The hypoxia inducible factors （Hifs） are evolutionarily conserved transcriptional factors that control homeostatic responses to low oxygen. In developing bone, Hif-1 generated signals induce angiogenesis necessary f...The hypoxia inducible factors （Hifs） are evolutionarily conserved transcriptional factors that control homeostatic responses to low oxygen. In developing bone, Hif-1 generated signals induce angiogenesis necessary for osteoblast specification, but in mature bone, loss of Hif-1 in osteoblasts resulted in a more rapid accumulation of bone. These findings suggested that Hif-1 exerts distinct developmental functions and acts as a negative regulator of bone formation. To investigate the function of Hif-1a in osteoanabolic signaling, we assessed the effect of Hif-1a loss-of-function on bone formation in response to intermittent parathyroid hormone （PTH）. Mice lacking Hif-1a in osteoblasts and osteocytes form more bone in response to PTH, likely through a larger increase in osteoblast activity and increased sensitivity to the hormone. Consistent with this effect, exposure of primary mouse osteoblasts to PTH resulted in the rapid induction of Hif-1a protein levels via a post-transcriptional mechanism. The enhanced anabolic response appears to result from the removal of Hif-1a-mediated suppression of β-catenin transcriptional activity. Together, these data indicate that Hif-1a functions in the mature skeleton to restrict osteoanabolic signaling. The availability of pharmacological agents that reduce Hif-1a function suggests the value in further exploration of this pathway to optimize the therapeutic benefits of PTH.展开更多
Studies have demonstrated that DL-3-n-butylphthalide can significantly alleviate oxygen glucose deprivation-induced injury of human umbilical vein endothelial cells at least partly associated with its enhancement on o...Studies have demonstrated that DL-3-n-butylphthalide can significantly alleviate oxygen glucose deprivation-induced injury of human umbilical vein endothelial cells at least partly associated with its enhancement on oxygen glucose deprivation-induced hypoxia inducible factor-1α expression.In this study,we hypothesized that DL-3-n-butylphthalide can protect against oxygen glucose deprivation-induced injury of newborn rat brain microvascular endothelial cells by means of upregulating hypoxia inducible factor-1α expression.MTT assay and Hoechst staining results showed that DL-3-n-butylphthalide protected brain microvascular endothelial cells against oxygen glucose deprivation-induced injury in a dose-dependent manner.Western blot and immunofluorescent staining results further confirmed that the protective effect was related to upregulation of hypoxia inducible factor-1α.Real-time RT-PCR reaction results showed that DL-3-n-butylphthalide reduced apoptosis by inhibiting downregulation of pro-apoptotic gene caspase-3 mRNA expression and upregulation of apoptosis-executive protease bcl-2 mRNA expression;however,DL-3-n-butylphthalide had no protective effects on brain microvascular endothelial cells after knockdown of hypoxia inducible factor-1α by small interfering RNA.These findings suggest that DL-3-n-butylphthalide can protect brain microvascular endothelial cells against oxygen glucose deprivation-induced injury by upregulating bcl-2 expression and downregulating caspase-3 expression though hypoxia inducible factor-1α pathway.展开更多
BACKGROUND Hypoxia-inducible factor 1α(HIF-1α)plays a crucial role in the prognosis of breast cancer,but the current evidence remains inconclusive.AIM To provide comprehensive evidence about the correlation of alter...BACKGROUND Hypoxia-inducible factor 1α(HIF-1α)plays a crucial role in the prognosis of breast cancer,but the current evidence remains inconclusive.AIM To provide comprehensive evidence about the correlation of altered HIF-1αexpression with overall survival(OS)and disease-free survival(DFS)in breast cancer patients.METHODS A systematic search was conducted in PubMed,Embase,and Web of Science databases to collect relevant articles that were published before April 8,2024.A meta-analysis was used to assess the impact of altered HIF-1αexpression on the OS and DFS of breast cancer patients.Subgroup and sensitivity analyses were also performed in this meta-analysis.RESULTS This meta-analysis included 40 studies.The average percentage of breast cancer patients with high HIF-1αexpression was 39.6%.The overall meta-analysis results demonstrated that high HIF-1αexpression is strongly linked to poor outcomes in patients of breast cancer.Compared with low HIF-1αexpression,the overall hazard ratio for OS in patients with high HIF-1αexpression was 1.47[95%confidence interval(CI):1.29-1.69],and the overall hazard ratio for DFS was 1.82(95%CI:1.56-2.12).Furthermore,both OS[1.18(95%CI:1.01-1.38)]and DFS[1.79(95%CI:1.03-3.11)]were markedly shorter in triple-negative breast cancer cases with high HIF-1αexpression.Subgroup analysis revealed that the antibody used to detect HIF-1αexpression affected only the correlation linking HIF-1αexpression to DFS in breast cancer patients(P=0.0004).Furthermore,the sensitivity analysis demonstrates that the overall conclusions of the meta-analysis were unaffected by the removal of individual studies.CONCLUSION Compared to patients with low HIF-1αexpression,those with high expression level had shorter OS and DFS.However,the prognostic significance of high HIF-1αexpression varies across molecularly stratified breast cancer cohorts needs to be further elucidated.展开更多
OBJECTIVE:To investigate the impact of Shenhua tablet(肾华片,SHT)on renal macrophage polarization and renal injury in mice with diabetic kidney disease(DKD)and to explore the potential mechanism involving the hypoxia-...OBJECTIVE:To investigate the impact of Shenhua tablet(肾华片,SHT)on renal macrophage polarization and renal injury in mice with diabetic kidney disease(DKD)and to explore the potential mechanism involving the hypoxia-inducible factor-1α(HIF-1α)and pyruvate kinase M2(PKM2)signaling pathway,along with the glycolysis metabolism pathway.METHODS:The animals were divided into the following groups:Model,Control,dapagliflozin,SHT low-dose,SHT medium-dose,and SHT high-dose.We assessed 24-hour urine protein(24 h-UTP)levels,urinary albuminto-creatinine ratio,and regularly monitored fasting blood glucose during the treatment period.After treatment,we examined renal tissue structure,renal function(urea nitrogen,uric acid,creatinine,cystatin C,β2-microglobulin),and glycolysis in renal macrophages.Additionally,we observed macrophage polarization in renal tissue and measured inflammatory factors(tumor necrosis factor-α,interleukin-1β,interleukin-6,interleukin-10,monocyte chemoattractant protein-1)to assess the immunoinflammatory status of the renal tissue.Finally,we investigated the expression of the HIF-1α/PKM2 signaling pathway in macrophages to explore its role in the glycolysis process.RESULTS:SHT shows a beneficial effect in treating DKD by reducing 24 h-UTP,regulating blood glucose levels,improving renal tissue structure,protecting renal function,inhibiting macrophage glycolysis,reducing macrophage transformation to the M1 state,and suppressing the expression of the HIF-1α/PKM2 signaling pathway.CONCLUSION:SHT may exert renoprotective effects by inhibiting macrophage glycolysis via the HIF-1α/PKM2 signaling pathway.This inhibition decreases macrophage M1 polarization and reduces immunoinflammatory injury in the renal tissue of DKD mice.展开更多
BACKGROUND Hypoxia in oral cancer promotes tumoral invasion by inducing epithelial-mesenchymal transition,leading to aggressive tumor progression.AIM To characterize the expression of hypoxia-inducible factor 1-alpha(...BACKGROUND Hypoxia in oral cancer promotes tumoral invasion by inducing epithelial-mesenchymal transition,leading to aggressive tumor progression.AIM To characterize the expression of hypoxia-inducible factor 1-alpha(HIF-1α)at the invasive tumor front(ITF)in comparison to tumor islands(TI)in oral squamous cell carcinoma(OSCC)and to explore its relationship with E-cadherin and Vimentin expression.METHODS Thirty-eight cases of OSCC and five cases of normal oral mucosa(NOM)were included in this study.The ITF was identified based on the region and immune expression of AE1/AE3.Immunohistochemistry was performed to assess the expression of HIF-1α,Vimentin,and E-cadherin.The immunostaining was analyzed using an immunoreactive score,and the results were illustrated using immunofluorescence.RESULTS HIF-1αexpression was significantly higher in the TI region compared to the ITF region(P=0.0134).Additionally,a significant difference was observed between TI and NOM(P=0.0115).In the ITF regions,HIF-1αexpression showed a significant correlation with Vimentin expression,with higher levels of HIF-1αassociated with increased Vimentin expression(P=0.017).CONCLUSION Based on the results of this study,HIF-1αappears to play a distinct role in OSCC tumor progression,underscoring the importance of exploring hypoxia-driven changes in cellular phenotype at the ITF of OSCC.Further research is needed to better understand their impact on OSCC prognosis.展开更多
Objective MicroRNA-1(miR-1)aggravates myocardial ischemia–reperfusion(I/R)injury,whereas insulin-like growth factor-1(IGF-1)maintains cardiomyocyte homeostasis.In this study,the aim is to investigate whether miR-1 ca...Objective MicroRNA-1(miR-1)aggravates myocardial ischemia–reperfusion(I/R)injury,whereas insulin-like growth factor-1(IGF-1)maintains cardiomyocyte homeostasis.In this study,the aim is to investigate whether miR-1 can exacerbate I/R injury through the regulation of IGF-1.Methods The infarct area,lactate dehydrogenase,miR-1 level,and apoptosis level were examined in the Langendorff isolated rat I/R model.The hypoxia–reoxygenation model of rat cardiacmyocytes and H9c2 cells were developed to determine the levels of miR-1,IGF-1 mRNA,and IGF-1 protein.Furthermore,the dual-luciferase assay was used to verify the relationship between miR-1 and IGF-1.Results Overexpression of miR-1 increased the level of apoptosis and decreased the IGF-1 expression.However,inhibition of miR-1 expression decreased the level of apoptosis,alleviated the degree of injury,and increased the IGF-1 expression.Overexpression of IGF-1 also reduced the degree of cellular damage and level of apoptosis caused by the overexpression of miR-1.When IGF-1 was knocked down,myocardial cells displayed more severe damage and a higher apoptosis level,even with decreased levels of miR-1.Conclusion miR-1 promotes apoptosis and aggravates I/R injury by downregulating IGF-1.展开更多
BACKGROUND Pancreatic cancer(PC)is associated with some of the worst prognoses of all major cancers.Thymoquinone(TQ)has a long history in traditional medical practice and is known for its anti-cancer,anti-inflammatory...BACKGROUND Pancreatic cancer(PC)is associated with some of the worst prognoses of all major cancers.Thymoquinone(TQ)has a long history in traditional medical practice and is known for its anti-cancer,anti-inflammatory,anti-fibrosis and antioxidant pharmacological activities.Recent studies on hypoxia-inducible factor-1α(HIF-1α)and PC have shown that HIF-1αaffects the occurrence and development of PC in many aspects.In addition,TQ could inhibit the development of renal cancer by decreasing the expression of HIF-1α.Therefore,we speculate whether TQ affects HIF-1αexpression in PC cells and explore the mechanism.AIM To elucidate the effect of TQ in PC cells and the regulatory mechanism of HIF-1αexpression.METHODS Cell counting kit-8 assay,Transwell assay and flow cytometry were performed to detect the effects of TQ on the proliferative activity,migration and invasion ability and apoptosis of PANC-1 cells and normal pancreatic duct epithelial(hTERTHPNE)cells.Quantitative real-time polymerase chain reaction and western blot assay were performed to detect the expression of HIF-1αmRNA and protein in PC cells.The effects of TQ on the HIF-1αprotein initial expression pathway and ubiquitination degradation in PANC-1 cells were examined by western blot assay and co-immunoprecipitation.RESULTS TQ significantly inhibited proliferative activity,migration,and invasion ability and promoted apoptosis of PANC-1 cells;however,no significant effects on hTERT-HPNE cells were observed.TQ significantly reduced the mRNA and protein expression levels of HIF-1αin PANC-1,AsPC-1,and BxPC-3 cells.TQ significantly inhibited the expression of the HIF-1αinitial expression pathway(PI3K/AKT/mTOR)related proteins,and promoted the ubiquitination degradation of the HIF-1αprotein in PANC-1 cells.TQ had no effect on the hydroxylation and von Hippel Lindau protein mediated ubiquitination degradation of the HIF-1αprotein but affected the stability of the HIF-1αprotein by inhibiting the interaction between HIF-1αand HSP90,thus promoting its ubiquitination degradation.CONCLUSION The regulatory mechanism of TQ on HIF-1αprotein expression in PC cells was mainly to promote the ubiquitination degradation of the HIF-1αprotein by inhibiting the interaction between HIF-1αand HSP90;Secondly,TQ reduced the initial expression of HIF-1αprotein by inhibiting the PI3K/AKT/mTOR pathway.展开更多
BACKGROUND Helicobacter pylori(H.pylori)colonizes the human gastric mucosa and is implicated in the development of gastric cancer(GC).The tumor microenvironment is characterized by hypoxia,where hypoxia-inducible fact...BACKGROUND Helicobacter pylori(H.pylori)colonizes the human gastric mucosa and is implicated in the development of gastric cancer(GC).The tumor microenvironment is characterized by hypoxia,where hypoxia-inducible factor-1α(HIF-1α)plays a key role as a transcription factor,but the mechanisms underlying H.pylori-induced HIF-1αexpression and carcinogenesis remain unclear.AIM To explore the underlying mechanism of H.pylori-induced HIF-1αexpression in promoting the malignant biological behavior of gastric epithelial cells(GES-1).METHODS The study was conducted with human GES-1 cells in vitro.Relative protein levels of methyltransferase-like protein 14(METTL14),HIF-1α,main proteins of the PI3K/AKT pathway,epithelial-mesenchymal transition(EMT)biomarkers,and invasion indicators were detected by Western blot.Relative mRNA levels of METTL14 and HIF-1αwere detected by quantitative reverse transcription-polymerase chain reaction.mRNA stability was evaluated using actinomycin D,and the interaction between METTL14 and HIF-1αwas confirmed by immunofluorescence staining.Cell proliferation and migration were evaluated by cell counting kit-8 assay and wound healing assay,respectively.RESULTS H.pylori promoted HIF-1αexpression and activated the PI3K/AKT pathway.Notably,METTL14 was downregulated in H.pylori-infected gastric mucosal epithelial cells and positively regulated HIF-1αexpression.Functional experiments showed that the overexpression of HIF-1αor knockdown of METTL14 enhanced the activity of the PI3K/AKT pathway,thereby driving a series of malignant transformation,such as EMT and cell proliferation,migration,and invasion.By contrast,the knockdown of HIF-1αor overexpression of METTL14 had an opposite effect.CONCLUSION H.pylori-induced underexpression of METTL14 promotes the translation of HIF-1αand accelerates tumor progression by activating the PI3K/AKT pathway.These results provide novel insights into the carcinogenesis of GC.展开更多
BACKGROUND Stromal cell derived factor-1(SDF-1)plays a pivotal role in the recruitment of stem cells to injured livers.However,the changes of SDF-l in patients with hepatitis B virus(HBV)-related acute-on-chronic live...BACKGROUND Stromal cell derived factor-1(SDF-1)plays a pivotal role in the recruitment of stem cells to injured livers.However,the changes of SDF-l in patients with hepatitis B virus(HBV)-related acute-on-chronic liver failure(ACLF)have yet to be elucidated.AIM To study the SDF-1 changes in patients with HBV-related ACLF.METHODS 30 patients with HBV-related ACLF,27 patients with chronic hepatitis B and 20 healthy individuals are involved in our study.The SDF-l mRNA expression in liver tissue was detected by quantitative real-time polymerase chain reaction.Immunohistochemical staining was performed to illustrate the expression of SDFl,CXC receptor 4(CXCR4)and Ki67.The serum SDF-l concentrations were also detected by enzyme-linked immunosorbent assays.RESULTS The expression of SDF-1 mRNA from ACLF patients was remarkably higher than that from other patients(both P<0.05).The expression of SDF-l,CXCR4 and Ki67 from ACLF were the highest among the three groups(all P<0.01).The serum SDF-l levels in ACLF patients were significantly lower than that in other patients(both P<0.01).Moreover,in ACLF patients,the serum SDF-1 Levels were positively correlated with serum total bilirubin and international normalized ratio.In addition,the serum SDF-l levels in survival were significantly lower compared with the non-survivals(P<0.05).The area under the curve for the serum SDF-1 level in predicting 28-d mortality was 0.722(P<0.05).CONCLUSION This study provides the SDF-1 changes in patients with HBV-related ACLF.The SDF-1 Level at admission may serve as a promising prognostic marker for predicting short-term prognosis.展开更多
BACKGROUND Acute myeloid leukemia(AML)is a disease in which immature hematopoietic cells accumulate in the bone marrow and continuously expand,inhibiting hematopoiesis.The treatment and prognosis of this disease have ...BACKGROUND Acute myeloid leukemia(AML)is a disease in which immature hematopoietic cells accumulate in the bone marrow and continuously expand,inhibiting hematopoiesis.The treatment and prognosis of this disease have always been unsatisfactory.AIM To investigate the correlation between vascular endothelial growth factor(VEGF)and transforming growth factor-β1(TGFβ1)expression and prognosis in older adults with AML.METHODS This study enrolled 80 patients with AML(AML group),including 36 with complete response(AML-CR),23 with partial response(AML-PR),and 21 with no response(AML-NR).The expression levels of VEGF and TGFβ1 were detected by reverse transcription polymerase chain reaction in bone marrow mononuclear cells isolated from 56 healthy controls.Kaplan-Meier analysis was performed to assess overall survival(OS)and progression-or disease-free survival(DFS).Prognostic risk factors were analyzed using a Cox proportional hazards model.RESULTS The AML group showed a VEGF level of 2.68±0.16.VEGF expression was lower in patients with AML-CR than those with AML-PR or AML-NR(P<0.05).TGFβ1 expression in the AML group was 0.33±0.05.Patients with AML-CR showed a higher TGFβ1 expression than those with AML-PR or AML-NR(P<0.05).VEGF and TGFβ1 expression in patients with AML was significantly correlated with the counts of leukocytes,platelets,hemoglobin,and peripheral blood immature cells(P<0.05);Kaplan-Meier survival analysis revealed that patients with high TGFβ1 expression had better OS and DFS than those with low TGFβ1 expression(P<0.05),whereas patients with low VEGF levels showed better OS and DFS than those with high VEGF levels(P<0.05).VEGF,TGFβ1,and platelet count were identified by the Cox proportional hazards model as independent risk factors for OS(P<0.05),while VEGF,TGFβ1,and white blood cell count were independent risk factors for DFS(P<0.05).CONCLUSION Decreased VEGF expression and increased TGFβ1 expression in patients with AML provide valuable references for determining and individualizing clinical treatment strategies.展开更多
Macrophages undergo dynamic transitions between M1 and M2 states,exerting profound influences on both inflammatory and regenerative processes.The biocompatible and wound-healing properties of decellularized amniotic m...Macrophages undergo dynamic transitions between M1 and M2 states,exerting profound influences on both inflammatory and regenerative processes.The biocompatible and wound-healing properties of decellularized amniotic membrane(d AM)make it a subject of exploration for its potential impact on the anti-inflammatory response of macrophages.Experimental findings unequivocally demonstrate that d AM promotes anti-inflammatory M2 polarization of macrophage,with its cytokine-rich content posited as a potential mediator.The application of RNA sequencing unveils differential gene expression,implicating the hypoxia inducible factor-1α(HIF-1α)signaling pathway in this intricate interplay.Subsequent investigation further demonstrates that d AM facilitates anti-inflammatory M2 polarization of macrophage through the upregulation of epidermal growth factor(EGF),which,in turn,activates the phosphatidylinositol 3-kinase(PI3K)/protein kinase B(AKT)pathway and stabilizes HIF-1α.This cascade results in a noteworthy augmentation of anti-inflammatory gene expression.This study significantly contributes to advancing our comprehension of d AM's immunomodulatory role in tissue repair,thereby suggesting promising therapeutic potential.展开更多
目的探讨幽门螺杆菌(Hp)阳性早期胃癌患者肿瘤组织中转化生长因子-β_(1)(TGF-β_(1))mRNA、金属基质蛋白酶-2(MMP-2)mRNA、青霉素结合蛋白1A(PBP1A)m RNA表达水平与复发的关系,并分析其对复发的预测价值。方法选取2018年3月至2023年7...目的探讨幽门螺杆菌(Hp)阳性早期胃癌患者肿瘤组织中转化生长因子-β_(1)(TGF-β_(1))mRNA、金属基质蛋白酶-2(MMP-2)mRNA、青霉素结合蛋白1A(PBP1A)m RNA表达水平与复发的关系,并分析其对复发的预测价值。方法选取2018年3月至2023年7月南阳市中心医院收治的214例Hp阳性早期胃癌患者进行前瞻性研究,所有患者均行内镜黏膜下剥离术(ESD),采用实时荧光定量聚合酶链反应(qRT-PCR)法检测肿瘤组织、癌旁组织中TGF-β_(1)m RNA、MMP-2 m RNA、PBP1A m RNA表达水平,并分析其与临床病理特征相关性。依据ESD术后是否复发分为复发组、未复发组,采用q RT-PCR法检测两组患者的TGF-β_(1)m RNA、MMP-2 m RNA、PBP1A m RNA表达水平。采用偏相关性分析肿瘤组织中TGF-β_(1)m RNA、MMP-2 m RNA、PBP1A m RNA表达水平与复发的关系。采用受试者工作特征(ROC)曲线分析TGF-β_(1)m RNA、MMP-2 mRNA、PBP1A m RNA表达水平对复发的预测价值。结果肿瘤组织中TGF-β_(1)mRNA、MMP-2 m RNA表达水平分别为1.04±0.26、1.45±0.31,明显高于癌旁组织的0.85±0.14、1.18±0.25,PBP1A m RNA表达水平为0.31±0.10,明显低于癌旁组织的0.43±0.12,差异均有统计学意义(P<0.05);列联相关系数C分析显示,肿瘤组织中TGF-β_(1)mRNA、MMP-2 m RNA表达水平与临床分期、浸润深度、淋巴结转移呈正相关(P<0.05),与分化程度呈负相关(P<0.05),而PBP1A m RNA表达水平与临床分期、浸润深度、淋巴结转移呈负相关(P<0.05),与分化程度呈正相关(P<0.05);复发组患者的TGF-β_(1)mRNA、MMP-2 m RNA表达水平分别为1.31±0.25、1.74±0.31,明显高于未复发组的1.01±0.20、1.42±0.25,PBP1A mRNA表达水平为0.18±0.05,明显低于未复发组的0.32±0.10,差异均有统计学意义(P<0.05);偏相关性分析显示,肿瘤组织中TGF-β_(1)mRNA、MMP-2m RNA、PBP1A m RNA表达水平与复发显著相关(P<0.05);TGF-β_(1)mRNA、MMP-2 mRNA、PBP1A mRNA单项及联合预测复发的曲线下面积(AUC)分别为0.755、0.742、0.795、0.915,敏感度为75.00%、70.00%、75.00%、80.00%,特异度为72.25%、67.54%、76.95%、95.81%,且预测效能显著高于各指标单独预测价值(Z=2.376、2.413、1.997,P=0.018、0.016、0.046)。结论Hp阳性早期胃癌患者肿瘤组织中TGF-β_(1)m RNA、MMP-2 m RNA表达水平升高,PBP1A m RNA表达水平降低,且与临床病理特征、复发密切相关,联合检测其水平对复发具有较高的预测价值。展开更多
This study investigated the regulatory potential of salidroside(SAL),a primary active compound in Rhodiola rosea L.,on osteoclast differentiation by modulating the hypoxia-inducible factor 1-alpha(HIF-1α)pathway in o...This study investigated the regulatory potential of salidroside(SAL),a primary active compound in Rhodiola rosea L.,on osteoclast differentiation by modulating the hypoxia-inducible factor 1-alpha(HIF-1α)pathway in osteoblasts.Luciferase reporter assay and chromatin immunoprecipitation(Ch IP)assay were employed to validate whether the receptor activator of nuclear factor-κB ligand(RANKL)is the downstream target gene of HIF-1αin osteoblasts.The study also utilized lipopolysaccharide(LPS)-induced mouse osteolysis to examine the impact of SAL on osteolysis in vivo.Furthermore,conditioned medium(CM)from SAL-pretreated osteoblasts was used to investigate the paracrine effects on osteoclastogenesis through the HIF-1αpathway.Hypoxic condition-induced overexpression of HIF-1αupregulated RANKL levels by binding to the RANKL promoter and enhancing transcription in osteoblastic cells.In vivo,SAL significantly alleviated bone tissue hypoxia and decreased the expression of HIF-1αby downregulating the expression of RANKL,vascular endothelial growth factor(VEGF),interleukin 6(IL-6),and angiopoietin-like 4(ANGPTL4).In the paracrine experiment,conditioned media from SAL-pretreated osteoblasts inhibited differentiation through the HIF-1α/RANKL,VEGF,IL-6,and ANGPTL4 pathways.RANKL emerges as the downstream target gene regulated by HIF-1αin osteoblasts.SAL significantly alleviates bone tissue hypoxia and bone loss in LPS-induced osteolysis through the HIF-1α/RANKL,VEGF,IL-6,and ANGPTL4 pathways.SAL inhibits osteoclast differentiation by regulating osteoblast paracrine secretion.展开更多
Objective: To investigate the specific mechanism of hypoxia-inducible factor 1 alpha (HIF-1α) in the regulation of human sperm apoptosis, and to provide a new theoretical reference and scientific basis for the diagno...Objective: To investigate the specific mechanism of hypoxia-inducible factor 1 alpha (HIF-1α) in the regulation of human sperm apoptosis, and to provide a new theoretical reference and scientific basis for the diagnosis and treatment of asthenospermia and other related conditions. Methods: Semen samples were categorized into the normal group and asthenospermia group based on sperm motility criteria. HIF-1α interfering agent cobalt chloride (CoCl2) and guanylate cyclase activator (Lificiguat, YC-1) were added respectively, with a control group established accordingly. Sperm motility (using anterior viability rate as an index), apoptosis level, ATP level, mitochondrial membrane potential, and reactive oxygen species (ROS) level were measured. The expression levels of HIF-1α, p-PI3K, and Bcl-2 in the samples were analyzed using Western blotting. Results: Following CoCl2 treatment, there was a significant increase in sperm apoptosis compared to the normal control group (12.51% ± 2.50% VS 11.15% ± 2.42%);additionally, sperm motility (45.34% ± 3.37% VS 51.36% ± 11.68%), ATP production (11.51 ± 2.87 nM/µL VS 14.99 ± 2.83 nM/µL), ROS levels, and mitochondrial membrane potential all decreased significantly (all P α and p-PI3K increased significantly while Bcl-2 expression decreased (all P α in the YC-1 treatment group were decreased, and the expression level of Bcl-2 was increased (all P α can influence human sperm apoptosis and motility through the PI3K signaling pathway.展开更多
AIM:To explore the impact of insulin-like growth factor-1 receptorα(IGF-1Rα)on the differentiation fate of optic-cupderived retinal stem cells(OC-RSCs)into retinal ganglion cells(RGCs)in vitro.METHODS:OC-RSCs were i...AIM:To explore the impact of insulin-like growth factor-1 receptorα(IGF-1Rα)on the differentiation fate of optic-cupderived retinal stem cells(OC-RSCs)into retinal ganglion cells(RGCs)in vitro.METHODS:OC-RSCs were isolated from optic cups of rats on embryonic day 12.5,and high-purity OC-RSCs were obtained by conditioned culture and passage.Differentiation of OC-RSCs into RGCs under different serum concentrations was examined using flow cytometry,and the serum concentration with high interference with differentiation ratio was selected.Furthermore,the effect of blocking IGF-1Rαon the differentiation of OC-RSCs into RGCs was analyzed through immunocytochemistry and Western blotting.RESULTS:Immunohistochemical analysis revealed IGF-1Rαwas highly expressed in rat embryos at day 12.5.OC-RSCs were isolated and purified,and high-purity OCRSCs were obtained.When 2.5%serum was administered,the ratio of differentiated RGCs(Thy-1.1 positive)decreased significantly,and the results of immunoblotting also confirmed the blockade of IGF-1Rαreduced Thy-1.1 protein expression.CONCLUSION:IGF-1Rαblocking can reduce the differentiation of OC-RSCs into RGCs.展开更多
BACKGROUND Bletilla striata polysaccharides(BSP)have antioxidant,immune regulation,and anti-fibrotic activities.However,the therapeutic effect and mechanisms underlying the action of BSP in metabolic dysfunction-assoc...BACKGROUND Bletilla striata polysaccharides(BSP)have antioxidant,immune regulation,and anti-fibrotic activities.However,the therapeutic effect and mechanisms underlying the action of BSP in metabolic dysfunction-associated steatotic liver disease(MASLD)have not been fully understood.AIMTo investigate the therapeutic effects and mechanisms of BSP on MASLD by centering on the hepatocyte nuclearfactor kappa B p65(RelA)/hepatocyte nuclear factor-1 alpha(HNF1α)signaling.METHODSA mouse model of MASLD was induced by feeding with a high-fat-diet(HFD)and a hepatocyte model of steatosiswas induced by treatment with sodium oleate(SO)and sodium palmitate(SP).The therapeutic effects of BSP onMASLD were examined in vivo and in vitro.The mechanisms underlying the action of BSP were analyzed for theireffect on lipid metabolism disorder,endoplasmic reticulum(ER)stress,and the RelA/HNF1αsignaling.RESULTSHFD feeding reduced hepatocyte RelA and HNF1αexpression,induced ER stress,lipid metabolism disorder,andnecroptosis in mice,which were significantly mitigated by treatment with BSP.Furthermore,treatment with BSP orBSP-containing conditional rat serum significantly attenuated the sodium oleate/sodium palmitate(SO/SP)-induced hepatocyte steatosis by decreasing lipid accumulation,and lipid peroxidation,and enhancing theexpression of RelA,and HNF1α.The therapeutic effects of BSP on MASLD were partially abrogated by RELAsilencing in mice and RELA knockout in hepatocytes.RELA silencing or knockout significantly down-regulatedHNF1αexpression,and remodeled ER stress and oxidative stress responses during hepatic steatosis.CONCLUSIONTreatment with BSP ameliorates MASLD,associated with enhancing the RelA/HNF1αsignaling,remodeling ERstress and oxidative stress responses in hepatocytes.展开更多
Idiopathic pulmonary fibrosis(IPF)is a progressive and fatal interstitial lung disease characterized by excessive fibrotic remodeling,for which effective therapeutic options remain severely limited.Among the pathogeni...Idiopathic pulmonary fibrosis(IPF)is a progressive and fatal interstitial lung disease characterized by excessive fibrotic remodeling,for which effective therapeutic options remain severely limited.Among the pathogenic mechanisms implicated in IPF,epithelial-to-mesenchymal transition(EMT)is recognized as a pivotal driver of fibroblast activation and extracellular matrix deposition.In this study,we aimed to develop low-molecular-weight dextran sulfate sodium(LMW-DSS)derivatives and assess their capacity to interfere with EMT,thereby offering novel therapeutic avenues for IPF management.Starting with dextran(2 kDa)as a precursor,we successfully synthesized two sulfated derivatives,DSS-LS and DSS-HS,via distinct sulfonation processes.Using a TGF-β1-stimulated A549 alveolar epithelial cell model,we demonstrated that LMW-DSS compounds exhibited no cytotoxicity,as validated by CCK-8 viability assays.Importantly,Transwell migration assays revealed that LMW-DSS markedly attenuated TGF-β1-induced A549 cell migration,indicating a potent anti-fibrotic effect.Moreover,qPCR and Western blotting analyses confirmed that LMW-DSS significantly suppressed the expression and secretion of key pro-fibrotic mediators,including TGF-β1 and VEGF-A,and downregulated critical EMT-associated markers such as Snail and vimentin.Notably,reducedα-SMA expression following LMW-DSS treatment further substantiated its role in hindering EMT progression.Collectively,these findings highlighted the capacity of LMW-DSS to effectively impede EMT and fibrotic processes,thereby delaying the progression of pulmonary fibrosis.This work not only underscored the therapeutic potential of LMW-DSS in IPF but also provided compelling experimental evidence to support its development as a promising anti-fibrotic agent for clinical application.展开更多
基金Support was provided by a Career Development Award (RCR, BX001284) from the Veterans Administration
文摘The hypoxia inducible factors （Hifs） are evolutionarily conserved transcriptional factors that control homeostatic responses to low oxygen. In developing bone, Hif-1 generated signals induce angiogenesis necessary for osteoblast specification, but in mature bone, loss of Hif-1 in osteoblasts resulted in a more rapid accumulation of bone. These findings suggested that Hif-1 exerts distinct developmental functions and acts as a negative regulator of bone formation. To investigate the function of Hif-1a in osteoanabolic signaling, we assessed the effect of Hif-1a loss-of-function on bone formation in response to intermittent parathyroid hormone （PTH）. Mice lacking Hif-1a in osteoblasts and osteocytes form more bone in response to PTH, likely through a larger increase in osteoblast activity and increased sensitivity to the hormone. Consistent with this effect, exposure of primary mouse osteoblasts to PTH resulted in the rapid induction of Hif-1a protein levels via a post-transcriptional mechanism. The enhanced anabolic response appears to result from the removal of Hif-1a-mediated suppression of β-catenin transcriptional activity. Together, these data indicate that Hif-1a functions in the mature skeleton to restrict osteoanabolic signaling. The availability of pharmacological agents that reduce Hif-1a function suggests the value in further exploration of this pathway to optimize the therapeutic benefits of PTH.
基金supported by the National Natural Science Foundation of China,No.30471917 and 30770766
文摘Studies have demonstrated that DL-3-n-butylphthalide can significantly alleviate oxygen glucose deprivation-induced injury of human umbilical vein endothelial cells at least partly associated with its enhancement on oxygen glucose deprivation-induced hypoxia inducible factor-1α expression.In this study,we hypothesized that DL-3-n-butylphthalide can protect against oxygen glucose deprivation-induced injury of newborn rat brain microvascular endothelial cells by means of upregulating hypoxia inducible factor-1α expression.MTT assay and Hoechst staining results showed that DL-3-n-butylphthalide protected brain microvascular endothelial cells against oxygen glucose deprivation-induced injury in a dose-dependent manner.Western blot and immunofluorescent staining results further confirmed that the protective effect was related to upregulation of hypoxia inducible factor-1α.Real-time RT-PCR reaction results showed that DL-3-n-butylphthalide reduced apoptosis by inhibiting downregulation of pro-apoptotic gene caspase-3 mRNA expression and upregulation of apoptosis-executive protease bcl-2 mRNA expression;however,DL-3-n-butylphthalide had no protective effects on brain microvascular endothelial cells after knockdown of hypoxia inducible factor-1α by small interfering RNA.These findings suggest that DL-3-n-butylphthalide can protect brain microvascular endothelial cells against oxygen glucose deprivation-induced injury by upregulating bcl-2 expression and downregulating caspase-3 expression though hypoxia inducible factor-1α pathway.
基金Supported by the Henan Province Medical Science and Technology Tackling Plan Joint Construction Project,No.LHGJ20220684Zhengzhou University Tianjian Advanced Biomedical Laboratory Funding Project,No.BS20240101.
文摘BACKGROUND Hypoxia-inducible factor 1α(HIF-1α)plays a crucial role in the prognosis of breast cancer,but the current evidence remains inconclusive.AIM To provide comprehensive evidence about the correlation of altered HIF-1αexpression with overall survival(OS)and disease-free survival(DFS)in breast cancer patients.METHODS A systematic search was conducted in PubMed,Embase,and Web of Science databases to collect relevant articles that were published before April 8,2024.A meta-analysis was used to assess the impact of altered HIF-1αexpression on the OS and DFS of breast cancer patients.Subgroup and sensitivity analyses were also performed in this meta-analysis.RESULTS This meta-analysis included 40 studies.The average percentage of breast cancer patients with high HIF-1αexpression was 39.6%.The overall meta-analysis results demonstrated that high HIF-1αexpression is strongly linked to poor outcomes in patients of breast cancer.Compared with low HIF-1αexpression,the overall hazard ratio for OS in patients with high HIF-1αexpression was 1.47[95%confidence interval(CI):1.29-1.69],and the overall hazard ratio for DFS was 1.82(95%CI:1.56-2.12).Furthermore,both OS[1.18(95%CI:1.01-1.38)]and DFS[1.79(95%CI:1.03-3.11)]were markedly shorter in triple-negative breast cancer cases with high HIF-1αexpression.Subgroup analysis revealed that the antibody used to detect HIF-1αexpression affected only the correlation linking HIF-1αexpression to DFS in breast cancer patients(P=0.0004).Furthermore,the sensitivity analysis demonstrates that the overall conclusions of the meta-analysis were unaffected by the removal of individual studies.CONCLUSION Compared to patients with low HIF-1αexpression,those with high expression level had shorter OS and DFS.However,the prognostic significance of high HIF-1αexpression varies across molecularly stratified breast cancer cohorts needs to be further elucidated.
基金National Natural Science Foundation of China:Basic Research on the Mechanism of Organ Immune Damage and the Diagnosis and Treatment of Integrated Traditional Chinese and Western Medicine(No.32141005)。
文摘OBJECTIVE:To investigate the impact of Shenhua tablet(肾华片,SHT)on renal macrophage polarization and renal injury in mice with diabetic kidney disease(DKD)and to explore the potential mechanism involving the hypoxia-inducible factor-1α(HIF-1α)and pyruvate kinase M2(PKM2)signaling pathway,along with the glycolysis metabolism pathway.METHODS:The animals were divided into the following groups:Model,Control,dapagliflozin,SHT low-dose,SHT medium-dose,and SHT high-dose.We assessed 24-hour urine protein(24 h-UTP)levels,urinary albuminto-creatinine ratio,and regularly monitored fasting blood glucose during the treatment period.After treatment,we examined renal tissue structure,renal function(urea nitrogen,uric acid,creatinine,cystatin C,β2-microglobulin),and glycolysis in renal macrophages.Additionally,we observed macrophage polarization in renal tissue and measured inflammatory factors(tumor necrosis factor-α,interleukin-1β,interleukin-6,interleukin-10,monocyte chemoattractant protein-1)to assess the immunoinflammatory status of the renal tissue.Finally,we investigated the expression of the HIF-1α/PKM2 signaling pathway in macrophages to explore its role in the glycolysis process.RESULTS:SHT shows a beneficial effect in treating DKD by reducing 24 h-UTP,regulating blood glucose levels,improving renal tissue structure,protecting renal function,inhibiting macrophage glycolysis,reducing macrophage transformation to the M1 state,and suppressing the expression of the HIF-1α/PKM2 signaling pathway.CONCLUSION:SHT may exert renoprotective effects by inhibiting macrophage glycolysis via the HIF-1α/PKM2 signaling pathway.This inhibition decreases macrophage M1 polarization and reduces immunoinflammatory injury in the renal tissue of DKD mice.
基金Supported by Comisión Sectorial de Investigación Científica(CSIC-Research Group 88180)The Agencia Nacional de Investigación e Innovación/Sistema Nacional de Investigadores(ANII/SNI)The Programa de Desarrollo de las Ciencias Básicas(PEDECIBA),Uruguay.
文摘BACKGROUND Hypoxia in oral cancer promotes tumoral invasion by inducing epithelial-mesenchymal transition,leading to aggressive tumor progression.AIM To characterize the expression of hypoxia-inducible factor 1-alpha(HIF-1α)at the invasive tumor front(ITF)in comparison to tumor islands(TI)in oral squamous cell carcinoma(OSCC)and to explore its relationship with E-cadherin and Vimentin expression.METHODS Thirty-eight cases of OSCC and five cases of normal oral mucosa(NOM)were included in this study.The ITF was identified based on the region and immune expression of AE1/AE3.Immunohistochemistry was performed to assess the expression of HIF-1α,Vimentin,and E-cadherin.The immunostaining was analyzed using an immunoreactive score,and the results were illustrated using immunofluorescence.RESULTS HIF-1αexpression was significantly higher in the TI region compared to the ITF region(P=0.0134).Additionally,a significant difference was observed between TI and NOM(P=0.0115).In the ITF regions,HIF-1αexpression showed a significant correlation with Vimentin expression,with higher levels of HIF-1αassociated with increased Vimentin expression(P=0.017).CONCLUSION Based on the results of this study,HIF-1αappears to play a distinct role in OSCC tumor progression,underscoring the importance of exploring hypoxia-driven changes in cellular phenotype at the ITF of OSCC.Further research is needed to better understand their impact on OSCC prognosis.
基金supported by the National Natural Science Foundation of China(81473453,81673800)the Projects of International Science and Technology Cooperation in Henan(182102410084).
文摘Objective MicroRNA-1(miR-1)aggravates myocardial ischemia–reperfusion(I/R)injury,whereas insulin-like growth factor-1(IGF-1)maintains cardiomyocyte homeostasis.In this study,the aim is to investigate whether miR-1 can exacerbate I/R injury through the regulation of IGF-1.Methods The infarct area,lactate dehydrogenase,miR-1 level,and apoptosis level were examined in the Langendorff isolated rat I/R model.The hypoxia–reoxygenation model of rat cardiacmyocytes and H9c2 cells were developed to determine the levels of miR-1,IGF-1 mRNA,and IGF-1 protein.Furthermore,the dual-luciferase assay was used to verify the relationship between miR-1 and IGF-1.Results Overexpression of miR-1 increased the level of apoptosis and decreased the IGF-1 expression.However,inhibition of miR-1 expression decreased the level of apoptosis,alleviated the degree of injury,and increased the IGF-1 expression.Overexpression of IGF-1 also reduced the degree of cellular damage and level of apoptosis caused by the overexpression of miR-1.When IGF-1 was knocked down,myocardial cells displayed more severe damage and a higher apoptosis level,even with decreased levels of miR-1.Conclusion miR-1 promotes apoptosis and aggravates I/R injury by downregulating IGF-1.
基金Supported by Health Commission of Qinghai Province,No.2021-wjzdx-18.
文摘BACKGROUND Pancreatic cancer(PC)is associated with some of the worst prognoses of all major cancers.Thymoquinone(TQ)has a long history in traditional medical practice and is known for its anti-cancer,anti-inflammatory,anti-fibrosis and antioxidant pharmacological activities.Recent studies on hypoxia-inducible factor-1α(HIF-1α)and PC have shown that HIF-1αaffects the occurrence and development of PC in many aspects.In addition,TQ could inhibit the development of renal cancer by decreasing the expression of HIF-1α.Therefore,we speculate whether TQ affects HIF-1αexpression in PC cells and explore the mechanism.AIM To elucidate the effect of TQ in PC cells and the regulatory mechanism of HIF-1αexpression.METHODS Cell counting kit-8 assay,Transwell assay and flow cytometry were performed to detect the effects of TQ on the proliferative activity,migration and invasion ability and apoptosis of PANC-1 cells and normal pancreatic duct epithelial(hTERTHPNE)cells.Quantitative real-time polymerase chain reaction and western blot assay were performed to detect the expression of HIF-1αmRNA and protein in PC cells.The effects of TQ on the HIF-1αprotein initial expression pathway and ubiquitination degradation in PANC-1 cells were examined by western blot assay and co-immunoprecipitation.RESULTS TQ significantly inhibited proliferative activity,migration,and invasion ability and promoted apoptosis of PANC-1 cells;however,no significant effects on hTERT-HPNE cells were observed.TQ significantly reduced the mRNA and protein expression levels of HIF-1αin PANC-1,AsPC-1,and BxPC-3 cells.TQ significantly inhibited the expression of the HIF-1αinitial expression pathway(PI3K/AKT/mTOR)related proteins,and promoted the ubiquitination degradation of the HIF-1αprotein in PANC-1 cells.TQ had no effect on the hydroxylation and von Hippel Lindau protein mediated ubiquitination degradation of the HIF-1αprotein but affected the stability of the HIF-1αprotein by inhibiting the interaction between HIF-1αand HSP90,thus promoting its ubiquitination degradation.CONCLUSION The regulatory mechanism of TQ on HIF-1αprotein expression in PC cells was mainly to promote the ubiquitination degradation of the HIF-1αprotein by inhibiting the interaction between HIF-1αand HSP90;Secondly,TQ reduced the initial expression of HIF-1αprotein by inhibiting the PI3K/AKT/mTOR pathway.
基金Supported by The Key Research and Development and Promotion Special Project of Henan Province,No.222102310069National Natural Science Foundation of China,No.82073618.
文摘BACKGROUND Helicobacter pylori(H.pylori)colonizes the human gastric mucosa and is implicated in the development of gastric cancer(GC).The tumor microenvironment is characterized by hypoxia,where hypoxia-inducible factor-1α(HIF-1α)plays a key role as a transcription factor,but the mechanisms underlying H.pylori-induced HIF-1αexpression and carcinogenesis remain unclear.AIM To explore the underlying mechanism of H.pylori-induced HIF-1αexpression in promoting the malignant biological behavior of gastric epithelial cells(GES-1).METHODS The study was conducted with human GES-1 cells in vitro.Relative protein levels of methyltransferase-like protein 14(METTL14),HIF-1α,main proteins of the PI3K/AKT pathway,epithelial-mesenchymal transition(EMT)biomarkers,and invasion indicators were detected by Western blot.Relative mRNA levels of METTL14 and HIF-1αwere detected by quantitative reverse transcription-polymerase chain reaction.mRNA stability was evaluated using actinomycin D,and the interaction between METTL14 and HIF-1αwas confirmed by immunofluorescence staining.Cell proliferation and migration were evaluated by cell counting kit-8 assay and wound healing assay,respectively.RESULTS H.pylori promoted HIF-1αexpression and activated the PI3K/AKT pathway.Notably,METTL14 was downregulated in H.pylori-infected gastric mucosal epithelial cells and positively regulated HIF-1αexpression.Functional experiments showed that the overexpression of HIF-1αor knockdown of METTL14 enhanced the activity of the PI3K/AKT pathway,thereby driving a series of malignant transformation,such as EMT and cell proliferation,migration,and invasion.By contrast,the knockdown of HIF-1αor overexpression of METTL14 had an opposite effect.CONCLUSION H.pylori-induced underexpression of METTL14 promotes the translation of HIF-1αand accelerates tumor progression by activating the PI3K/AKT pathway.These results provide novel insights into the carcinogenesis of GC.
基金Science and Technology Project of Hengshui,No.2019014061Z.
文摘BACKGROUND Stromal cell derived factor-1(SDF-1)plays a pivotal role in the recruitment of stem cells to injured livers.However,the changes of SDF-l in patients with hepatitis B virus(HBV)-related acute-on-chronic liver failure(ACLF)have yet to be elucidated.AIM To study the SDF-1 changes in patients with HBV-related ACLF.METHODS 30 patients with HBV-related ACLF,27 patients with chronic hepatitis B and 20 healthy individuals are involved in our study.The SDF-l mRNA expression in liver tissue was detected by quantitative real-time polymerase chain reaction.Immunohistochemical staining was performed to illustrate the expression of SDFl,CXC receptor 4(CXCR4)and Ki67.The serum SDF-l concentrations were also detected by enzyme-linked immunosorbent assays.RESULTS The expression of SDF-1 mRNA from ACLF patients was remarkably higher than that from other patients(both P<0.05).The expression of SDF-l,CXCR4 and Ki67 from ACLF were the highest among the three groups(all P<0.01).The serum SDF-l levels in ACLF patients were significantly lower than that in other patients(both P<0.01).Moreover,in ACLF patients,the serum SDF-1 Levels were positively correlated with serum total bilirubin and international normalized ratio.In addition,the serum SDF-l levels in survival were significantly lower compared with the non-survivals(P<0.05).The area under the curve for the serum SDF-1 level in predicting 28-d mortality was 0.722(P<0.05).CONCLUSION This study provides the SDF-1 changes in patients with HBV-related ACLF.The SDF-1 Level at admission may serve as a promising prognostic marker for predicting short-term prognosis.
基金the Ethic Committee of Suzhou Hospital of Anhui Medical University(Approval No.C2024003).
文摘BACKGROUND Acute myeloid leukemia(AML)is a disease in which immature hematopoietic cells accumulate in the bone marrow and continuously expand,inhibiting hematopoiesis.The treatment and prognosis of this disease have always been unsatisfactory.AIM To investigate the correlation between vascular endothelial growth factor(VEGF)and transforming growth factor-β1(TGFβ1)expression and prognosis in older adults with AML.METHODS This study enrolled 80 patients with AML(AML group),including 36 with complete response(AML-CR),23 with partial response(AML-PR),and 21 with no response(AML-NR).The expression levels of VEGF and TGFβ1 were detected by reverse transcription polymerase chain reaction in bone marrow mononuclear cells isolated from 56 healthy controls.Kaplan-Meier analysis was performed to assess overall survival(OS)and progression-or disease-free survival(DFS).Prognostic risk factors were analyzed using a Cox proportional hazards model.RESULTS The AML group showed a VEGF level of 2.68±0.16.VEGF expression was lower in patients with AML-CR than those with AML-PR or AML-NR(P<0.05).TGFβ1 expression in the AML group was 0.33±0.05.Patients with AML-CR showed a higher TGFβ1 expression than those with AML-PR or AML-NR(P<0.05).VEGF and TGFβ1 expression in patients with AML was significantly correlated with the counts of leukocytes,platelets,hemoglobin,and peripheral blood immature cells(P<0.05);Kaplan-Meier survival analysis revealed that patients with high TGFβ1 expression had better OS and DFS than those with low TGFβ1 expression(P<0.05),whereas patients with low VEGF levels showed better OS and DFS than those with high VEGF levels(P<0.05).VEGF,TGFβ1,and platelet count were identified by the Cox proportional hazards model as independent risk factors for OS(P<0.05),while VEGF,TGFβ1,and white blood cell count were independent risk factors for DFS(P<0.05).CONCLUSION Decreased VEGF expression and increased TGFβ1 expression in patients with AML provide valuable references for determining and individualizing clinical treatment strategies.
基金supported by the National Natural Science Foundation of China(No.82302772)Guizhou Basic Research Project(No.ZK[2023]General 201)partially supported by Wuhan Kangchuang Biotechnology Co.,Ltd。
文摘Macrophages undergo dynamic transitions between M1 and M2 states,exerting profound influences on both inflammatory and regenerative processes.The biocompatible and wound-healing properties of decellularized amniotic membrane(d AM)make it a subject of exploration for its potential impact on the anti-inflammatory response of macrophages.Experimental findings unequivocally demonstrate that d AM promotes anti-inflammatory M2 polarization of macrophage,with its cytokine-rich content posited as a potential mediator.The application of RNA sequencing unveils differential gene expression,implicating the hypoxia inducible factor-1α(HIF-1α)signaling pathway in this intricate interplay.Subsequent investigation further demonstrates that d AM facilitates anti-inflammatory M2 polarization of macrophage through the upregulation of epidermal growth factor(EGF),which,in turn,activates the phosphatidylinositol 3-kinase(PI3K)/protein kinase B(AKT)pathway and stabilizes HIF-1α.This cascade results in a noteworthy augmentation of anti-inflammatory gene expression.This study significantly contributes to advancing our comprehension of d AM's immunomodulatory role in tissue repair,thereby suggesting promising therapeutic potential.
文摘目的探讨幽门螺杆菌(Hp)阳性早期胃癌患者肿瘤组织中转化生长因子-β_(1)(TGF-β_(1))mRNA、金属基质蛋白酶-2(MMP-2)mRNA、青霉素结合蛋白1A(PBP1A)m RNA表达水平与复发的关系,并分析其对复发的预测价值。方法选取2018年3月至2023年7月南阳市中心医院收治的214例Hp阳性早期胃癌患者进行前瞻性研究,所有患者均行内镜黏膜下剥离术(ESD),采用实时荧光定量聚合酶链反应(qRT-PCR)法检测肿瘤组织、癌旁组织中TGF-β_(1)m RNA、MMP-2 m RNA、PBP1A m RNA表达水平,并分析其与临床病理特征相关性。依据ESD术后是否复发分为复发组、未复发组,采用q RT-PCR法检测两组患者的TGF-β_(1)m RNA、MMP-2 m RNA、PBP1A m RNA表达水平。采用偏相关性分析肿瘤组织中TGF-β_(1)m RNA、MMP-2 m RNA、PBP1A m RNA表达水平与复发的关系。采用受试者工作特征(ROC)曲线分析TGF-β_(1)m RNA、MMP-2 mRNA、PBP1A m RNA表达水平对复发的预测价值。结果肿瘤组织中TGF-β_(1)mRNA、MMP-2 m RNA表达水平分别为1.04±0.26、1.45±0.31,明显高于癌旁组织的0.85±0.14、1.18±0.25,PBP1A m RNA表达水平为0.31±0.10,明显低于癌旁组织的0.43±0.12,差异均有统计学意义(P<0.05);列联相关系数C分析显示,肿瘤组织中TGF-β_(1)mRNA、MMP-2 m RNA表达水平与临床分期、浸润深度、淋巴结转移呈正相关(P<0.05),与分化程度呈负相关(P<0.05),而PBP1A m RNA表达水平与临床分期、浸润深度、淋巴结转移呈负相关(P<0.05),与分化程度呈正相关(P<0.05);复发组患者的TGF-β_(1)mRNA、MMP-2 m RNA表达水平分别为1.31±0.25、1.74±0.31,明显高于未复发组的1.01±0.20、1.42±0.25,PBP1A mRNA表达水平为0.18±0.05,明显低于未复发组的0.32±0.10,差异均有统计学意义(P<0.05);偏相关性分析显示,肿瘤组织中TGF-β_(1)mRNA、MMP-2m RNA、PBP1A m RNA表达水平与复发显著相关(P<0.05);TGF-β_(1)mRNA、MMP-2 mRNA、PBP1A mRNA单项及联合预测复发的曲线下面积(AUC)分别为0.755、0.742、0.795、0.915,敏感度为75.00%、70.00%、75.00%、80.00%,特异度为72.25%、67.54%、76.95%、95.81%,且预测效能显著高于各指标单独预测价值(Z=2.376、2.413、1.997,P=0.018、0.016、0.046)。结论Hp阳性早期胃癌患者肿瘤组织中TGF-β_(1)m RNA、MMP-2 m RNA表达水平升高,PBP1A m RNA表达水平降低,且与临床病理特征、复发密切相关,联合检测其水平对复发具有较高的预测价值。
基金supported by grants from the National Natural Science Foundation of China(Nos.81572852 and 82104671)the Great Program of the Science Foundation of Tianjin(No.18JCZDJC33200)+1 种基金Heilongjiang Province Fund(No.LH2020H102)Tianjin Key Medical Discipline(Specialty)Construction Project(No.TJYXZDXK-032A)。
文摘This study investigated the regulatory potential of salidroside(SAL),a primary active compound in Rhodiola rosea L.,on osteoclast differentiation by modulating the hypoxia-inducible factor 1-alpha(HIF-1α)pathway in osteoblasts.Luciferase reporter assay and chromatin immunoprecipitation(Ch IP)assay were employed to validate whether the receptor activator of nuclear factor-κB ligand(RANKL)is the downstream target gene of HIF-1αin osteoblasts.The study also utilized lipopolysaccharide(LPS)-induced mouse osteolysis to examine the impact of SAL on osteolysis in vivo.Furthermore,conditioned medium(CM)from SAL-pretreated osteoblasts was used to investigate the paracrine effects on osteoclastogenesis through the HIF-1αpathway.Hypoxic condition-induced overexpression of HIF-1αupregulated RANKL levels by binding to the RANKL promoter and enhancing transcription in osteoblastic cells.In vivo,SAL significantly alleviated bone tissue hypoxia and decreased the expression of HIF-1αby downregulating the expression of RANKL,vascular endothelial growth factor(VEGF),interleukin 6(IL-6),and angiopoietin-like 4(ANGPTL4).In the paracrine experiment,conditioned media from SAL-pretreated osteoblasts inhibited differentiation through the HIF-1α/RANKL,VEGF,IL-6,and ANGPTL4 pathways.RANKL emerges as the downstream target gene regulated by HIF-1αin osteoblasts.SAL significantly alleviates bone tissue hypoxia and bone loss in LPS-induced osteolysis through the HIF-1α/RANKL,VEGF,IL-6,and ANGPTL4 pathways.SAL inhibits osteoclast differentiation by regulating osteoblast paracrine secretion.
文摘Objective: To investigate the specific mechanism of hypoxia-inducible factor 1 alpha (HIF-1α) in the regulation of human sperm apoptosis, and to provide a new theoretical reference and scientific basis for the diagnosis and treatment of asthenospermia and other related conditions. Methods: Semen samples were categorized into the normal group and asthenospermia group based on sperm motility criteria. HIF-1α interfering agent cobalt chloride (CoCl2) and guanylate cyclase activator (Lificiguat, YC-1) were added respectively, with a control group established accordingly. Sperm motility (using anterior viability rate as an index), apoptosis level, ATP level, mitochondrial membrane potential, and reactive oxygen species (ROS) level were measured. The expression levels of HIF-1α, p-PI3K, and Bcl-2 in the samples were analyzed using Western blotting. Results: Following CoCl2 treatment, there was a significant increase in sperm apoptosis compared to the normal control group (12.51% ± 2.50% VS 11.15% ± 2.42%);additionally, sperm motility (45.34% ± 3.37% VS 51.36% ± 11.68%), ATP production (11.51 ± 2.87 nM/µL VS 14.99 ± 2.83 nM/µL), ROS levels, and mitochondrial membrane potential all decreased significantly (all P α and p-PI3K increased significantly while Bcl-2 expression decreased (all P α in the YC-1 treatment group were decreased, and the expression level of Bcl-2 was increased (all P α can influence human sperm apoptosis and motility through the PI3K signaling pathway.
文摘AIM:To explore the impact of insulin-like growth factor-1 receptorα(IGF-1Rα)on the differentiation fate of optic-cupderived retinal stem cells(OC-RSCs)into retinal ganglion cells(RGCs)in vitro.METHODS:OC-RSCs were isolated from optic cups of rats on embryonic day 12.5,and high-purity OC-RSCs were obtained by conditioned culture and passage.Differentiation of OC-RSCs into RGCs under different serum concentrations was examined using flow cytometry,and the serum concentration with high interference with differentiation ratio was selected.Furthermore,the effect of blocking IGF-1Rαon the differentiation of OC-RSCs into RGCs was analyzed through immunocytochemistry and Western blotting.RESULTS:Immunohistochemical analysis revealed IGF-1Rαwas highly expressed in rat embryos at day 12.5.OC-RSCs were isolated and purified,and high-purity OCRSCs were obtained.When 2.5%serum was administered,the ratio of differentiated RGCs(Thy-1.1 positive)decreased significantly,and the results of immunoblotting also confirmed the blockade of IGF-1Rαreduced Thy-1.1 protein expression.CONCLUSION:IGF-1Rαblocking can reduce the differentiation of OC-RSCs into RGCs.
基金National Natural Science Foundation of China,No.32260089Science and Technology Research Foundation of Guizhou Province,No.QKHJC-ZK(2022)YB642+3 种基金Science and Technology Research Foundation of Hubei Province,No.2022BCE030Science and Technology Research Foundation of Changzhou City,No.CE20225040Science and Technology Research Foundation of Zunyi City,No.ZSKHHZ(2022)344 and No.ZSKHHZ(2022)360WBE Liver Fibrosis Foundation,No.CFHPC2025028.
文摘BACKGROUND Bletilla striata polysaccharides(BSP)have antioxidant,immune regulation,and anti-fibrotic activities.However,the therapeutic effect and mechanisms underlying the action of BSP in metabolic dysfunction-associated steatotic liver disease(MASLD)have not been fully understood.AIMTo investigate the therapeutic effects and mechanisms of BSP on MASLD by centering on the hepatocyte nuclearfactor kappa B p65(RelA)/hepatocyte nuclear factor-1 alpha(HNF1α)signaling.METHODSA mouse model of MASLD was induced by feeding with a high-fat-diet(HFD)and a hepatocyte model of steatosiswas induced by treatment with sodium oleate(SO)and sodium palmitate(SP).The therapeutic effects of BSP onMASLD were examined in vivo and in vitro.The mechanisms underlying the action of BSP were analyzed for theireffect on lipid metabolism disorder,endoplasmic reticulum(ER)stress,and the RelA/HNF1αsignaling.RESULTSHFD feeding reduced hepatocyte RelA and HNF1αexpression,induced ER stress,lipid metabolism disorder,andnecroptosis in mice,which were significantly mitigated by treatment with BSP.Furthermore,treatment with BSP orBSP-containing conditional rat serum significantly attenuated the sodium oleate/sodium palmitate(SO/SP)-induced hepatocyte steatosis by decreasing lipid accumulation,and lipid peroxidation,and enhancing theexpression of RelA,and HNF1α.The therapeutic effects of BSP on MASLD were partially abrogated by RELAsilencing in mice and RELA knockout in hepatocytes.RELA silencing or knockout significantly down-regulatedHNF1αexpression,and remodeled ER stress and oxidative stress responses during hepatic steatosis.CONCLUSIONTreatment with BSP ameliorates MASLD,associated with enhancing the RelA/HNF1αsignaling,remodeling ERstress and oxidative stress responses in hepatocytes.
基金the National Natural Science Foundation of China(Grant Nos.92478133,81930097,and 82151223)by the State Key Laboratory of Natural and Biomimetic Drugs(Grant No.K202430).
文摘Idiopathic pulmonary fibrosis(IPF)is a progressive and fatal interstitial lung disease characterized by excessive fibrotic remodeling,for which effective therapeutic options remain severely limited.Among the pathogenic mechanisms implicated in IPF,epithelial-to-mesenchymal transition(EMT)is recognized as a pivotal driver of fibroblast activation and extracellular matrix deposition.In this study,we aimed to develop low-molecular-weight dextran sulfate sodium(LMW-DSS)derivatives and assess their capacity to interfere with EMT,thereby offering novel therapeutic avenues for IPF management.Starting with dextran(2 kDa)as a precursor,we successfully synthesized two sulfated derivatives,DSS-LS and DSS-HS,via distinct sulfonation processes.Using a TGF-β1-stimulated A549 alveolar epithelial cell model,we demonstrated that LMW-DSS compounds exhibited no cytotoxicity,as validated by CCK-8 viability assays.Importantly,Transwell migration assays revealed that LMW-DSS markedly attenuated TGF-β1-induced A549 cell migration,indicating a potent anti-fibrotic effect.Moreover,qPCR and Western blotting analyses confirmed that LMW-DSS significantly suppressed the expression and secretion of key pro-fibrotic mediators,including TGF-β1 and VEGF-A,and downregulated critical EMT-associated markers such as Snail and vimentin.Notably,reducedα-SMA expression following LMW-DSS treatment further substantiated its role in hindering EMT progression.Collectively,these findings highlighted the capacity of LMW-DSS to effectively impede EMT and fibrotic processes,thereby delaying the progression of pulmonary fibrosis.This work not only underscored the therapeutic potential of LMW-DSS in IPF but also provided compelling experimental evidence to support its development as a promising anti-fibrotic agent for clinical application.
