Xinjiang,China(No.2022jzbj105)Science and Technology Program of Urumqi Municipal Health and Wellness Commission(No.202360).
文摘AIM:To assess the relationship between serological parameters and the prognosis of young patients with retinal vein occlusion(RVO)after intravitreal conbercept injection(IVC).METHODS:This study enrolled 100 young patients(≤50 years old)diagnosed with RVO-related macular edema(RVO-ME)who had been undergoing IVC at the 474 Hospital in Xinjiang between January 2022 and October 2023.Patients were categorized into two groups:70 eyes in the effective group and 30 eyes in the ineffective group.The effective group comprised patients exhibiting a visual acuity improvement of≥2 lines at the last follow-up,with resolved ME and central macular thickness(CMT)<300μm.Conversely,the ineffective group included patients with visual acuity improvement of<1 line,persistent ME,and CMT≥300μm at the last follow-up.Serological parameters,including white blood cell count,neutrophil count,lymphocyte count,monocyte count,and mean platelet volume were assessed before treatment.The correlation between bestcorrected visual acuity(BCVA)and neutrophil-to-lymphocyte ratio(NLR),platelet-to-lymphocyte ratio(PLR),systemic immune inflammation index(SII),and systemic immune response index(SIRI)was analyzed.Additionally,the association between these serological parameters and the efficacy of IVC was explored.RESULTS:Three months after treatment,the effective group demonstrated a significant improvement in BCVA from 0.82±0.20 to 0.36±0.10,with a concurrent decrease in CMT from 661.28±163.90 to 200.61±82.45μm(P<0.001).Conversely,the ineffective group exhibited minimal changes in BCVA(0.86±0.25 to 0.82±0.14)and CMT(669.84±164.95 to 492.13±138.67μm,P<0.001).The differences in BCVA and CMT between the two groups were statistically significant(P<0.001).According to subgroup analysis,in patients with central RVO(CRVO),BCVA improved from 0.82±0.23 to 0.49±0.12 in the effective group and from 0.80±0.18 to 0.76±0.22 in the ineffective group(P<0.001).The CMT changes followed a similar pattern.In patients with branch RVO(BRVO),comparable trends in BCVA and CMT changes were observed between the effective and ineffective groups(P<0.001).Additionally,the effective group exhibited higher PLR and SII values than the ineffective group(P<0.05).Further CRVO and BRVO subgroups analysis exhibited consistent PLR and SII value trends.CONCLUSION:Compared to other inflammatory factors,elevated PLR and SII levels before treatment are better predictors of outcomes in young RVO-ME patients undergoing IVC treatment.
基金supported by European Regional Development Funds RE0022527 ZEBRATOX(EU-Région Réunion-French State national counterpart,to Nicolas Diotel and Jean-Loup Bascands).
文摘After brain damage,regenerative angiogenesis and neurogenesis have been shown to occur simultaneously in mammals,suggesting a close link between these processes.However,the mechanisms by which these processes interact are not well understood.In this work,we aimed to study the correlation between angiogenesis and neurogenesis after a telencephalic stab wound injury.To this end,we used zebrafish as a relevant model of neuroplasticity and brain repair mechanisms.First,using the Tg(fli1:EGFP×mpeg1.1:mCherry)zebrafish line,which enables visualization of blood vessels and microglia respectively,we analyzed regenerative angiogenesis from 1 to 21 days post-lesion.In parallel,we monitored brain cell proliferation in neurogenic niches localized in the ventricular zone by using immunohistochemistry.We found that after brain damage,the blood vessel area and width as well as expression of the fli1 transgene and vascular endothelial growth factor(vegfaa and vegfbb)were increased.At the same time,neural stem cell proliferation was also increased,peaking between 3 and 5 days post-lesion in a manner similar to angiogenesis,along with the recruitment of microglia.Then,through pharmacological manipulation by injecting an anti-angiogenic drug(Tivozanib)or Vegf at the lesion site,we demonstrated that blocking or activating Vegf signaling modulated both angiogenic and neurogenic processes,as well as microglial recruitment.Finally,we showed that inhibition of microglia by clodronate-containing liposome injection or dexamethasone treatment impairs regenerative neurogenesis,as previously described,as well as injury-induced angiogenesis.In conclusion,we have described regenerative angiogenesis in zebrafish for the first time and have highlighted the role of inflammation in this process.In addition,we have shown that both angiogenesis and neurogenesis are involved in brain repair and that microglia and inflammation-dependent mechanisms activated by Vegf signaling are important contributors to these processes.This study paves the way for a better understanding of the effect of Vegf on microglia and for studies aimed at promoting angiogenesis to improve brain plasticity after brain injury.
基金Supported by the National Natural Science Foundation of China,No.82100639,No.82200630,and No.81970526Postdoctoral Scientific Research Foundation of Shanghai Ninth People’s Hospital,Shanghai Jiao Tong University School of Medicine,No.202401023+3 种基金Clinical Research Program of Ninth People’s Hospital,Shanghai Jiao Tong University School of Medicine,No.JYLJ202124Shanghai Municipal Commission of Health and Family Planning,No.20244Y0195 and No.20234Y0132the Fundamental Research Program Funding of Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,No.JYZZ162Science Foundation of Xinjiang Uygur Natural Autonomous Region,No.2022D01F17.
文摘BACKGROUND Liver cirrhosis and portal hypertension(PHT)can lead to lymphatic abnormalities and coagulation dysfunction.Because lymphangiogenesis may relieve liver cirrhosis and PHT,the present study investigated the gene expression alterations in the lymphatic system and the effectiveness of platelet-mediated lymphangiogenesis in improving liver cirrhosis and PHT.AIM To investigate the role of lymphangiogenesis in preclinical PHT models.METHODS Immunohistochemistry and transcriptome sequencing of bile duct ligation(BDL)and control lymphatic samples were conducted to reveal the indicated signaling pathways.Functional enrichment analyses were performed on the differentially expressed genes and hub genes.Adenoviral infection of vascular endothelial growth factor C(VEGF-C),plateletrich plasma(PRP),and VEGF3 receptor(VEGFR)inhibitor MAZ-51 was used as an intervention for the lymphatic system in PHT models.Histology,hemodynamic tests and western blot analyses were performed to demonstrate the effects of lymphatic intervention in PHT patients.RESULTS Lymphangiogenesis was increased in the BDL rat model.Transcriptome sequencing analysis of the extrahepatic lymphatic system revealed its close association with platelet adherence,aggregation,and activation.The role of PHT in the rat model was investigated by activating(PRP)and inhibiting(MAZ-51)the lymphatic system.PRP promoted lymphangiogenesis,which increased lymphatic drainage,alleviated portal pressure,reduced liver fibrosis,inhibited inflammation,inhibited angiogenesis,and suppressed mesenteric artery remodeling.MAZ-51 reversed the above improvements.CONCLUSION Via VEGF-C/VEGFR-3,platelets impede fibrosis,angiogenesis,and mesenteric artery remodeling,ultimately alleviating PHT.Thus,platelet intervention is a therapeutic approach for cirrhosis and PHT.
基金Supported by the Natural Science Foundation of Guangxi Province,No.2019GXNSFAA185030 and No.2023GXNSFBA026129the Scientific Research Project of the Second Affiliated Hospital of Guangxi Medical University,No.EFYKY2020013the Cultivation Science Foundation of the Second Affiliated Hospital of Guangxi Medical University,No.GJPY2023005 and No.GJPY2023009.
文摘BACKGROUND In patients with colorectal cancer(CRC),tumour metastasis is the leading cause of death.The search for key genes involved in metastasis of CRC is imperative for improved prognoses and treatments.SPDL1 has been implicated in the deve-lopment of CRC,however,its mechanism of action remains unclear.AIM To investigate the role and mechanism of action by which SPDL1 inhibits the development and metastasis of CRC.METHODS In this study,we examined the relationship between SPDL1 expression and CRC prognosis using immunohistochemistry.Survival analyses were performed using Kaplan-Meier analysis and log-rank test.After knocking down SPDL1 in the HCT116 cancer cell line changes in cell viability,migration,invasion,and gene expression were examined using a cell counting kit 8 assay,Transwell assay,and Western blot.The effect of SPDL1 on the cell cycle was assessed using flow cy-tometry.RNA sequencing was used to analyse the effect of SPDL1 on gene expression of CRC cells.The mechanism of action of SPDL1 in CRC was further clarified using U0126,an inhibitor of the mitogen-activated protein kinase signaling pathway.RESULTS SPDL1 is expressed at low levels in tissues of patients with CRC,and this reduced expression is associated with poor prognosis.Functionally,low expression of SPDL1 in CRC promotes cell proliferation,migration,invasion,and affects the cell cycle.Mechanistically,SPDL1 affects the progression of CRC through its regulation of the process of epithelial-mesenchymal transition(EMT)and of the epidermal growth factor receptor(EGFR)/extracellular signal-regulated kinase(ERK)signaling pathways.CONCLUSION This study showed that the loss of SPDL1 may induce EMT and promote cell migration and invasion in CRC through the EGFR/ERK pathway.
文摘BACKGROUND Interleukin-22(IL-22)belongs to the IL-10 cytokine family,recognized for its ability to modulate diverse immune responses.Previous studies have indicated that IL-22 promotes cancer advancement and metastasis.However,the precise function of IL-22 in colorectal cancer(CRC)remains unclear.AIM To investigate the role of IL-22 in promoting stem cell-like characteristics and chemotherapy resistance in CRC cells,as well as to elucidate the mechanisms underlying these effects.METHODS HCT116 cells were treated with IL-22(50 ng/mL)and oxaliplatin(L-OHP,5μg/mL).A series of functional assays-including cell counting kit-8 assay,tumor sphere formation assay,and cell apoptosis assay-were conducted to assess the effects of IL-22 on cell viability and stem cell-like characteristics.The expression of stemness-related markers(SOX2,Oct4,NANOG,and Bmi-1)was examined using Western blot analysis.Additionally,the total and phosphorylated levels of epidermal growth factor receptor(EGFR),protein kinase B(AKT),and extracellular signal-regulated kinase(ERK)were evaluated by Western blot.An EGFR inhibitor,osimertinib(Osi),was used to assess the pathway's functional relevance.RESULTS IL-22 treatment promotes CRC cell proliferation,enhances sphere formation,and elevates the expression of stem cell markers,including SOX2,Oct4,NANOG,and Bmi-1.IL-22 treatment increases the phosphorylation of EGFR,AKT,and ERK.Additionally,IL-22 treatment mitigates the cytotoxic effects and the ability to induce apoptosis of L-OHP.Furthermore,IL-22 treatment activated the EGFR/ERK signaling pathway by increasing the phosphorylation of EGFR,AKT,and ERK.Importantly,the use of the EGFR inhibitor Osi significantly counteracted the chemoresistance induced by IL-22 in CRC cells.CONCLUSION IL-22 promotes tumor growth and induces chemotherapy resistance in CRC cells by activating the EGFR/ERK signaling pathway.These findings suggest that targeting IL-22 or its downstream signaling may offer novel therapeutic strategies in CRC.
基金Supported by the Jiangsu Provincial Health and Family Planning Commission Personnel Talent Project,No.R2017005.
文摘BACKGROUND Although targeted therapy provides survival benefits for patients with metastatic colorectal cancer,some patients develop resistance to these treatments.Human epidermal growth factor receptor 2(HER2)is overexpressed in a subset of pa-tients with colorectal cancer and has been established as a therapeutic target.CASE SUMMARY This case report describes a Chinese patient with HER2-amplified advanced rectal cancer who showed no response to chemotherapy and targeted therapies against epidermal growth factor receptor and vascular endothelial growth factor but achieved a remarkable response following treatment with immune checkpoint inhibitors(ICIs)in combination with pyrotinib.The combination of oxaliplatin and ICIs with pyrotinib demonstrates synergistic effects after late-stage disease progression.CONCLUSION ICIs and pyrotinib may be effective in treating HER2-amplified advanced rectal cancer.Chemotherapy following disease progression could enhance efficacy synergistically.
基金supported by grants from the National Key Research and Development Program of China(2020YFA0803900)the National Natural Science Foundation of China(U23A20407,82414020,81703631)the Hubei Provincial Natural Science Foundation of China(2024AFB742)。
文摘Prenatal caffeine exposure(PCE)leads to intrauterine growth retardation and altered glucose homeostasis after birth,but the underlying mechanism remains unclear.This study aims to investigate the alteration of pancreatic development and insulin biosynthesis in the PCE female offspring and explore the intrauterine programming mechanism.Pregnant rats were orally treated with 120 mg/(kg·day)of caffeine from gestational day(GD)9 to 20.Results showed that fetal pancreaticβ-cells in the PCE group exhibited reduced mass and impaired insulin synthesis function,as evidenced by decreased expression of developmental and functional genes and reduced pancreatic insulin content.At postnatal week(PW)12,the PCE offspring exhibited glucose intolerance,diminishedβ-cell mass,and lower blood insulin levels.However,by PW28,glucose tolerance showed some improvement.Both in vivo and in vitro findings collectively indicated that excessive serum corticosterone(CORT)levels of the PCE fetuses may act through the activation of the pancreatic glucocorticoid receptor(GR)and recruitment of histone deacetylase 9(HDAC9),leading to H3K9 deacetylation in promoter and downregulation of insulin-like growth factor 1(IGF1),thereby inhibiting pancreatic islet morphogenesis and insulin synthesis in fetal rats.Furthermore,the PCE offspring after birth exhibited decreased blood CORT levels,increased H3K9 acetylation in promoter and upregulated gene expression of the pancreatic IGF1 promoter region,accompanied by elevated insulin biosynthesis.However,when exposed to chronic stress,the above changes were totally reversed.Conclusively,“glucocorticoid-insulin like growth factor 1(GC-IGF1)axis”programming may be involved in pancreaticβ-cell dysplasia and dysfunction in the PCE female offspring.
基金Supported by CAMS Innovation Fund for Medical Sciences CIFMS,No.2023-I2M-3-012.
文摘BACKGROUND Human epidermal growth factor receptor 2(HER2)-positive gastric cancer(GC)represents a distinct molecular cancer subtype that is often associated with a poor prognosis.While perioperative chemotherapy regimens are currently the primary recommendation for locally advanced HER2-positive GC,combination therapies incorporating immune checkpoint inhibitors are under active investigation.CASE SUMMARY The present case describes a patient with locally advanced HER2-positive GC who underwent perioperative treatment with chemotherapy combined with trastuzumab.Although significant tumor shrinkage was observed,surgical pathology results did not confirm the achievement of a pathological complete response.The current treatment strategies for advanced GC were also reviewed.Relevant case reports,retrospective studies,and prospective clinical trials were retrieved for analysis after searching the PubMed/MEDLINE,EMBASE,Cochrane Library,Web of Science,and American Society of Clinical Oncology/European Society for Medical Oncology conference abstracts between 2014 and 2024.CONCLUSION Large-scale phase III clinical trials are needed to verify the efficacy of combined neoadjuvant treatment application for GC.
基金Supported by Tianjin Municipal Education Commission Scientific Research Program,China,No.2022KJ271.
文摘BACKGROUND Yinchenhao decoction(YCHD)is a traditional Chinese medicine widely used to treat liver damage caused by obstructive jaundice(OJ).Although YCHD has demonstrated protective effects against liver damage,reduced apoptosis,and mitigated oxidative stress in OJ,the precise molecular mechanisms involved remain poorly understood.AIM To investigate the beneficial effects of YCHD on OJ and elucidate the underlying mechanisms.METHODS The active constituents of YCHD were identified using liquid chromatography tandem mass spectrometry,and their potential targets for OJ treatment were predicted through network pharmacology.Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed.An OJ rat model was established by common bile duct ligation.Rats were divided into three groups:Sham surgery(S Group),model(O Group),and YCHD(Y Group).YCHD was administered to Group Y for one week.Bilirubin levels,liver function parameters,and bile acid concentrations in blood and urine were measured by enzyme-linked immunosorbent assay.The bile acid renal clearance rate(Clr)was calculated.Histopathological evaluation of liver and kidney tissues was performed using hematoxylin-eosin staining.Western blotting was utilized to assess the expression of key bile acid metabolism and transport proteins in both liver and kidney tissues.The expression of the constitutive androstane receptor(CAR)and its nuclear localization were evaluated by immunohistochemistry.Molecular docking studies identified the epidermal growth factor receptor(EGFR)as a potential target of YCHD's active components.An OJ cell model was created using human liver(L02)and renal tubular epithelial(HK-2)cells,which were treated with YCHD-containing serum.Western blotting and immunofluorescence assays were employed to evaluate CAR expression and its nuclear localization in relation to EGFR activation.RESULTS Network analysis identified the EGFR signaling pathway as a key mechanism through which YCHD exerts its effects on OJ.In vivo experiments showed that YCHD improved liver function,reduced OJ-induced pathology in liver and kidney tissues,and decreased serum bile acid content by enhancing bile acid Clr and urine output.YCHD also increased CAR expression and nuclear heterotopy,upregulating proteins involved in bile acid metabolism and transport,including CYP3A4,UGT1A1,MRP3,and MRP4 in the liver,and MRP2 and MRP4 in the kidneys.In vitro,YCHD increased CAR expression and nuclear heterotopy in L02 and HK-2 cells,an effect that was reversed by EGFR agonists.CONCLUSION YCHD enhances bile acid metabolism in the liver and promotes bile acid excretion in the kidneys,ameliorating liver damage caused by OJ.These effects are likely mediated by the upregulation of CAR and its nuclear translocation.
基金supported by the National Natural Science Foundation of China(Nos.91949123 and 81871155).
文摘The onset of pregnancy is marked by the formation of a zygote,while the culmination of gestation is manifested by the delivery of a fetus.Meanwhile,a successful pregnancy entails a meticulously coordinated sequence of events from embryo implantation to sustained decidualization of the uterus to placental development and childbirth.The decidual reaction,a pivotal process occurring within the endometrium during pregnancy,is finely regulated by sex steroids and cytokines.Notably,fibroblast growth factors(FGFs),particularly FGF2,play a critical role in this physiological cascade.Dysregulated FGF expression may trigger inadequate decidualization,precipitating a spectrum of adverse pregnancy outcomes,including preeclampsia,recurrent implantation failure,and miscarriage.Furthermore,the human decidua,distinct from most mammalian species and similar to great apes,undergoes regular cycles of formation and shedding,independent of the presence of the embryo in the endometrium.This process is also tightly controlled by various FGFs.In this review,we comprehensively compare diverse research decidualization models,delineate the trend of endometrial FGFs during the menstrual cycle,and provide a synopsis of endometrial diseases triggered by FGF dysregulation.
基金This study was approved by the ethics committee of the First People’s Hospital of Fuzhou City(No.FZ202103).
文摘BACKGROUND Gastric cancer is one of the most common malignant tumors worldwide,with its incidence and mortality rates ranking among the highest in gastrointestinal cancers.The overexpression or gene amplification of human epidermal growth factor receptor 2(HER-2)occurs in approximately 15%-20%of gastric cancers and serves as a critical molecular target influencing prognosis and treatment out-comes.For patients with HER-2-positive gastric cancer,trastuzumab combined with platinum-based chemotherapy has been established as the standard first-line treatment.However,despite the demonstrated clinical benefits in prolonging survival,the overall efficacy remains limited.In recent years,with the successful application of immune checkpoint inhibitors(ICIs)in various malignant tumors,combining ICIs with existing standard treatment regimens has emerged as a promising approach to enhance the therapeutic efficacy of HER-2-positive gastric cancer.Nevertheless,the efficacy and prognostic factors of ICIs combined with trastuzumab and chemotherapy in HER-2-positive gastric cancer remain unclear.AIM To analyze the efficacy of ICIs combined with standard treatment regimens and the prognostic factors in patients with advanced HER-2-positive gastric cancer.METHODS Clinical data from 104 patients with advanced HER-2-positive gastric cancer who were treated at our hospital between March 2021 and May 2023 were retrospectively analyzed.Patients were divided into a control group(n=54,treated with trastuzumab combined with platinum-based chemotherapy as the standard regimen)and an observation group(n=50,treated with ICIs in addition to the standard regimen).The therapeutic efficacy,survival outcomes,and adverse reactions were compared between the two groups.Univariate and Cox multivariate analyses were performed to identify factors influencing patient prognosis.RESULTS With a median follow-up time of 14.6 months,there were no significant differences between the two groups in terms of objective response rate or disease control rate(P>0.05).The median progression-free survival(mPFS)and mPFS for patients with immunohistochemistry 3+in the observation group were significantly higher than those in the control group(P<0.05).Among patients in the observation group,those with positive programmed death-ligand 1(PD-L1)expression had a significantly higher mPFS than those with negative PD-L1 expression(P<0.05).Regarding adverse events,significant differences were observed between the two groups in hypothyroidism and neutropenia(P<0.05).Cox multivariate analysis showed that Eastern Cooperative Oncology Group(ECOG)performance status,peritoneal metastasis,positive programmed death-1 expression,and treatment regimen were independent factors influencing PFS(hazard ratio>1,P<0.05).CONCLUSION ICIs combined with standard treatment regimens for patients with advanced HER-2-positive gastric cancer demonstrate favorable clinical efficacy,significantly prolonging PFS with manageable safety.ECOG performance status,peritoneal metastasis,positive PD-L1 expression,and treatment regimen are independent factors influ-encing PFS,warranting increased clinical attention to patients exhibiting these factors.
文摘OBJECTIVES:To investigate the effect of Bushen Tongluo recipe(BSTLR, 补肾通络方) on rats with diabetic kidney disease(DKD) and to explore the underlying mechanism of action. METHODS:The rat model of DKD was established, and rats were treated with different doses of BSTLR. Body weight and the levels of urinary protein, α1-microglobulin, glucose, blood urea nitrogen, creatinine, Cystatin C, superoxide dismutase, malondialdehyde, and catalase were analyzed biochemically or by enzyme-linked immunosorbent assay. The pathological damage to renal tissues was assessed by hematoxylin-eosin staining. Immunohistochemical staining was carried out to detect the expression levels of fibronectin, E-cadherin, α-smooth muscle actin, laminin, vimentin, collagen type Ⅳ in kidney tissues. Western blot analysis was conducted to analyze the expression levels of Nephrin, Desmin, Podocin, transforming growth factor-β1, mothers against decapentaplegic homolog 3(Smad3), Notch1, jagged, hairy and enhancer of split 1(Hes1) in kidney tissues, and the expression levels of maternally expressed gene 3(MEG3) and mi R-145 were measured by quantitative reverse transcription-polymerase chain reaction. Moreover, dual-luciferase reporter assay was employed to verify the binding of mi R-145 to MEG3. RESULTS:BSTLR increased the body weight of DKD rats, effectively ameliorated the renal function and pathological injury in DKD, regulated the balance of renal oxidative stress, inhibited the TGF/Notch signaling pathway, and affected the variations in the lnc RNA MEG3/mi R-145 axis. CONCLUSION:BSTLR improved oxidative stress homeostasis, inhibited the TGF/Notch signaling pathway, and regulated the lnc RNA MEG3/mi R-145 axis, effectively delaying the progression of DKD.
基金Supported by Science and Technology Innovation Project of China Academy of Chinese Medical Sciences of Study on the Mechanism of Qufeng Jiejing Formula in Regulating Mitogen-activated Protein Kinase Signaling Pathway to Inhibit Phenotypic Transformation of Airway Smooth Muscle Cells in Asthma(No.CI2021A01108)Cultivation Project of The National Natural Science Foundation of China of Xiyuan Hospital,China Academy of Chinese Medical Sciences of Research on the Role of Traditional Chinese Medicines-Qufeng Jiejing in the Proliferation,Migration and Phenotypic Transformation of Airway Smooth Muscle Cells in Asthma(No.XY20-17)。
文摘OBJECTIVE:To explore the role and mechanism of Qufeng Jiejing(祛风解痉,QFJJ)formula in the asthma progression.METHODS:The Bagg Albino/c mice treated with Ovalbumin and AL(OH)3,and airway smooth muscle cells(ASMCs)treated with platelet-derived growth factor(PDGF)-BB to establish a asthma model in vivo and in vitro.The cell morphology was observed with microscope and immunofluorescence staining.The cell viability was assessed with methyl thiazolyl tetrazolium assay.The tumor necrosis factor-αlpha(TNF-α),interleukin-1beta(IL-1β),laminin,fibronectin and collagen IV levels in the ASMCs were detected with corresponding enzyme linked immunosorbent assay kits.Transwell and wound healing assays were conducted to test the cell migration.The TGF-β1,Smad2 and Smad3 levels were measured with Western blot.RESULTS:We found that QFJJ formula treatment dramatically decreased the cell viability,TNF-α,IL-1β,laminin,fibronectin and collagen IV levels in the PDGFBB stimulated ASMCs.Additionally,the protein levels of TGF-β1,Smad2 and Smad3 in the PDGF-BB stimulated ASMCs were prominently depleted after QFJJ formula treatment.Besides,SRI treatment neutralized the role of QFJJ formula in the PDGF-BB stimulated ASMCs.CONCLUSION:QFJJ formula effectively relieved the asthma progression through ameliorate the ASMCs function,which was achieved through suppressing the TGF-β1/Smads signaling pathway.
基金supported by a grant from the Excellent Young Scholars Cultivation Project of Fujian Medical University Union Hospital,No.2022XH026(to HC)Joint Funds for the Innovation of Science and Technology in Fujian Province,No.2019Y9058(to XL)the Natural Science Foundation of Fujian Province,No.2020J011017(to XL)。
文摘Adipose-derived stem cell,one type of mesenchymal stem cells,is a promising approach in treating ischemia-reperfusion injury caused by occlusion of the middle cerebral artery.However,its application has been limited by the complexities of the ischemic microenvironment.Hydrogel scaffolds,which are composed of hyaluronic acid and chitosan,exhibit excellent biocompatibility and biodegradability,making them promising candidates as cell carriers.Vascular endothelial growth factor is a crucial regulatory factor for stem cells.Both hyaluronic acid and chitosan have the potential to make the microenvironment more hospitable to transplanted stem cells,thereby enhancing the therapeutic effect of mesenchymal stem cell transplantation in the context of stroke.Here,we found that vascular endothelial growth factor significantly improved the activity and paracrine function of adipose-derived stem cells.Subsequently,we developed a chitosan-hyaluronic acid hydrogel scaffold that incorporated vascular endothelial growth factor and first injected the scaffold into an animal model of cerebral ischemiareperfusion injury.When loaded with adipose-derived stem cells,this vascular endothelial growth factor–loaded scaffold markedly reduced neuronal apoptosis caused by oxygen-glucose deprivation/reoxygenation and substantially restored mitochondrial membrane potential and axon morphology.Further in vivo experiments revealed that this vascular endothelial growth factor–loaded hydrogel scaffold facilitated the transplantation of adipose-derived stem cells,leading to a reduction in infarct volume and neuronal apoptosis in a rat model of stroke induced by transient middle cerebral artery occlusion.It also helped maintain mitochondrial integrity and axonal morphology,greatly improving rat motor function and angiogenesis.Therefore,utilizing a hydrogel scaffold loaded with vascular endothelial growth factor as a stem cell delivery system can mitigate the adverse effects of ischemic microenvironment on transplanted stem cells and enhance the therapeutic effect of stem cells in the context of stroke.
文摘The aging process is an inexorable fact throughout our lives and is considered a major factor in develo ping neurological dysfunctions associated with cognitive,emotional,and motor impairments.Aging-associated neurodegenerative diseases are characterized by the progressive loss of neuronal structure and function.
文摘BACKGROUND Diabetes is characterized by insulin resistance as well as impaired insulin production,withβ-cell dysfunction playing a critical role in disease progression.Exercise is known to improve insulin sensitivity,but its effects on pancreatic islet quality and function remain poorly understood.This work hypothesized that swimming training enhances glycemic control and insulin secretion by upregulating the insulin-like growth factor 1(IGF-1)/phosphatidylinositol 3-kinase/protein kinase B(PI3K/AKT)pathway in streptozotocin(STZ)-induced diabetic rats.AIM To investigate the effects of swimming on pancreatic islet quality and function in STZ-induced diabetic rats via the IGF-1/PI3K/AKT pathway.METHODS Twenty-six Sprague-Dawley rats were grouped into diabetic and control groups,with each group further split into exercise and sedentary subgroups.Diabetic rats were induced with STZ.The exercise groups underwent swimming training for 60 minutes/day,5 days/week,for 8 weeks.Body weight,food intake,blood glucose,insulin,lipids,and muscle glycogen were measured.Pancreatic islet morphology and the protein expression levels of IGF-1,PI3K,and AKT were analyzed.Data were analyzed using two-way repeated-measure ANOVA,followed by Tukey’s post-hoc test.RESULTS Exercise training significantly improved body weight[diabetic exercise group(D-Ex):390.66±50.14 g vs diabetic sedentary group(D-Sed):315.89±50.12 g,P<0.05],reduced blood glucose(D-Ex:12.21±4.43 mmol/L vs D-Sed:17.79±2.05 mmol/L,P<0.05),and increased insulin levels(D-Ex:53.50±15.31 pmol/L vs D-Sed:25.31±10.23 pmol/L,P<0.05)in diabetic rats.It also enhanced islet morphology,increased IGF-1 expression,and activated the PI3K/AKT pathway(P<0.05).In-vitro experiments confirmed that IGF-1 positively regulated insulin expression and inhibitedβ-cell apoptosis via the PI3K/AKT pathway.CONCLUSION Exercise training improves pancreatic islet quality and function in diabetic rats by modulating the IGF-1/PI3K/AKT pathway,highlighting its therapeutic potential for diabetes management.
基金supported by the Basic Science Research Program through the National Research Foundation of Korea(NRF)and funded by the Ministry of Education(2021R1I1A3056002,to Jinu Kim,RS-2023-00274853,to Daeun MOON).
文摘The epidermal growth factor receptor(EGFR)is a transmembrane glycoprotein that plays a crucial role in signal transduction and cellular responses.This review explores the function of EGFR in kidney physiology and its implications for various kidney diseases.EGFR signaling is essential for kidney function and repair mechanisms,and its dysregulation significantly impacts both acute and chronic kidney conditions.The review discusses the normal distribution of EGFR in kidney tubular segments,the mechanism of its activation and inhibition,and the therapeutic potential of EGFR-targeting antagonists and ligands.Additionally,it explores the pathophysiological characteristics observed in rodent models of kidney diseases through pharmacological and genetic inhibition of EGFR,highlighting therapeutic challenges and limitations such as species differences,variability in disease models,and potential adverse effects.Overall,the findings underscore the multifaceted role of EGFR in kidney diseases,influencing inflammation,fibrosis,and tissue injury.This complex involvement suggests that targeting EGFR may be a beneficial therapeutic strategy for managing these conditions,potentially mitigating inflammation and fibrosis while promoting tissue repair.
基金Supported by the Natural Science Foundation of Jiangxi Province,No.20242BAB25489National Natural Science Foundation of China,No.82260211 and No.81460092+1 种基金Key Research and Development Project in Jiangxi Province,No.20203BBG73058Chinese Medicine Science and Technology Project in Jiangxi Province,No.2020A0166。
文摘BACKGROUND Diabetic retinopathy(DR)is the leading cause of vision loss in patients with diabetes.The vascular endothelial growth factor(VEGF)pathway plays a critical role in the pathogenesis of DR,and ranibizumab,an anti-VEGF agent,has shown promise in its treatment.Signal transducer and activator of transcription 3(STAT3)is involved in inflammatory processes and cellular signaling,while glial fibrillary acidic protein(GFAP)is a marker of glial cell activation,both contributing to retinal damage in DR.However,the mechanisms by which ranibizumab affect early-stage DR through the VEGF/STAT3/GFAP pathway are not fully understood.AIM To investigate the role of ranibizumab in early DR via the VEGF/STAT3/GFAP pathway.METHODS Adult retinal pigment epithelial 19(ARPE-19)cells and human retinal microvascular endothelial cells(HRMECs)were cultured under high-glucose conditions to simulate a diabetic environment.The effects of ranibizumab on cytokine mRNA and protein expression were analyzed by quantitative polymerase chain reaction and Western blot analysis.A diabetic rat model was induced with streptozotocin(60 mg/kg).Retinal changes,including retinal ganglion cell(RGC)apoptosis,vascular alterations,and cytokine expression,were evaluated using fundus fluorescein angiography,hematoxylin and eosin and periodic acid Schiff staining,immunofluorescence,confocal imaging,and Western blot analysis.RESULTS High-glucose conditions significantly increased the mRNA and protein levels of VEGF,STAT3,GFAP,and other cytokines in ARPE-19 and HRMECs.However,these levels were partially suppressed by ranibizumab.RGC apoptosis,vascular leakage,and elevated cytokine expression were observed during early-stage DR in diabetic rats.Ranibizumab treatment in diabetic rats reduced cytokine expression,restored RGCs,and repaired vascular networks.CONCLUSION Intravitreal ranibizumab modulates the VEGF/STAT3/GFAP pathway,suppresses cytokine expression,and promotes retinal repair,effectively delaying or preventing early DR progression.
