Magnolol,a compound extracted from Magnolia officinalis,demonstrates potential efficacy in addressing metabolic dysfunction and cardiovascular diseases.Its biological activities encompass anti-inflammatory,antioxidant...Magnolol,a compound extracted from Magnolia officinalis,demonstrates potential efficacy in addressing metabolic dysfunction and cardiovascular diseases.Its biological activities encompass anti-inflammatory,antioxidant,anticoagulant,and anti-diabetic effects.Growth/differentiation factor-15(GDF-15),a member of the transforming growth factorβsuperfamily,is considered a potential therapeutic target for metabolic disorders.This study investigated the impact of magnolol on GDF-15 production and its underlying mechanism.The research examined the pharmacological effect of magnolol on GDF-15 expression in vitro and in vivo,and determined the involvement of endoplasmic reticulum(ER)stress signaling in this process.Luciferase reporter assays,chromatin immunoprecipitation,and in vitro DNA binding assays were employed to examine the regulation of GDF-15 by activating transcription factor 4(ATF4),CCAAT enhancer binding proteinγ(CEBPG),and CCCTC-binding factor(CTCF).The study also investigated the effect of magnolol and ATF4 on the activity of a putative enhancer located in the intron of the GDF-15 gene,as well as the influence of single nucleotide polymorphisms(SNPs)on magnolol and ATF4-induced transcription activity.Results demonstrated that magnolol triggers GDF-15 production in endothelial cells(ECs),hepatoma cell line G2(HepG2)and hepatoma cell line 3B(Hep3B)cell lines,and primary mouse hepatocytes.The cooperative binding of ATF4 and CEBPG upstream of the GDF-15 gene or the E1944285 enhancer located in the intron led to full-power transcription of the GDF-15 gene.SNP alleles were found to impact the magnolol and ATF4-induced transcription activity of GDF-15.In high-fat diet ApoE^(-/-)mice,administration of magnolol induced GDF-15 production and partially suppressed appetite through GDF-15.These findings suggest that magnolol regulates GDF-15 expression through priming of promoter and enhancer activity,indicating its potential as a drug for the treatment of metabolic disorders.展开更多
BACKGROUND Noninvasive tests are crucial for the management and follow-up of patients with autoimmune hepatitis,but their validation is limited because of insufficient data.AIM To investigate the diagnostic performanc...BACKGROUND Noninvasive tests are crucial for the management and follow-up of patients with autoimmune hepatitis,but their validation is limited because of insufficient data.AIM To investigate the diagnostic performance of three fibrosis noninvasive tests[FibroTest,vibration-controlled transient elastography(VCTE),and the fibrosis-4 index(FIB-4)and two activity biomarkers(alanine aminotransferase(ALT)and ActiTest].METHODS This study enrolled 103 patients for whom liver biopsy,hepatic elastography results,and laboratory markers were available.Diagnostic performance was assessed with receiver operating characteristic(ROC)curves,the Obuchowski measure(OM),and the Bayesian latent class model.RESULTS FibroTest and VCTE outperformed FIB-4 in cases of significant fibrosis(≥F2),with areas under the ROC curve of 0.83[95%confidence interval(CI):0.73-0.90],0.86(95%CI:0.77-0.92),and 0.71(95%CI:0.60-0.80),respectively.The mean(standard error)OM values were 0.92(0.01),0.93(0.01),and 0.88(0.02)for FibroTest,VCTE,and FIB-4,respectively;FibroTest and VCTE performed comparably,and both were superior to FIB-4(P=0.03 and P=0.005).The areas under the ROC curve values for activity biomarkers were 0.86(95%CI:0.76-0.92)for ActiTest and 0.84(95%CI:0.73-0.90)for ALT(P=0.06).The OM values for ActiTest and ALT were 0.92(0.02)and 0.90(0.02),respectively(P=0.005).CONCLUSION FibroTest and VCTE outperformed FIB-4 according to the OM.FibroTest-ActiTest facilitated the evaluation of both fibrosis and activity.展开更多
Hepatocellular carcinoma(HCC)remains a leading cause of cancer-related mortality globally,with limited therapeutic progress for advanced stages.The aberrant fibroblast growth factor 19(FGF19)-fibroblast growth factor ...Hepatocellular carcinoma(HCC)remains a leading cause of cancer-related mortality globally,with limited therapeutic progress for advanced stages.The aberrant fibroblast growth factor 19(FGF19)-fibroblast growth factor receptor 4(FGFR4)axis promotes oncogenesis and is linked to targeted-immunotherapy of HCC.Multi-kinase inhibitors(MKIs)enhance anti-tumor effects by targeting this axis and FGF19 overexpression upregulates programmed cell death ligand 1 in tumor microenvironment.Clinical studies have demonstrated the efficacy of selective FGFR4 inhibitors in HCC treatment,with enhanced anti-tumor effects when combined with MKIs or immune checkpoint inhibitors.Phase I clinical trials of Irpagratinib(ABSK-011)demonstrated an objective response rate of 43.5%,which increased to 55.6%combined with atezolizumab.FGF19 also serves as a biomarker for HCC.This review systematically summarizes the literature retri-eved from PubMed and other databases using search terms“HCC”,“fibroblast growth factor 19”,“fibroblast growth factor receptor 4”,“FGFR4 inhibitor”,“targeted therapy”,“multi-kinase inhibitor”,“immunotherapy”,“immune checkpoint inhibitor”,and“biomarker”.It also firstly synthesizes combination strategies and underlying mechanisms between FGFR4 inhibitors and targeted-immunotherapy,addressing critical gaps in existing reviews.Additionally,we discuss the potential of FGF19 as a predictive biomarker,integrating mechanistic and clinical evidence to advance precision HCC therapeutics.展开更多
We revisit the issue of whether the effective potential for the conformal factor of the metric,which is generated by quantized matter fields,possesses a non-vanishing vacuum expectation value(VEV)or not.We prove that ...We revisit the issue of whether the effective potential for the conformal factor of the metric,which is generated by quantized matter fields,possesses a non-vanishing vacuum expectation value(VEV)or not.We prove that the effective potential has a vanishing vacuum expectation value on the basis of a global GL(4)symmetry.We also account for why there seems to be two different effective potentials for the conformal factor in a theory,one of which gives rise to a vanishing VEV for the conformal factor,whereas the other has a non-vanishing VEV.展开更多
BACKGROUND Pancreatic cancer(PC)is one of the most aggressive malignancies characterized by rapid progression and poor prognosis.The involvement of cancer stem cells(CSCs)and Octamer transcription factor 4(OCT4)in PC ...BACKGROUND Pancreatic cancer(PC)is one of the most aggressive malignancies characterized by rapid progression and poor prognosis.The involvement of cancer stem cells(CSCs)and Octamer transcription factor 4(OCT4)in PC pathobiology is being increasingly recognized.AIM To investigate the role of OCT4 in pancreatic CSCs and its effect on PC cell prolif-eration,migration,drug sensitivity,and stemness maintenance.METHODS We analyzed OCT4 and CD133 expression in PC tissues and cell lines.BxPC-3 cells were used to assess the effects of OCT4 modulation on cellular behavior.Proliferation,migration,and stemness of BxPC-3 cells were evaluated,and the PI3K/AKT/mTOR pathway was examined to gain mechanistic insights.RESULTS OCT4 and CD133 were significantly overexpressed in PC tissues.OCT4 mo-dulation altered BxPC-3 cell proliferation,invasion,and stemness,with OCT4 overexpression(OV-OCT4)enhancing these properties and OCT4 interference decreasing them.OV-OCT4 activated the PI3K/AKT/mTOR pathway,which correlated with an increase in PC stem cells(PCSC).CONCLUSION OCT4 plays a crucial role in PCSCs by influencing the aggressiveness and drug resistance of PC cells,thus presenting itself as a potential therapeutic target.展开更多
Alzheimer's disease is the most prevalent chronic neurodegenerative disorder worldwide,with no sufficient cure.Ongoing research is focused on developing new therapies aimed at preventing or delaying the onset of s...Alzheimer's disease is the most prevalent chronic neurodegenerative disorder worldwide,with no sufficient cure.Ongoing research is focused on developing new therapies aimed at preventing or delaying the onset of symptoms,slowing disease progression,and improving cognitive and behavioral outcomes in individuals affected by Alzheimer's disease.Among the various pathological changes associated with this condition,blood-brain barrier(BBB)leakage plays a crucial role as it serves as a vital boundary for maintaining central nervous system(CNS)health.Preserving the integrity and functionality of the BBB is essential to protect the brain from amyloid-β accumulation,neuroinflammation,and neuronal degeneration.This review summarizes models of Alzheimer's disease characterized by BBB leakage over time.More importantly,we introduce Krüppel-l ike factor 4(KLF4),a transcription factor involved in vascular systems,and discuss its relevance to Alzheimer's disease.By elucidating the functions of KLF4 within both vascular and CNSs,this review highlights its potential role in modulating BBB integrity in Alzheimer's pathology,which may contribute to therapeutic strategies for managing this debilitating condition.展开更多
Recessive resistance mediated by mutations in the eukaryotic translation initiation factor 4E(eIF4E),has proven effective against diverse potyviruses and is extensively utilized in breeding programs.However,the rise o...Recessive resistance mediated by mutations in the eukaryotic translation initiation factor 4E(eIF4E),has proven effective against diverse potyviruses and is extensively utilized in breeding programs.However,the rise of resistance-breaking(RB)strains and emerging potyviral species necessitates the development of more durable and broad-spectrum resistance strategies.In this study,our field survey in Yunnan,China,identified potato virus Y(PVY)RB isolates,as well as the prevalence of tobacco vein banding mosaic virus(TVBMV)and chilli veinal mottle virus(ChiVMV),in tobacco carrying the recessive va locus,which lacks the eIF4E1-S susceptibility gene,due to a chromosomal deletion.Protein interaction and viral infection assays demonstrated that both eIF4E1-S and eIFiso4E-T are used by PVY RB as susceptibility factors for infection,with the combined inactivation of these genes confering durable resistance.Similarly,the knockout of eIFiso4E-S,in the va genetic background,provided effective resistance to TVBMV and reduced susceptibility to ChiVMV.Notably,pyramiding mutations in eIFiso4E-S and eIFiso4E-T,in va tobacco,generated plants exhibiting robust,broad-spectrum resistance,to all three viruses,without compromising plant development.These findings underscore the potential of stacking eIF4E mutations to engineer durable,broad-spectrum resistance to potyviruses in tobacco,offering a promising strategy for crop improvement.展开更多
基金supported by the National Natural Science Foundation of China(Nos.82171552 and 82170479)the Natural Science Foundation of Shanghai Ctiy(No.21ZR1457500)the Science and Technology Bureau of Shanghai Putuo District(No.ptkwws202102).
文摘Magnolol,a compound extracted from Magnolia officinalis,demonstrates potential efficacy in addressing metabolic dysfunction and cardiovascular diseases.Its biological activities encompass anti-inflammatory,antioxidant,anticoagulant,and anti-diabetic effects.Growth/differentiation factor-15(GDF-15),a member of the transforming growth factorβsuperfamily,is considered a potential therapeutic target for metabolic disorders.This study investigated the impact of magnolol on GDF-15 production and its underlying mechanism.The research examined the pharmacological effect of magnolol on GDF-15 expression in vitro and in vivo,and determined the involvement of endoplasmic reticulum(ER)stress signaling in this process.Luciferase reporter assays,chromatin immunoprecipitation,and in vitro DNA binding assays were employed to examine the regulation of GDF-15 by activating transcription factor 4(ATF4),CCAAT enhancer binding proteinγ(CEBPG),and CCCTC-binding factor(CTCF).The study also investigated the effect of magnolol and ATF4 on the activity of a putative enhancer located in the intron of the GDF-15 gene,as well as the influence of single nucleotide polymorphisms(SNPs)on magnolol and ATF4-induced transcription activity.Results demonstrated that magnolol triggers GDF-15 production in endothelial cells(ECs),hepatoma cell line G2(HepG2)and hepatoma cell line 3B(Hep3B)cell lines,and primary mouse hepatocytes.The cooperative binding of ATF4 and CEBPG upstream of the GDF-15 gene or the E1944285 enhancer located in the intron led to full-power transcription of the GDF-15 gene.SNP alleles were found to impact the magnolol and ATF4-induced transcription activity of GDF-15.In high-fat diet ApoE^(-/-)mice,administration of magnolol induced GDF-15 production and partially suppressed appetite through GDF-15.These findings suggest that magnolol regulates GDF-15 expression through priming of promoter and enhancer activity,indicating its potential as a drug for the treatment of metabolic disorders.
文摘BACKGROUND Noninvasive tests are crucial for the management and follow-up of patients with autoimmune hepatitis,but their validation is limited because of insufficient data.AIM To investigate the diagnostic performance of three fibrosis noninvasive tests[FibroTest,vibration-controlled transient elastography(VCTE),and the fibrosis-4 index(FIB-4)and two activity biomarkers(alanine aminotransferase(ALT)and ActiTest].METHODS This study enrolled 103 patients for whom liver biopsy,hepatic elastography results,and laboratory markers were available.Diagnostic performance was assessed with receiver operating characteristic(ROC)curves,the Obuchowski measure(OM),and the Bayesian latent class model.RESULTS FibroTest and VCTE outperformed FIB-4 in cases of significant fibrosis(≥F2),with areas under the ROC curve of 0.83[95%confidence interval(CI):0.73-0.90],0.86(95%CI:0.77-0.92),and 0.71(95%CI:0.60-0.80),respectively.The mean(standard error)OM values were 0.92(0.01),0.93(0.01),and 0.88(0.02)for FibroTest,VCTE,and FIB-4,respectively;FibroTest and VCTE performed comparably,and both were superior to FIB-4(P=0.03 and P=0.005).The areas under the ROC curve values for activity biomarkers were 0.86(95%CI:0.76-0.92)for ActiTest and 0.84(95%CI:0.73-0.90)for ALT(P=0.06).The OM values for ActiTest and ALT were 0.92(0.02)and 0.90(0.02),respectively(P=0.005).CONCLUSION FibroTest and VCTE outperformed FIB-4 according to the OM.FibroTest-ActiTest facilitated the evaluation of both fibrosis and activity.
基金Supported by Chen Xiao-Ping Foundation for the Development of Science and Technology of Hubei Province,No.CXPJJH124001-2406National Natural Science Foundation of China,No.U23A20483.
文摘Hepatocellular carcinoma(HCC)remains a leading cause of cancer-related mortality globally,with limited therapeutic progress for advanced stages.The aberrant fibroblast growth factor 19(FGF19)-fibroblast growth factor receptor 4(FGFR4)axis promotes oncogenesis and is linked to targeted-immunotherapy of HCC.Multi-kinase inhibitors(MKIs)enhance anti-tumor effects by targeting this axis and FGF19 overexpression upregulates programmed cell death ligand 1 in tumor microenvironment.Clinical studies have demonstrated the efficacy of selective FGFR4 inhibitors in HCC treatment,with enhanced anti-tumor effects when combined with MKIs or immune checkpoint inhibitors.Phase I clinical trials of Irpagratinib(ABSK-011)demonstrated an objective response rate of 43.5%,which increased to 55.6%combined with atezolizumab.FGF19 also serves as a biomarker for HCC.This review systematically summarizes the literature retri-eved from PubMed and other databases using search terms“HCC”,“fibroblast growth factor 19”,“fibroblast growth factor receptor 4”,“FGFR4 inhibitor”,“targeted therapy”,“multi-kinase inhibitor”,“immunotherapy”,“immune checkpoint inhibitor”,and“biomarker”.It also firstly synthesizes combination strategies and underlying mechanisms between FGFR4 inhibitors and targeted-immunotherapy,addressing critical gaps in existing reviews.Additionally,we discuss the potential of FGF19 as a predictive biomarker,integrating mechanistic and clinical evidence to advance precision HCC therapeutics.
基金supported in part by the JSPS Kakenhi under Grant No.21K03539。
文摘We revisit the issue of whether the effective potential for the conformal factor of the metric,which is generated by quantized matter fields,possesses a non-vanishing vacuum expectation value(VEV)or not.We prove that the effective potential has a vanishing vacuum expectation value on the basis of a global GL(4)symmetry.We also account for why there seems to be two different effective potentials for the conformal factor in a theory,one of which gives rise to a vanishing VEV for the conformal factor,whereas the other has a non-vanishing VEV.
基金Supported by Inner Mongolia Natural Science Foundation and the 3rd Affiliated of Inner Medical University,No.2021MS08067.
文摘BACKGROUND Pancreatic cancer(PC)is one of the most aggressive malignancies characterized by rapid progression and poor prognosis.The involvement of cancer stem cells(CSCs)and Octamer transcription factor 4(OCT4)in PC pathobiology is being increasingly recognized.AIM To investigate the role of OCT4 in pancreatic CSCs and its effect on PC cell prolif-eration,migration,drug sensitivity,and stemness maintenance.METHODS We analyzed OCT4 and CD133 expression in PC tissues and cell lines.BxPC-3 cells were used to assess the effects of OCT4 modulation on cellular behavior.Proliferation,migration,and stemness of BxPC-3 cells were evaluated,and the PI3K/AKT/mTOR pathway was examined to gain mechanistic insights.RESULTS OCT4 and CD133 were significantly overexpressed in PC tissues.OCT4 mo-dulation altered BxPC-3 cell proliferation,invasion,and stemness,with OCT4 overexpression(OV-OCT4)enhancing these properties and OCT4 interference decreasing them.OV-OCT4 activated the PI3K/AKT/mTOR pathway,which correlated with an increase in PC stem cells(PCSC).CONCLUSION OCT4 plays a crucial role in PCSCs by influencing the aggressiveness and drug resistance of PC cells,thus presenting itself as a potential therapeutic target.
基金Guangzhou Municipal Science and Technology Project,Grant/Award Number:2024A03J0071National Natural Science Foundation of China,Grant/Award Number:82471386Key Laboratory of Guangdong Higher Education Institutes,Grant/Award Number:2021KSYS009。
文摘Alzheimer's disease is the most prevalent chronic neurodegenerative disorder worldwide,with no sufficient cure.Ongoing research is focused on developing new therapies aimed at preventing or delaying the onset of symptoms,slowing disease progression,and improving cognitive and behavioral outcomes in individuals affected by Alzheimer's disease.Among the various pathological changes associated with this condition,blood-brain barrier(BBB)leakage plays a crucial role as it serves as a vital boundary for maintaining central nervous system(CNS)health.Preserving the integrity and functionality of the BBB is essential to protect the brain from amyloid-β accumulation,neuroinflammation,and neuronal degeneration.This review summarizes models of Alzheimer's disease characterized by BBB leakage over time.More importantly,we introduce Krüppel-l ike factor 4(KLF4),a transcription factor involved in vascular systems,and discuss its relevance to Alzheimer's disease.By elucidating the functions of KLF4 within both vascular and CNSs,this review highlights its potential role in modulating BBB integrity in Alzheimer's pathology,which may contribute to therapeutic strategies for managing this debilitating condition.
基金supported by National Natural Science Foundation of China(31860490)YNTC funds(2023530000241007 and 2017YN02)+1 种基金Yunnan Daguan Lab(YNDG202302ZY01)CLZ is supported by the Postdoctoral Fellowship Program of CPSF under grant number GZC20241527。
文摘Recessive resistance mediated by mutations in the eukaryotic translation initiation factor 4E(eIF4E),has proven effective against diverse potyviruses and is extensively utilized in breeding programs.However,the rise of resistance-breaking(RB)strains and emerging potyviral species necessitates the development of more durable and broad-spectrum resistance strategies.In this study,our field survey in Yunnan,China,identified potato virus Y(PVY)RB isolates,as well as the prevalence of tobacco vein banding mosaic virus(TVBMV)and chilli veinal mottle virus(ChiVMV),in tobacco carrying the recessive va locus,which lacks the eIF4E1-S susceptibility gene,due to a chromosomal deletion.Protein interaction and viral infection assays demonstrated that both eIF4E1-S and eIFiso4E-T are used by PVY RB as susceptibility factors for infection,with the combined inactivation of these genes confering durable resistance.Similarly,the knockout of eIFiso4E-S,in the va genetic background,provided effective resistance to TVBMV and reduced susceptibility to ChiVMV.Notably,pyramiding mutations in eIFiso4E-S and eIFiso4E-T,in va tobacco,generated plants exhibiting robust,broad-spectrum resistance,to all three viruses,without compromising plant development.These findings underscore the potential of stacking eIF4E mutations to engineer durable,broad-spectrum resistance to potyviruses in tobacco,offering a promising strategy for crop improvement.
文摘目的:观察葛根芩连汤辅助0.1%糠酸莫米松乳膏及盐酸西替利嗪片治疗特应性皮炎(Atopic dermatitis,AD)患者的临床疗效以及血清中神经生长因子(Nerve growth factor,NGF)和神经营养因子4(Neurotrophin-4,NT-4)水平的影响。方法:选取2021年5月-2023年5月收入笔者医院的AD患者60例,根据治疗方案的差异随机分为对照组(西药治疗)、观察组(西药治疗+中药辅助治疗)每组30例。对照组采用外用糠酸莫米松乳膏,口服盐酸西替利嗪进行干预治疗,观察组在对照组基础上采用葛根芩连汤辅助进行治疗。观察两组患者治疗前、后血清中NGF、NT-4水平、瘙痒视觉模拟评分(Visual analogue scale,VAS)、湿疹面积及严重指数(Eczema area and severity index,EASI)评分,治疗后临床疗效及不良反应发生率。结果:治疗前两组患者血清中NGF、NT-4水平、VAS评分、EASI评分相比差异无统计学意义(P>0.05),经治疗后两组患者血清中NGF、NT-4水平、VAS评分、EASI评分均较同组治疗前显著降低(P<0.05),且观察组优于对照组(P<0.05);经治疗后,观察组患者临床疗效总有效率高于对照组,不良反应发生率低于对照组(P<0.05)。结论:葛根芩连汤辅助西药治疗AD可下调患者血清中NGF、NT-4水平,减轻瘙痒症状及皮损程度,改善临床症状,降低不良事件的发生率,值得临床推广应用。
