Sortilin-related receptor 1(SORL1)is a critical gene associated with late-onset Alzheimer’s disease.SORL1 contributes to the development and progression of this neurodegenerative condition by affecting the transport ...Sortilin-related receptor 1(SORL1)is a critical gene associated with late-onset Alzheimer’s disease.SORL1 contributes to the development and progression of this neurodegenerative condition by affecting the transport and metabolism of intracellularβ-amyloid precursor protein.To better understand the underlying mechanisms of SORL1 in the pathogenesis of late-onset Alzheimer s disease,in this study,we established a mouse model of SorI1 gene knockout using cluste red regularly inters paced short palindro mic repeats-associated protein 9 technology.We found that Sorl1-knocko ut mice displayed deficits in learning and memory.Furthermore,the expression of brain-derived neurotrophic factor was significantly downregulated in the hippocampus and co rtex,and amyloidβ-protein deposits were observed in the brains of 5orl1-knockout mice.In vitro,hippocampal neuronal cell synapses from homozygous Sorl1-knockout mice were impaired.The expression of synaptic proteins,including Drebrin and NR2B,was significantly reduced,and also their colocalization.Additionally,by knocking out the Sorl1 gene in N2a cells,we found that expression of the N-methyl-D-aspartate receptor,NR2B,and cyclic adenosine monophosphate-response element binding protein was also inhibited.These findings suggest that SORL1 participates in the pathogenesis of late-onset Alzheimer s disease by regulating the N-methyl-D-aspartate receptor NR2B/cyclic adenosine monophosphate-response element binding protein signaling axis.展开更多
Fas-associated factor 1 (FAF1) is a scaffolding protein that plays multiple functions, and dysregulation of FAF1 is associated withmany types of diseases such as cancers. FAF1 contains multiple ubiquitin-related domai...Fas-associated factor 1 (FAF1) is a scaffolding protein that plays multiple functions, and dysregulation of FAF1 is associated withmany types of diseases such as cancers. FAF1 contains multiple ubiquitin-related domains (UBA, UBL1, UBL2, UAS, and UBX), eachdomain interacting with a specific partner. In particular, the interaction of UBL1 with heat shock protein 70 (Hsp70) is associatedwith tumor formation, although the molecular understanding remains unknown. In this study, the structural analysis revealed thatHis160 of FAF1 is important for its interaction with Hsp70. The association of Hsp70 with FAF1 is required for the interaction withIQGAP1. FAF1 negatively regulates RhoA activation by FAF1–Hsp70 complex formation, which then interacts with IQGAP1. Thesesteps play a key role in maintaining the stability of cell-to-cell junction. We conclude that FAF1 plays a critical role in the structureand function of adherens junction during tissue homeostasis and morphogenesis by suppressing RhoA activation, which induces theactivation of Rho-associated protein kinase, phosphorylation of myosin light chain, formation of actin stress fiber, and disruptionof adherens junction. In addition, depletion of FAF1 increased collective invasion in a 3D spheroid cell culture. These results provideinsightinto how the FAF1–Hsp70 complex acts as a novelregulator ofthe adherens junction integrity. The complex can be a potentialtherapeutic target to inhibit tumorigenesis and metastasis.展开更多
Diabetic cardiomyopathy is a disorder of the cardiac muscle that affects patients with diabetes.The exact mechanisms underlying diabetic cardiomyopathy are mostly unknown,but several factors have been implicated in th...Diabetic cardiomyopathy is a disorder of the cardiac muscle that affects patients with diabetes.The exact mechanisms underlying diabetic cardiomyopathy are mostly unknown,but several factors have been implicated in the pathogenesis of the disease and its progression towards heart failure,including endothelial dysfunction,autonomic neuropathy,metabolic alterations,oxidative stress,and alterations in ion homeostasis,especially calcium transients[1].In Military Medical Research,Jiang et al.[2]sought to determine the functional role of complement factor D(Adipsin)in the pathophysiology of diabetic cardiomyopathy.展开更多
Glioblastoma multiforme(GBM)is an aggressive primary brain tumor characterized by extensive heterogeneity and vascular proliferation.Hypoxic conditions in the tissue microenvironment are considered a pivotal player le...Glioblastoma multiforme(GBM)is an aggressive primary brain tumor characterized by extensive heterogeneity and vascular proliferation.Hypoxic conditions in the tissue microenvironment are considered a pivotal player leading tumor progression.Specifically,hypoxia is known to activate inducible factors,such as hypoxia-inducible factor 1alpha(HIF-1α),which in turn can stimulate tumor neo-angiogenesis through activation of various downward mediators,such as the vascular endothelial growth factor(VEGF).Here,we aimed to explore the role of HIF-1α/VEGF immunophenotypes alone and in combination with other prognostic markers or clinical and image analysis data,as potential biomarkers of GBM prognosis and treatment efficacy.We performed a systematic review(Medline/Embase,and Pubmed database search was completed by 16th of April 2024 by two independent teams;PRISMA 2020).We evaluated methods of immunoassays,cell viability,or animal or patient survival methods of the retrieved studies to assess unbiased data.We used inclusion criteria,such as the evaluation of GBM prognosis based on HIF-1α/VEGF expression,other biomarkers or clinical and imaging manifestations in GBM related to HIF-1α/VEGF expression,application of immunoassays for protein expression,and evaluation of the effectiveness of GBM therapeutic strategies based on HIF-1α/VEGF expression.We used exclusion criteria,such as data not reporting both HIF-1αand VEGF or prognosis.We included 50 studies investigating in total 1319 GBM human specimens,18 different cell lines or GBM-derived stem cells,and 6 different animal models,to identify the association of HIF-1α/VEGF immunophenotypes,and with other prognostic factors,clinical and macroscopic data in GBM prognosis and therapeutic approaches.We found that increased HIF-1α/VEGF expression in GBM correlates with oncogenic factors,such as miR-210-3p,Oct4,AKT,COX-2,PDGF-C,PLDO3,M2 polarization,or ALK,leading to unfavorable survival.Reduced HIF-1α/VEGF expression correlates with FIH-1,ADNP,or STAT1 upregulation,as well as with clinical manifestations,like epileptogenicity,and a favorable prognosis of GBM.Based on our data,HIF-1αor VEGF immunophenotypes may be a useful tool to clarify MRI-PET imaging data distinguishing between GBM tumor progression and pseudoprogression.Finally,HIF-1α/VEGF immunophenotypes can reflect GBM treatment efficacy,including combined first-line treatment with histone deacetylase inhibitors,thimerosal,or an active metabolite of irinotecan,as well as STAT3 inhibitors alone,and resulting in a favorable tumor prognosis and patient survival.These data were supported by a combination of variable methods used to evaluate HIF-1α/VEGF immunophenotypes.Data limitations may include the use of less sensitive detection methods in some cases.Overall,our data support HIF-1α/VEGF’s role as biomarkers of GBM prognosis and treatment efficacy.展开更多
Introduction:Chemokine-like factor 1(CKLF1)is a chemokine that is overexpressed in several diseases.Our previousfindings revealed a significant increase in CKLF1 expression in the ischemic brain,suggesting its potential...Introduction:Chemokine-like factor 1(CKLF1)is a chemokine that is overexpressed in several diseases.Our previousfindings revealed a significant increase in CKLF1 expression in the ischemic brain,suggesting its potential as a therapeutic target for ischemic stroke.Methods:In this study,we examined the expression dynamics of CKLF1 in both in vivo and in vitro models of ischemic cardiac injury.Myocardial infarction(MI)was induced in vivo by ligation of the left anterior descending artery(LAD)of the rat heart.The levels of CKLF1,Creatine Kinase MB Isoenzyme(CK-MB),and Lactate dehydrogenase(LDH)in the serum were detected using Enzyme-linked immunosorbent assay(ELISA).The expression of CKLF1 in the infarcted area was detected by immunohistochemistry,immunofluorescence,quantitative PCR(qPCR),and Western blotting(WB).H9C2 and AC16 cardiomyocytes cultured in vitro were subjected to oxygen and glucose deprivation(OGD).LDH was used to detect cell damage,and CKLF1 expression was detected by qPCR and WB.Results:CKLF1 mRNA and protein expression were significantly increased in h9c2 cells at 1.5 h and in AC16 cells at 4 h after OGD.The serum CK-MB in rats increased significantly on thefirst day after infarction,while the LDH concentration increased significantly on the third day after infarction.CKLF1 blood levels significantly increased on thefirst day following MI in rats.CKLF1 expression notably increased in the infarct area on days 1,3,and 7 post-MI.In MI tissue,CKLF1 colocalizes with cardiomyocytes,macrophages,and neutrophils.Conclusion:CKLF1 was substantially expressed during myocardial ischemia injury both in vivo and in vitro and was colocalized with macrophages and neutrophils,indicating that CKLF1 is expected to be a biomarker and a drug target for the treatment of myocardial infarction.展开更多
Hypoxia-inducible factor 1(HIF1)has a crucial function in the regulation of oxygen levels in mammalian cells,especially under hypoxic conditions.Its importance in cardiovascular diseases,particularly in cardiac ischem...Hypoxia-inducible factor 1(HIF1)has a crucial function in the regulation of oxygen levels in mammalian cells,especially under hypoxic conditions.Its importance in cardiovascular diseases,particularly in cardiac ischemia,is because of its ability to alleviate cardiac dysfunction.The oxygen-responsive subunit,HIF1α,plays a crucial role in this process,as it has been shown to have cardioprotective effects in myocardial infarction through regulating the expression of genes affecting cellular survival,angiogenesis,and metabolism.Furthermore,HIF1αexpression induced reperfusion in the ischemic skeletal muscle,and hypoxic skin wounds in diabetic animal models showed reduced HIF1αexpression.Increased expression of HIF1αhas been shown to reduce apoptosis and oxidative stress in cardiomyocytes during acute myocardial infarction.Genetic variations in HIF1αhave also been found to correlate with altered responses to ischemic cardiovascular disease.In addition,a link has been established between the circadian rhythm and hypoxic molecular signaling pathways,with HIF1αfunctioning as an oxygen sensor and circadian genes such as period circadian regulator 2 responding to changes in light.This editorial analyzes the relationship between HIF1αand the circadian rhythm and highlights its significance in myocardial adaptation to hypoxia.Understanding the changes in molecular signaling pathways associated with diseases,specifically cardiovascular diseases,provides the opportunity for innovative therapeutic interventions,especially in low-oxygen environments such as myocardial infarction.展开更多
Drought stress impairs crop growth and development.BEL1-like family transcription factors may be involved in plant response to drought stress,but little is known of the molecular mechanism by which these proteins regu...Drought stress impairs crop growth and development.BEL1-like family transcription factors may be involved in plant response to drought stress,but little is known of the molecular mechanism by which these proteins regulate plant response and defense to drought stress.Here we show that the BEL1-like transcription factor GhBLH5-A05 functions in cotton(Gossypium hirsutum)response and defense to drought stress.Expression of GhBLH5-A05 in cotton was induced by drought stress.Overexpression of GhBLH5-A05 in both Arabidopsis and cotton increased drought tolerance,whereas silencing GhBLH5-A05 in cotton resulted in elevated sensitivity to drought stress.GhBLH5-A05 binds to cis elements in the promoters of GhRD20-A09 and GhDREB2C-D05 to activate the expression of these genes.GhBLH5-A05 interacted with the KNOX transcription factor GhKNAT6-A03.Co-expression of GhBLH5-A05 and GhKNAT6-A03 increased the transcription of GhRD20-A09 and GhDREB2C-D05.We conclude that GhBLH5-A05 acts as a regulatory factor with GhKNAT6-A03 functioning in cotton response to drought stress by activating the expression of the drought-responsive genes GhRD20-A09 and GhDREB2C-D05.展开更多
BACKGROUND Gastrointestinal stromal tumors(GISTs)are typical gastrointestinal tract neoplasms.Imatinib is the first-line therapy for GIST patients.Drug resistance limits the long-term effectiveness of imatinib.The reg...BACKGROUND Gastrointestinal stromal tumors(GISTs)are typical gastrointestinal tract neoplasms.Imatinib is the first-line therapy for GIST patients.Drug resistance limits the long-term effectiveness of imatinib.The regulatory effect of insulin-like growth factor 2(IGF2)has been confirmed in various cancers and is related to resistance to chemotherapy and a worse prognosis.AIM To further investigate the mechanism of IGF2 specific to GISTs.METHODS IGF2 was screened and analyzed using Gene Expression Omnibus(GEO:GSE225819)data.After IGF2 knockdown or overexpression by transfection,the phenotypes(proliferation,migration,invasion,apoptosis)of GIST cells were characterized by cell counting kit 8,Transwell,and flow cytometry assays.We used western blotting to evaluate pathway-associated and epithelial-mesenchymal transition(EMT)-associated proteins.We injected transfected cells into nude mice to establish a tumor xenograft model and observed the occurrence and metastasis of GIST.RESULTS Data from the GEO indicated that IGF2 expression is high in GISTs,associated with liver metastasis,and closely related to drug resistance.GIST cells with high expression of IGF2 had increased proliferation and migration,invasiveness and EMT.Knockdown of IGF2 significantly inhibited those activities.In addition,OEIGF2 promoted GIST metastasis in vivo in nude mice.IGF2 activated IGF1R signaling in GIST cells,and IGF2/IGF1R-mediated glycolysis was required for GIST with liver metastasis.GIST cells with IGF2 knockdown were sensitive to imatinib treatment when IGF2 overexpression significantly raised imatinib resistance.Moreover,2-deoxy-D-glucose(a glycolysis inhibitor)treatment reversed IGF2 overexpressionmediated imatinib resistance in GISTs.CONCLUSION IGF2 targeting of IGF1R signaling inhibited metastasis and decreased imatinib resistance by driving glycolysis in GISTs.展开更多
Interfering with the ferroptosis pathway is a new strategy for the treatment of spinal cord injury.Fibroblast growth factor 21 can inhibit ferro ptosis and promote neurofunctional recovery,while heme oxygenase-1 is a ...Interfering with the ferroptosis pathway is a new strategy for the treatment of spinal cord injury.Fibroblast growth factor 21 can inhibit ferro ptosis and promote neurofunctional recovery,while heme oxygenase-1 is a regulator of iron and reactive oxygen species homeostasis.The relationship between heme oxygenase-1and ferroptosis remains controve rsial.In this study,we used a spinal co rd injury rat model to show that the levels of fibroblast growth factor 21 in spinal co rd tissue decreased after spinal cord injury.In addition,there was a significant aggravation of ferroptosis and a rapid increase in heme oxygenase-1 expression after spinal cord injury.Furthe r,heme oxygenase-1 aggravated fe rroptosis after spinal cord injury,while fibroblast growth factor 21 inhibited fe rroptosis by downregulating heme oxygenase-1.Thus,the activation of fibroblast growth factor 21 may provide a potential treatment for spinal co rd injury.These findings could provide a new potential mechanistic explanation for fibroblast growth factor 21 in the treatment of spinal cord injury.展开更多
This study aims to thoroughly investigate the axial power peaking factors (PPF) within the low-enriched uranium (LEU) core of the Ghana Research Reactor-1 (GHARR-1). This study uses advanced simulation tools, like the...This study aims to thoroughly investigate the axial power peaking factors (PPF) within the low-enriched uranium (LEU) core of the Ghana Research Reactor-1 (GHARR-1). This study uses advanced simulation tools, like the MCNPX code for analysing neutron behavior and the PARET/ANL code for understanding power variations, to get a clearer picture of the reactor’s performance. The analysis covers the initial six years of GHARR-1’s operation and includes projections for its whole 60-year lifespan. We closely observed the patterns of both the highest and average PPFs at 21 axial nodes, with measurements taken every ten years. The findings of this study reveal important patterns in power distribution within the core, which are essential for improving the safety regulations and fuel management techniques of the reactor. We provide a meticulous approach, extensive data, and an analysis of the findings, highlighting the significance of continuous monitoring and analysis for proactive management of nuclear reactors. The findings of this study not only enhance our comprehension of nuclear reactor safety but also carry significant ramifications for sustainable energy progress in Ghana and the wider global context. Nuclear engineering is essential in tackling global concerns, such as the demand for clean and dependable energy sources. Research on optimising nuclear reactors, particularly in terms of safety and efficiency, is crucial for the ongoing advancement and acceptance of nuclear energy.展开更多
Introduction: Infant and child mortality is a worldwide concern, but developing countries such as Mali are more affected. The aim of this study was to investigate morbidity and factors associated with mortality in chi...Introduction: Infant and child mortality is a worldwide concern, but developing countries such as Mali are more affected. The aim of this study was to investigate morbidity and factors associated with mortality in children aged 1 month to 15 years. Methodology: This was a cross-sectional study which took place from January 1 to December 31, 2020 covering children aged 1 month to 15 years hospitalized at the Kalaban-Coro CSRéf. Data were entered into Excel and analyzed using SPSS version 20 software. Results: Five hundred children aged 1 months to 15 years were included. The age range 1 to 5 years (53.6%) and male sex (58.2%) were the most represented. Malaria (72.2%), acute respiratory infections (6.2%) and diarrhea/dehydration (3%) were the main morbidities. Mortality was estimated at 10.6%, and the two main causes of death were malaria (56.6%) and acute respiratory infections (7.54%). Univariate analysis revealed a statistically significant association between the dependent variable (death) and age (p Conclusion: This study confirms the high rate of infant and child morbidity and mortality in our health facilities. Strengthening human resources and intensifying behavior-change communication can help reverse the trend.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
BACKGROUND Epidermal growth factor receptor(EGFR)mutation and c-ros oncogene 1(ROS1)rearrangement are key genetic alterations and predictive tumor markers for non-small cell lung cancer(NSCLC)and are typically conside...BACKGROUND Epidermal growth factor receptor(EGFR)mutation and c-ros oncogene 1(ROS1)rearrangement are key genetic alterations and predictive tumor markers for non-small cell lung cancer(NSCLC)and are typically considered to be mutually exc-lusive.EGFR/ROS1 co-mutation is a rare event,and the standard treatment appr-oach for such cases is still equivocal.CASE SUMMARY Herein,we report the case of a 64-year-old woman diagnosed with lung adenocar-cinoma,with concomitant EGFR L858R mutation and ROS1 rearrangement.The patient received two cycles of chemotherapy after surgery,but the disease prog-ressed.Following 1-month treatment with gefitinib,the disease progressed again.However,after switching to crizotinib,the lesion became stable.Currently,crizotinib has been administered for over 53 months with a remarkable treatment effect.CONCLUSION The efficacy of EGFR tyrosine kinase inhibitors and crizotinib was vastly different in this NSCLC patient with EGFR/ROS1 co-mutation.This report will aid future treatment of such patients.展开更多
Background and objective:Commonly plaguing in the frigid zone of the world,vitamin D deficiency,as indicated by low levels of 25-hydroxyvitamin D,exacerbated inflammatory responses and impaired endothelial function.Le...Background and objective:Commonly plaguing in the frigid zone of the world,vitamin D deficiency,as indicated by low levels of 25-hydroxyvitamin D,exacerbated inflammatory responses and impaired endothelial function.Leukoaraiosis(LA)is a prevalent cause of cognitive dysfunction in the elderly and is potentially associated with inflammatory responses.This study aimed to investigate the impact of vitamin D on the severity of LA.Methods:Patients with LA were categorized based on 3.0 T brain MRI findings into mild(N=43),moderate(N=40),or severe groups(N=29)using the Fazekas scale(scoring 1-6).A control group consisting of 41 healthy individuals was included.Serum fibrinogen C,homocysteine,plasma 25-hydroxyvitamin D,and intercellular cell adhesion molecule-1(ICAM-1)levels were measured using ELISA.Results:All LA severity groups exhibited lower plasma 25-hydroxyvitamin D levels compared to the control group,with a more pronounced decrease observed as LA severity increased.Low plasma 25-hydroxyvitamin D was identified as an independent risk factor for LA(P<0.05)according to Multiple logistic regression analysis.Additionally,a negative association was observed between 25-hydroxyvitamin D and vascular inflammatory factor ICAM-1.Conclusions:Disease severity positively correlated with levels of the inflammatory marker ICAM-1,worsening as plasma 25-hydroxyvitamin D concentration decreased.Low 25-hydroxyvitamin D emerged as an independent risk factor for LA,potentially exacerbating the inflammatory response.These findings suggest 25-hydroxyvitamin D supplementation as a potential therapeutic approach for LA.展开更多
基金supported by the Community Development Office of Hunan Provincial Science and Technology DepartmentChina,Nos.2020SK53613(to DH),21JJ31006(to DH)the Fundamental Research Funds of Central South University,Nos.CX20220375(to TX),2023zzts215(to MZ)。
文摘Sortilin-related receptor 1(SORL1)is a critical gene associated with late-onset Alzheimer’s disease.SORL1 contributes to the development and progression of this neurodegenerative condition by affecting the transport and metabolism of intracellularβ-amyloid precursor protein.To better understand the underlying mechanisms of SORL1 in the pathogenesis of late-onset Alzheimer s disease,in this study,we established a mouse model of SorI1 gene knockout using cluste red regularly inters paced short palindro mic repeats-associated protein 9 technology.We found that Sorl1-knocko ut mice displayed deficits in learning and memory.Furthermore,the expression of brain-derived neurotrophic factor was significantly downregulated in the hippocampus and co rtex,and amyloidβ-protein deposits were observed in the brains of 5orl1-knockout mice.In vitro,hippocampal neuronal cell synapses from homozygous Sorl1-knockout mice were impaired.The expression of synaptic proteins,including Drebrin and NR2B,was significantly reduced,and also their colocalization.Additionally,by knocking out the Sorl1 gene in N2a cells,we found that expression of the N-methyl-D-aspartate receptor,NR2B,and cyclic adenosine monophosphate-response element binding protein was also inhibited.These findings suggest that SORL1 participates in the pathogenesis of late-onset Alzheimer s disease by regulating the N-methyl-D-aspartate receptor NR2B/cyclic adenosine monophosphate-response element binding protein signaling axis.
基金Thisworkwas supported by the National Research Foundation of Korea(NRF)grant funded by the Ministry of Science and ICT(2017R1A2B3007224 and 2020R1A4A4079494 to E.E.K.2020R1F1A1055369 to K.-J.L.2019R1A2C2004052 to E.J.S.).S.S.and I.-K.S.were supported by Brain Korea 21 Plus(BK21 Plus)Project.
文摘Fas-associated factor 1 (FAF1) is a scaffolding protein that plays multiple functions, and dysregulation of FAF1 is associated withmany types of diseases such as cancers. FAF1 contains multiple ubiquitin-related domains (UBA, UBL1, UBL2, UAS, and UBX), eachdomain interacting with a specific partner. In particular, the interaction of UBL1 with heat shock protein 70 (Hsp70) is associatedwith tumor formation, although the molecular understanding remains unknown. In this study, the structural analysis revealed thatHis160 of FAF1 is important for its interaction with Hsp70. The association of Hsp70 with FAF1 is required for the interaction withIQGAP1. FAF1 negatively regulates RhoA activation by FAF1–Hsp70 complex formation, which then interacts with IQGAP1. Thesesteps play a key role in maintaining the stability of cell-to-cell junction. We conclude that FAF1 plays a critical role in the structureand function of adherens junction during tissue homeostasis and morphogenesis by suppressing RhoA activation, which induces theactivation of Rho-associated protein kinase, phosphorylation of myosin light chain, formation of actin stress fiber, and disruptionof adherens junction. In addition, depletion of FAF1 increased collective invasion in a 3D spheroid cell culture. These results provideinsightinto how the FAF1–Hsp70 complex acts as a novelregulator ofthe adherens junction integrity. The complex can be a potentialtherapeutic target to inhibit tumorigenesis and metastasis.
基金National Institutes of Health(NIH):National Heart,Lung,and Blood Institute(NHLBI:R01-HL164772,R01-HL159062,R01-HL146691,T32-HL144456)National Institute of Diabetes and Digestive and Kidney Diseases(NIDDK:R01-DK123259,R01-DK033823)+2 种基金National Center for Advancing Translational Sciences(NCATS:UL1-TR002556-06,UM1-TR004400)(to Gaetano Santulli)Diabetes Action Research and Education Foundation(to Gaetano Santulli)Monique Weill-Caulier and Irma T.Hirschl Trusts(to Gaetano Santulli).
文摘Diabetic cardiomyopathy is a disorder of the cardiac muscle that affects patients with diabetes.The exact mechanisms underlying diabetic cardiomyopathy are mostly unknown,but several factors have been implicated in the pathogenesis of the disease and its progression towards heart failure,including endothelial dysfunction,autonomic neuropathy,metabolic alterations,oxidative stress,and alterations in ion homeostasis,especially calcium transients[1].In Military Medical Research,Jiang et al.[2]sought to determine the functional role of complement factor D(Adipsin)in the pathophysiology of diabetic cardiomyopathy.
文摘Glioblastoma multiforme(GBM)is an aggressive primary brain tumor characterized by extensive heterogeneity and vascular proliferation.Hypoxic conditions in the tissue microenvironment are considered a pivotal player leading tumor progression.Specifically,hypoxia is known to activate inducible factors,such as hypoxia-inducible factor 1alpha(HIF-1α),which in turn can stimulate tumor neo-angiogenesis through activation of various downward mediators,such as the vascular endothelial growth factor(VEGF).Here,we aimed to explore the role of HIF-1α/VEGF immunophenotypes alone and in combination with other prognostic markers or clinical and image analysis data,as potential biomarkers of GBM prognosis and treatment efficacy.We performed a systematic review(Medline/Embase,and Pubmed database search was completed by 16th of April 2024 by two independent teams;PRISMA 2020).We evaluated methods of immunoassays,cell viability,or animal or patient survival methods of the retrieved studies to assess unbiased data.We used inclusion criteria,such as the evaluation of GBM prognosis based on HIF-1α/VEGF expression,other biomarkers or clinical and imaging manifestations in GBM related to HIF-1α/VEGF expression,application of immunoassays for protein expression,and evaluation of the effectiveness of GBM therapeutic strategies based on HIF-1α/VEGF expression.We used exclusion criteria,such as data not reporting both HIF-1αand VEGF or prognosis.We included 50 studies investigating in total 1319 GBM human specimens,18 different cell lines or GBM-derived stem cells,and 6 different animal models,to identify the association of HIF-1α/VEGF immunophenotypes,and with other prognostic factors,clinical and macroscopic data in GBM prognosis and therapeutic approaches.We found that increased HIF-1α/VEGF expression in GBM correlates with oncogenic factors,such as miR-210-3p,Oct4,AKT,COX-2,PDGF-C,PLDO3,M2 polarization,or ALK,leading to unfavorable survival.Reduced HIF-1α/VEGF expression correlates with FIH-1,ADNP,or STAT1 upregulation,as well as with clinical manifestations,like epileptogenicity,and a favorable prognosis of GBM.Based on our data,HIF-1αor VEGF immunophenotypes may be a useful tool to clarify MRI-PET imaging data distinguishing between GBM tumor progression and pseudoprogression.Finally,HIF-1α/VEGF immunophenotypes can reflect GBM treatment efficacy,including combined first-line treatment with histone deacetylase inhibitors,thimerosal,or an active metabolite of irinotecan,as well as STAT3 inhibitors alone,and resulting in a favorable tumor prognosis and patient survival.These data were supported by a combination of variable methods used to evaluate HIF-1α/VEGF immunophenotypes.Data limitations may include the use of less sensitive detection methods in some cases.Overall,our data support HIF-1α/VEGF’s role as biomarkers of GBM prognosis and treatment efficacy.
基金This work was supported by the National Natural Science Foundation of China(81873026,82074044,81900488,and 81730096)the Beijing Natural Science Foundation(7192135)+1 种基金the Health and Family Planning Commission of Hunan Province(202104010694)the Natural Science Foundation of Hunan Province(2022JJ80028,2023JJ60369).
文摘Introduction:Chemokine-like factor 1(CKLF1)is a chemokine that is overexpressed in several diseases.Our previousfindings revealed a significant increase in CKLF1 expression in the ischemic brain,suggesting its potential as a therapeutic target for ischemic stroke.Methods:In this study,we examined the expression dynamics of CKLF1 in both in vivo and in vitro models of ischemic cardiac injury.Myocardial infarction(MI)was induced in vivo by ligation of the left anterior descending artery(LAD)of the rat heart.The levels of CKLF1,Creatine Kinase MB Isoenzyme(CK-MB),and Lactate dehydrogenase(LDH)in the serum were detected using Enzyme-linked immunosorbent assay(ELISA).The expression of CKLF1 in the infarcted area was detected by immunohistochemistry,immunofluorescence,quantitative PCR(qPCR),and Western blotting(WB).H9C2 and AC16 cardiomyocytes cultured in vitro were subjected to oxygen and glucose deprivation(OGD).LDH was used to detect cell damage,and CKLF1 expression was detected by qPCR and WB.Results:CKLF1 mRNA and protein expression were significantly increased in h9c2 cells at 1.5 h and in AC16 cells at 4 h after OGD.The serum CK-MB in rats increased significantly on thefirst day after infarction,while the LDH concentration increased significantly on the third day after infarction.CKLF1 blood levels significantly increased on thefirst day following MI in rats.CKLF1 expression notably increased in the infarct area on days 1,3,and 7 post-MI.In MI tissue,CKLF1 colocalizes with cardiomyocytes,macrophages,and neutrophils.Conclusion:CKLF1 was substantially expressed during myocardial ischemia injury both in vivo and in vitro and was colocalized with macrophages and neutrophils,indicating that CKLF1 is expected to be a biomarker and a drug target for the treatment of myocardial infarction.
基金Supported by Croatian Ministry of Science and Education,Josip Juraj Strossmayer University of Osijek,Faculty of Dental Medicine and Health,Osijek,Croatia,No.IP7-FDMZ-2023West-Siberian Science and Education Center,Government of Tyumen District,Decree of 20.11.2020,No.928-rpMinistry of Science and Higher Education,No.FMEN 2022-0009.
文摘Hypoxia-inducible factor 1(HIF1)has a crucial function in the regulation of oxygen levels in mammalian cells,especially under hypoxic conditions.Its importance in cardiovascular diseases,particularly in cardiac ischemia,is because of its ability to alleviate cardiac dysfunction.The oxygen-responsive subunit,HIF1α,plays a crucial role in this process,as it has been shown to have cardioprotective effects in myocardial infarction through regulating the expression of genes affecting cellular survival,angiogenesis,and metabolism.Furthermore,HIF1αexpression induced reperfusion in the ischemic skeletal muscle,and hypoxic skin wounds in diabetic animal models showed reduced HIF1αexpression.Increased expression of HIF1αhas been shown to reduce apoptosis and oxidative stress in cardiomyocytes during acute myocardial infarction.Genetic variations in HIF1αhave also been found to correlate with altered responses to ischemic cardiovascular disease.In addition,a link has been established between the circadian rhythm and hypoxic molecular signaling pathways,with HIF1αfunctioning as an oxygen sensor and circadian genes such as period circadian regulator 2 responding to changes in light.This editorial analyzes the relationship between HIF1αand the circadian rhythm and highlights its significance in myocardial adaptation to hypoxia.Understanding the changes in molecular signaling pathways associated with diseases,specifically cardiovascular diseases,provides the opportunity for innovative therapeutic interventions,especially in low-oxygen environments such as myocardial infarction.
基金supported by the Project from the Ministry of Agriculture of China for Transgenic Research(2014ZX0800927B)the National Natural Science Foundation of China(31871667).
文摘Drought stress impairs crop growth and development.BEL1-like family transcription factors may be involved in plant response to drought stress,but little is known of the molecular mechanism by which these proteins regulate plant response and defense to drought stress.Here we show that the BEL1-like transcription factor GhBLH5-A05 functions in cotton(Gossypium hirsutum)response and defense to drought stress.Expression of GhBLH5-A05 in cotton was induced by drought stress.Overexpression of GhBLH5-A05 in both Arabidopsis and cotton increased drought tolerance,whereas silencing GhBLH5-A05 in cotton resulted in elevated sensitivity to drought stress.GhBLH5-A05 binds to cis elements in the promoters of GhRD20-A09 and GhDREB2C-D05 to activate the expression of these genes.GhBLH5-A05 interacted with the KNOX transcription factor GhKNAT6-A03.Co-expression of GhBLH5-A05 and GhKNAT6-A03 increased the transcription of GhRD20-A09 and GhDREB2C-D05.We conclude that GhBLH5-A05 acts as a regulatory factor with GhKNAT6-A03 functioning in cotton response to drought stress by activating the expression of the drought-responsive genes GhRD20-A09 and GhDREB2C-D05.
文摘BACKGROUND Gastrointestinal stromal tumors(GISTs)are typical gastrointestinal tract neoplasms.Imatinib is the first-line therapy for GIST patients.Drug resistance limits the long-term effectiveness of imatinib.The regulatory effect of insulin-like growth factor 2(IGF2)has been confirmed in various cancers and is related to resistance to chemotherapy and a worse prognosis.AIM To further investigate the mechanism of IGF2 specific to GISTs.METHODS IGF2 was screened and analyzed using Gene Expression Omnibus(GEO:GSE225819)data.After IGF2 knockdown or overexpression by transfection,the phenotypes(proliferation,migration,invasion,apoptosis)of GIST cells were characterized by cell counting kit 8,Transwell,and flow cytometry assays.We used western blotting to evaluate pathway-associated and epithelial-mesenchymal transition(EMT)-associated proteins.We injected transfected cells into nude mice to establish a tumor xenograft model and observed the occurrence and metastasis of GIST.RESULTS Data from the GEO indicated that IGF2 expression is high in GISTs,associated with liver metastasis,and closely related to drug resistance.GIST cells with high expression of IGF2 had increased proliferation and migration,invasiveness and EMT.Knockdown of IGF2 significantly inhibited those activities.In addition,OEIGF2 promoted GIST metastasis in vivo in nude mice.IGF2 activated IGF1R signaling in GIST cells,and IGF2/IGF1R-mediated glycolysis was required for GIST with liver metastasis.GIST cells with IGF2 knockdown were sensitive to imatinib treatment when IGF2 overexpression significantly raised imatinib resistance.Moreover,2-deoxy-D-glucose(a glycolysis inhibitor)treatment reversed IGF2 overexpressionmediated imatinib resistance in GISTs.CONCLUSION IGF2 targeting of IGF1R signaling inhibited metastasis and decreased imatinib resistance by driving glycolysis in GISTs.
基金supported by grants from Jiangsu Commission of Health,No.Z2021086(to XL)Science and Technology Program of Suzhou,Nos.SYSD2020008(to XL),SKYD2022012(to XL)+1 种基金Suzhou Municipal Health Commission,No.KJXW2020058(to XL)Science and Technology Program of Zhangjiagang,No.ZKS2018(to XL)。
文摘Interfering with the ferroptosis pathway is a new strategy for the treatment of spinal cord injury.Fibroblast growth factor 21 can inhibit ferro ptosis and promote neurofunctional recovery,while heme oxygenase-1 is a regulator of iron and reactive oxygen species homeostasis.The relationship between heme oxygenase-1and ferroptosis remains controve rsial.In this study,we used a spinal co rd injury rat model to show that the levels of fibroblast growth factor 21 in spinal co rd tissue decreased after spinal cord injury.In addition,there was a significant aggravation of ferroptosis and a rapid increase in heme oxygenase-1 expression after spinal cord injury.Furthe r,heme oxygenase-1 aggravated fe rroptosis after spinal cord injury,while fibroblast growth factor 21 inhibited fe rroptosis by downregulating heme oxygenase-1.Thus,the activation of fibroblast growth factor 21 may provide a potential treatment for spinal co rd injury.These findings could provide a new potential mechanistic explanation for fibroblast growth factor 21 in the treatment of spinal cord injury.
文摘This study aims to thoroughly investigate the axial power peaking factors (PPF) within the low-enriched uranium (LEU) core of the Ghana Research Reactor-1 (GHARR-1). This study uses advanced simulation tools, like the MCNPX code for analysing neutron behavior and the PARET/ANL code for understanding power variations, to get a clearer picture of the reactor’s performance. The analysis covers the initial six years of GHARR-1’s operation and includes projections for its whole 60-year lifespan. We closely observed the patterns of both the highest and average PPFs at 21 axial nodes, with measurements taken every ten years. The findings of this study reveal important patterns in power distribution within the core, which are essential for improving the safety regulations and fuel management techniques of the reactor. We provide a meticulous approach, extensive data, and an analysis of the findings, highlighting the significance of continuous monitoring and analysis for proactive management of nuclear reactors. The findings of this study not only enhance our comprehension of nuclear reactor safety but also carry significant ramifications for sustainable energy progress in Ghana and the wider global context. Nuclear engineering is essential in tackling global concerns, such as the demand for clean and dependable energy sources. Research on optimising nuclear reactors, particularly in terms of safety and efficiency, is crucial for the ongoing advancement and acceptance of nuclear energy.
文摘Introduction: Infant and child mortality is a worldwide concern, but developing countries such as Mali are more affected. The aim of this study was to investigate morbidity and factors associated with mortality in children aged 1 month to 15 years. Methodology: This was a cross-sectional study which took place from January 1 to December 31, 2020 covering children aged 1 month to 15 years hospitalized at the Kalaban-Coro CSRéf. Data were entered into Excel and analyzed using SPSS version 20 software. Results: Five hundred children aged 1 months to 15 years were included. The age range 1 to 5 years (53.6%) and male sex (58.2%) were the most represented. Malaria (72.2%), acute respiratory infections (6.2%) and diarrhea/dehydration (3%) were the main morbidities. Mortality was estimated at 10.6%, and the two main causes of death were malaria (56.6%) and acute respiratory infections (7.54%). Univariate analysis revealed a statistically significant association between the dependent variable (death) and age (p Conclusion: This study confirms the high rate of infant and child morbidity and mortality in our health facilities. Strengthening human resources and intensifying behavior-change communication can help reverse the trend.
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 Wu Jieping Medical Foundation,No.320.6750.2022-20-25and Chongqing Health Commission,No.[2020]68.
文摘BACKGROUND Epidermal growth factor receptor(EGFR)mutation and c-ros oncogene 1(ROS1)rearrangement are key genetic alterations and predictive tumor markers for non-small cell lung cancer(NSCLC)and are typically considered to be mutually exc-lusive.EGFR/ROS1 co-mutation is a rare event,and the standard treatment appr-oach for such cases is still equivocal.CASE SUMMARY Herein,we report the case of a 64-year-old woman diagnosed with lung adenocar-cinoma,with concomitant EGFR L858R mutation and ROS1 rearrangement.The patient received two cycles of chemotherapy after surgery,but the disease prog-ressed.Following 1-month treatment with gefitinib,the disease progressed again.However,after switching to crizotinib,the lesion became stable.Currently,crizotinib has been administered for over 53 months with a remarkable treatment effect.CONCLUSION The efficacy of EGFR tyrosine kinase inhibitors and crizotinib was vastly different in this NSCLC patient with EGFR/ROS1 co-mutation.This report will aid future treatment of such patients.
基金This work was supported by the National Natural Science Foundation of Heilongjiang Province of China(No.LH2020H051)Key R&D projects of Natural Science Foundation of Heilongjiang Province(No.2023ZX06C03)Foundation of Harbin Science Technology Bureau of China(No.2014RFQGJ042).
文摘Background and objective:Commonly plaguing in the frigid zone of the world,vitamin D deficiency,as indicated by low levels of 25-hydroxyvitamin D,exacerbated inflammatory responses and impaired endothelial function.Leukoaraiosis(LA)is a prevalent cause of cognitive dysfunction in the elderly and is potentially associated with inflammatory responses.This study aimed to investigate the impact of vitamin D on the severity of LA.Methods:Patients with LA were categorized based on 3.0 T brain MRI findings into mild(N=43),moderate(N=40),or severe groups(N=29)using the Fazekas scale(scoring 1-6).A control group consisting of 41 healthy individuals was included.Serum fibrinogen C,homocysteine,plasma 25-hydroxyvitamin D,and intercellular cell adhesion molecule-1(ICAM-1)levels were measured using ELISA.Results:All LA severity groups exhibited lower plasma 25-hydroxyvitamin D levels compared to the control group,with a more pronounced decrease observed as LA severity increased.Low plasma 25-hydroxyvitamin D was identified as an independent risk factor for LA(P<0.05)according to Multiple logistic regression analysis.Additionally,a negative association was observed between 25-hydroxyvitamin D and vascular inflammatory factor ICAM-1.Conclusions:Disease severity positively correlated with levels of the inflammatory marker ICAM-1,worsening as plasma 25-hydroxyvitamin D concentration decreased.Low 25-hydroxyvitamin D emerged as an independent risk factor for LA,potentially exacerbating the inflammatory response.These findings suggest 25-hydroxyvitamin D supplementation as a potential therapeutic approach for LA.
