The plant cell wall is an important interface for sensing pathogen attack and activating signaling pathways that promote plant immune responses.THESEUS1(THE1) acts as a sensor of cell wall integrity that controls cell...The plant cell wall is an important interface for sensing pathogen attack and activating signaling pathways that promote plant immune responses.THESEUS1(THE1) acts as a sensor of cell wall integrity that controls cell elongation during plant growth.However, no specific role for THE1 in plant defense responses has been reported. Here, we found that THE1 interacts with GUANINE EXCHANGE FACTOR4(GEF4)and that both proteins play regulatory roles in plant resistance to the necrotrophic fungus Botrytis cinerea.Genetic analysis showed that THE1 and GEF4 function in the same genetic pathway to mediate plant defense responses. In addition, using transcriptome analysis, we identified various genes(such as defense-related,secondary metabolite-related, and transcription factor genes) that are likely downstream targets in the THE1-GEF4 signaling pathway. Our results suggest that THE1 functions as an upstream regulator of GEF4 signaling to positively regulate defense responses against B. cinerea in Arabidopsis.展开更多
BACKGROUND The identification of key regulators ofβcell mass and function is crucial in developing effective therapeutic interventions for diabetes.Ras homolog enriched in brain 1(Rheb1),an upstream binding protein o...BACKGROUND The identification of key regulators ofβcell mass and function is crucial in developing effective therapeutic interventions for diabetes.Ras homolog enriched in brain 1(Rheb1),an upstream binding protein of mTOR,is a potential thera-peutic target forβcell in diabetes,while the underlying mechanisms remains un-known.METHODS Islets samples were collected from mouse and human donors.Min6 transformed cell line and mouse models including pancreatic orβ-cell specific knockout of Rheb1mice were established.Rapamycin(an mTORC1 inhibitor)and AICAR(an AMPK activator)was used to investigate mTORC1 or AMPK signaling inβcells.The effect of Rheb1 onβcell function via mTORC1,AMPK or other pathways were assessed using western blotting and immunofluorescence,etc.RESULTS In this study,we demonstrate that Rheb1 is highly expressed in islets from young human donors(below the age of 18)compared to adults.Furthermore,our findings reveal that Rheb1 facilitatesβ-cell proliferation through both mTORC1 and AMPK signaling pathways,rather than solely relying on mTORC1.Specifically,we observed that either AICAR or rapamycin alone could partially inhibit Rheb1-inducedβcell proliferation,while the combination of AICAR and rapamycin fully inhibits Rheb1-inducedβcell proliferation in Min6 transformed cell line and mouse islets.In addition,our study highlights the role of Rheb1 in maintainingβcell identity through activation of mTORC1 and Notch1 signaling pathways.Moreover,we also found that Rheb1 could positively regulate HNF4αinβcells,which is a significant transcription factor forβ-cell development and differentiation.CONCLUSION Overall,our findings reveal that Rheb1 regulatesβcell proliferation and identity andβ-cell development related significant marker,providing a promising novel therapeutic target for diabetes.展开更多
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 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
BACKGROUND Pancreatic cancer,characterized by aggressive proliferation and metastasis,is a lethal malignancy.The nightly hormone melatonin serves as a rhythm-regulating hormone,and is used to treat different cancers i...BACKGROUND Pancreatic cancer,characterized by aggressive proliferation and metastasis,is a lethal malignancy.The nightly hormone melatonin serves as a rhythm-regulating hormone,and is used to treat different cancers including pancreatic cancer.AIM To investigate how melatonin acts against human pancreatic cancer cell lines and analyze the biological processes that cause the observed effects.METHODS Panc-1 and AsPC-1 cells were treated with melatonin.Cell viability was measured using the cell counting kit-8 assay.Western blotting and immunofluorescence were used to analyze protein expression levels.Ferroptosis was measured by analyzing lipid reactive oxygen species and malondialdehyde levels;apoptosis was assessed using flow cytometry.RESULTS Melatonin significantly inhibited the viability,colony formation,migration,and invasion of Panc-1 and AsPC-1 cells.Additionally,melatonin activated the endoplasmic reticulum(ER)stress pathway(protein kinase R-like ER kinase eukaryotic initiation factor 2α-activating transcription factor 4),inhibited glutamine metabolism(alanine-serinecysteine transporter 2-glutaminase 1-glutathione peroxidase 4,alanine-serine-cysteine transporter 2-glutathione peroxidase 4),and promoted ferroptosis in pancreatic cancer cells.Co-treatment with a high melatonin concentration and protein kinase R-like ER kinase agonist(CCT020312)enhanced melatonin-induced ferroptosis in pancreatic cancer cells.Melatonin demonstrated a variety of anticancer effects by inhibiting autophagy.This was achieved through the increased expression of sequestosome-1 and decreased expression of light chain 3.Additionally,melatonin facilitated the promotion of apoptosis.CONCLUSION Melatonin induces ferroptosis in pancreatic cancer cells by activating transcription factor 4-dependent ER stress and inhibiting glutamine metabolism,promotes apoptosis in pancreatic cancer cells,and inhibits autophagy,leading to synergistic anticancer effects.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
BACKGROUND Colorectal cancer(CRC)is a malignant tumor characterized by high global incidence and mortality rates.Contemporary therapeutic modalities remain limited by suboptimal efficacy and adverse effects,thereby ne...BACKGROUND Colorectal cancer(CRC)is a malignant tumor characterized by high global incidence and mortality rates.Contemporary therapeutic modalities remain limited by suboptimal efficacy and adverse effects,thereby necessitating the pursuit of more efficacious treatment strategies.Within traditional Chinese medicine,spleen deficiency is regarded as a central pathogenic mechanism in CRC,persisting throughout the entire disease course.AIM To elucidate the mechanism by which modified Yigong San confers therapeutic efficacy against CRC,potentially exerting its effects through apoptosis regulation mediated by the enhancer of zeste homolog 2(EZH2)/methyltransferase-like 3(METTL3)/SRY-box transcription factor 4(SOX4)axis.METHODS In the clinical study,CRC tissues and corresponding adjacent normal samples that fulfilled inclusion criteria were procured.Quantitative reverse transcription polymerase chain reaction was employed to determine the transcriptional expression of EZH2 and METTL3 mRNA.For in vitro experimentation,SW-480 cells were allocated into five experimental conditions:Control,control+serum,control+negative control,control+overexpressing-EZH2,and control+overexpressing-EZH2+serum.The mRNA expression levels of EZH2,METTL3,SOX4,B-cell lymphoma 2,and Bax across groups were quantified via quantitative reverse transcription polymerase chain reaction,while protein levels were assessed using western blot analysis.The presence of EZH2 binding sites within the METTL3 promoter region was verified through chromatin immunoprecipitation polymerase chain reaction.The optimal concentration of drug-containing serum(5%,10%,15%)was determined using the Cell Counting Kit-8 assay.Cell migratory ability was evaluated via scratch assays,and apoptotic activity was quantified by flow cytometry.RESULTS The clinical findings demonstrated significantly elevated transcriptional levels of METTL3 and EZH2 mRNA in tumor tissues compared to their adjacent normal counterparts(P<0.05).In vitro,cells treated with modified Yigong San exhibited a substantial downregulation of EZH2,METTL3,SOX4,B-cell lymphoma 2,and Bax mRNA and protein levels(P<0.05),relative to the control group.Apoptotic rates were markedly increased,while migratory capacity was significantly attenuated.Furthermore,in EZH2-overexpressing cells treated with modified Yigong San,similar reductions in both mRNA and protein levels of the aforementioned targets were observed(P<0.05),concomitant with enhanced apoptosis and reduced migration.Chromatin immunoprecipitation polymerase chain reaction analysis confirmed EZH2 occupancy at specific loci within the METTL3 promoter.CONCLUSION Modified Yigong San exhibits both preventive and therapeutic potential against CRC,likely mediated through the regulation of apoptosis via the EZH2/METTL3/SOX4 signaling pathway.展开更多
This editorial highlighted the central role of pancreatic β-cell dysfunction in the pathogenesis of diabetes mellitus and discussed the emerging significance of Ras homolog enriched in brain 1(Rheb1)as a key regulato...This editorial highlighted the central role of pancreatic β-cell dysfunction in the pathogenesis of diabetes mellitus and discussed the emerging significance of Ras homolog enriched in brain 1(Rheb1)as a key regulator of β-cell mass and insulinsecretory capacity.While molecular mechanisms governing β-cell homeostasis remain incompletely defined,Yang et al have recently demonstrated that Rheb1 could promote β-cell proliferation through dual activation of mechanistic target of rapamycin complex 1 and AMP-activated protein kinase signaling pathways,rather than relying solely on mechanistic target of rapamycin complex 1.Notably,Rheb1 expression is higher in pancreatic islets from younger individuals and upregulates hepatocyte nuclear factor 4 alpha,which is recognized as a transcription factor essential for β-cell identity and insulin production.These insights position Rheb1 as a pivotal regulator of β-cell growth and metabolic function,with potential therapeutic implications for diabetes.Targeting Rheb1 may shift treatment paradigms from conventional glucose-lowering strategies towardβ-cell restoration,providing a novel approach to preserve or enhance functionalβ-cell mass in diabetic patients.Further investigation into Rheb1’s upstream regulators and downstream effectors may provide innovative therapeutic directions.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
Chemotherapy-induced intestinal mucositis(IM)is a prevalent complication affecting up to 80%of cancer patients undergoing treatment.Current therapies focus on symptomatic relief rather than addressing the underlying m...Chemotherapy-induced intestinal mucositis(IM)is a prevalent complication affecting up to 80%of cancer patients undergoing treatment.Current therapies focus on symptomatic relief rather than addressing the underlying mechanism.Recent advances in integrative medicine highlight the potential of traditional Chinese medicine formulations as alternatives or adjuncts to existing therapies.In this context,this editorial discusses the recent results of a study published by Qiu et al,which investigates the multifaceted potential of modified Pulsatilla decoction(PD),a formulation of PD with licorice(Glycyrrhiza uralensis)and Ejiao(Colla corii asini),on 5-fluorouracil-induced IM in mice to alleviate clinical symptoms including diarrhea,weight loss,and intestinal damage.A series of histological,biochemical,bioinformatic,and microbiological assays evaluated body weight,diarrhea scores,inflammatory cytokine profiles,oxidative stress modulation,and microbiota composition.The findings indicated a reduction in diarrhea and oxidative stress,as well as an improvement in body weight and intestinal histopathology.Furthermore,the modified PD suppressed the TLR4/MyD88/nuclear factor kappa-B inflammatory pathway and down-regulated key proinflammatory cytokines.Moreover,the study underscores the role of gut microbiota in IM pathogenesis.Modified PD treatment reshaped microbial diversity by promoting beneficial genera such as Bacteroides acidifaciens while suppressing pathogenic species like Salmonella.These findings suggest that the therapeutic effects of the modified PD extend beyond inflammation modulation to encompass microbiome reprogramming and mucosal barrier repair.Although the study provides significant insights,several limitations still prevail.The broader implications of modified PD in gastrointestinal disorders and integrative oncology need further exploration.展开更多
Objective: To study the prognostic value of the pathological margin and molecular margin marked by eIF4E and P53 protein in laryngeal carcinoma. Methods: The prognostic value of pathological and molecular margin was s...Objective: To study the prognostic value of the pathological margin and molecular margin marked by eIF4E and P53 protein in laryngeal carcinoma. Methods: The prognostic value of pathological and molecular margin was studied in 253 cases and 67 cases respectively, the latter were pathological negative margin chosen from the former. Immunohistochemisty was used to detect the expression of eIF4E and p53 proteins. Results: The rate of pathological, p53 and eIF4E positive margins was 20.2%, 19.4% and 32.8% respectively. The recurrent rate of those with positive margins was higher than that of negative margins, which including pathological margin (70.6% vs 35.1%, P =0.0000), p53 margin (69.2% vs 33.3%, P =0.018) and eIF4E margin (63.6% vs 28.9%, P =0.018); The survival rate of those with negative margins was higher than those with positive margins, including pathological margin (the 5-year cumulative survival rate was 37.52% and 64.37% respectively, P =0.0023), p53 margin (the 5-year cumulative survival rate was 24.62% and 75.69% respectively, P =0.0012) and eIF4E margin (the 5-year cumulative survival rate was 43.31% and 77.52% respectively, P =0.0006). Conclusion: The prognosis of those with both pathological and molecular positive margins was worse than that of the negative margins; Both the eIF4E and p53 were useful markers to pick out the poor prognostic patients from those with pathological negative margin, and the former seemed to be more potential.展开更多
Vascular smooth muscle cell （VSMC） differentiation and proliferation are two important physiological proc- esses during vascular development. The phenotypic alteration from differentiated to proliferative VSMC contr...Vascular smooth muscle cell （VSMC） differentiation and proliferation are two important physiological proc- esses during vascular development. The phenotypic alteration from differentiated to proliferative VSMC contrib- utes to the development of several major cardiovascular diseases including atherosclerosis, hypertension, resteno- sis after angioplasty or bypass, diabetic vascular complications, and transplantation arteriopathy. Since the VSMC phenotype in these pathological conditions resembles that of developing VSMC during embryonic development, understanding of the molecular mechanisms that control VSMC differentiation will provide fundamental insights into the pathological processes of these cardiovascular diseases. Although VSMC differentiation is usually ac- companied by an irreversible cell cycle exit, VSMC proliferation and differentiation occur concurrently during embryonic development. The molecular mechanisms simultaneously regulating these two processes, however, remain largely unknown. Our recent study demonstrates that cell division cycle 7, a key regulator of cell cycle, promotes both VSMC differentiation and proliferation through different mechanisms during the initial phase of VSMC differentiation. Conversely, Kriappel-like factor 4 appears to be a repressor for both VSMC differentia- tion and proliferation. This review attempts to highlight the novel role of cell division cycle 7 in TGF-β-induced VSMC differentiation and proliferation. The role of K141ppel-like factor 4 in suppressing these two processes will also be discussed.展开更多
基金supported by the National Natural Science Foundation of China(31400221)the Beijing Advanced Innovation Center for Tree Breeding by Molecular Design+1 种基金the Program for Changjiang Scholars and Innovative Research Team in University(IRT13047)the Fundamental Research Funds for the Central Universities(BLX2012038)
文摘The plant cell wall is an important interface for sensing pathogen attack and activating signaling pathways that promote plant immune responses.THESEUS1(THE1) acts as a sensor of cell wall integrity that controls cell elongation during plant growth.However, no specific role for THE1 in plant defense responses has been reported. Here, we found that THE1 interacts with GUANINE EXCHANGE FACTOR4(GEF4)and that both proteins play regulatory roles in plant resistance to the necrotrophic fungus Botrytis cinerea.Genetic analysis showed that THE1 and GEF4 function in the same genetic pathway to mediate plant defense responses. In addition, using transcriptome analysis, we identified various genes(such as defense-related,secondary metabolite-related, and transcription factor genes) that are likely downstream targets in the THE1-GEF4 signaling pathway. Our results suggest that THE1 functions as an upstream regulator of GEF4 signaling to positively regulate defense responses against B. cinerea in Arabidopsis.
基金Supported by National Natural Science Foundation of China,No.82430029,No.82330025,No.82370807,and No.82070807Leading Talents Program of Hunan Province,No.2022RC3078Natural Science Foundation of Hunan Province,China,No.2021JJ30976.
文摘BACKGROUND The identification of key regulators ofβcell mass and function is crucial in developing effective therapeutic interventions for diabetes.Ras homolog enriched in brain 1(Rheb1),an upstream binding protein of mTOR,is a potential thera-peutic target forβcell in diabetes,while the underlying mechanisms remains un-known.METHODS Islets samples were collected from mouse and human donors.Min6 transformed cell line and mouse models including pancreatic orβ-cell specific knockout of Rheb1mice were established.Rapamycin(an mTORC1 inhibitor)and AICAR(an AMPK activator)was used to investigate mTORC1 or AMPK signaling inβcells.The effect of Rheb1 onβcell function via mTORC1,AMPK or other pathways were assessed using western blotting and immunofluorescence,etc.RESULTS In this study,we demonstrate that Rheb1 is highly expressed in islets from young human donors(below the age of 18)compared to adults.Furthermore,our findings reveal that Rheb1 facilitatesβ-cell proliferation through both mTORC1 and AMPK signaling pathways,rather than solely relying on mTORC1.Specifically,we observed that either AICAR or rapamycin alone could partially inhibit Rheb1-inducedβcell proliferation,while the combination of AICAR and rapamycin fully inhibits Rheb1-inducedβcell proliferation in Min6 transformed cell line and mouse islets.In addition,our study highlights the role of Rheb1 in maintainingβcell identity through activation of mTORC1 and Notch1 signaling pathways.Moreover,we also found that Rheb1 could positively regulate HNF4αinβcells,which is a significant transcription factor forβ-cell development and differentiation.CONCLUSION Overall,our findings reveal that Rheb1 regulatesβcell proliferation and identity andβ-cell development related significant marker,providing a promising novel therapeutic target for diabetes.
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.
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Supported by Jinhua Municipal Science and Technology Bureau,No.2022-4-254.
文摘BACKGROUND Pancreatic cancer,characterized by aggressive proliferation and metastasis,is a lethal malignancy.The nightly hormone melatonin serves as a rhythm-regulating hormone,and is used to treat different cancers including pancreatic cancer.AIM To investigate how melatonin acts against human pancreatic cancer cell lines and analyze the biological processes that cause the observed effects.METHODS Panc-1 and AsPC-1 cells were treated with melatonin.Cell viability was measured using the cell counting kit-8 assay.Western blotting and immunofluorescence were used to analyze protein expression levels.Ferroptosis was measured by analyzing lipid reactive oxygen species and malondialdehyde levels;apoptosis was assessed using flow cytometry.RESULTS Melatonin significantly inhibited the viability,colony formation,migration,and invasion of Panc-1 and AsPC-1 cells.Additionally,melatonin activated the endoplasmic reticulum(ER)stress pathway(protein kinase R-like ER kinase eukaryotic initiation factor 2α-activating transcription factor 4),inhibited glutamine metabolism(alanine-serinecysteine transporter 2-glutaminase 1-glutathione peroxidase 4,alanine-serine-cysteine transporter 2-glutathione peroxidase 4),and promoted ferroptosis in pancreatic cancer cells.Co-treatment with a high melatonin concentration and protein kinase R-like ER kinase agonist(CCT020312)enhanced melatonin-induced ferroptosis in pancreatic cancer cells.Melatonin demonstrated a variety of anticancer effects by inhibiting autophagy.This was achieved through the increased expression of sequestosome-1 and decreased expression of light chain 3.Additionally,melatonin facilitated the promotion of apoptosis.CONCLUSION Melatonin induces ferroptosis in pancreatic cancer cells by activating transcription factor 4-dependent ER stress and inhibiting glutamine metabolism,promotes apoptosis in pancreatic cancer cells,and inhibits autophagy,leading to synergistic anticancer effects.
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 Liaoning Provincial Science and Technology Department Project,No.2023JH2/101700149Open Fund Project of Liaoning University of Traditional Chinese Medicine,No.zyzx2205.
文摘BACKGROUND Colorectal cancer(CRC)is a malignant tumor characterized by high global incidence and mortality rates.Contemporary therapeutic modalities remain limited by suboptimal efficacy and adverse effects,thereby necessitating the pursuit of more efficacious treatment strategies.Within traditional Chinese medicine,spleen deficiency is regarded as a central pathogenic mechanism in CRC,persisting throughout the entire disease course.AIM To elucidate the mechanism by which modified Yigong San confers therapeutic efficacy against CRC,potentially exerting its effects through apoptosis regulation mediated by the enhancer of zeste homolog 2(EZH2)/methyltransferase-like 3(METTL3)/SRY-box transcription factor 4(SOX4)axis.METHODS In the clinical study,CRC tissues and corresponding adjacent normal samples that fulfilled inclusion criteria were procured.Quantitative reverse transcription polymerase chain reaction was employed to determine the transcriptional expression of EZH2 and METTL3 mRNA.For in vitro experimentation,SW-480 cells were allocated into five experimental conditions:Control,control+serum,control+negative control,control+overexpressing-EZH2,and control+overexpressing-EZH2+serum.The mRNA expression levels of EZH2,METTL3,SOX4,B-cell lymphoma 2,and Bax across groups were quantified via quantitative reverse transcription polymerase chain reaction,while protein levels were assessed using western blot analysis.The presence of EZH2 binding sites within the METTL3 promoter region was verified through chromatin immunoprecipitation polymerase chain reaction.The optimal concentration of drug-containing serum(5%,10%,15%)was determined using the Cell Counting Kit-8 assay.Cell migratory ability was evaluated via scratch assays,and apoptotic activity was quantified by flow cytometry.RESULTS The clinical findings demonstrated significantly elevated transcriptional levels of METTL3 and EZH2 mRNA in tumor tissues compared to their adjacent normal counterparts(P<0.05).In vitro,cells treated with modified Yigong San exhibited a substantial downregulation of EZH2,METTL3,SOX4,B-cell lymphoma 2,and Bax mRNA and protein levels(P<0.05),relative to the control group.Apoptotic rates were markedly increased,while migratory capacity was significantly attenuated.Furthermore,in EZH2-overexpressing cells treated with modified Yigong San,similar reductions in both mRNA and protein levels of the aforementioned targets were observed(P<0.05),concomitant with enhanced apoptosis and reduced migration.Chromatin immunoprecipitation polymerase chain reaction analysis confirmed EZH2 occupancy at specific loci within the METTL3 promoter.CONCLUSION Modified Yigong San exhibits both preventive and therapeutic potential against CRC,likely mediated through the regulation of apoptosis via the EZH2/METTL3/SOX4 signaling pathway.
基金Supported by Hubei Provincial Natural Science Foundation,No.2025AFB845Graduate Innovation and Entrepreneurship Fund of Wuhan University of Science and Technology,No.JCX2024044.
文摘This editorial highlighted the central role of pancreatic β-cell dysfunction in the pathogenesis of diabetes mellitus and discussed the emerging significance of Ras homolog enriched in brain 1(Rheb1)as a key regulator of β-cell mass and insulinsecretory capacity.While molecular mechanisms governing β-cell homeostasis remain incompletely defined,Yang et al have recently demonstrated that Rheb1 could promote β-cell proliferation through dual activation of mechanistic target of rapamycin complex 1 and AMP-activated protein kinase signaling pathways,rather than relying solely on mechanistic target of rapamycin complex 1.Notably,Rheb1 expression is higher in pancreatic islets from younger individuals and upregulates hepatocyte nuclear factor 4 alpha,which is recognized as a transcription factor essential for β-cell identity and insulin production.These insights position Rheb1 as a pivotal regulator of β-cell growth and metabolic function,with potential therapeutic implications for diabetes.Targeting Rheb1 may shift treatment paradigms from conventional glucose-lowering strategies towardβ-cell restoration,providing a novel approach to preserve or enhance functionalβ-cell mass in diabetic patients.Further investigation into Rheb1’s upstream regulators and downstream effectors may provide innovative therapeutic directions.
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.
文摘Chemotherapy-induced intestinal mucositis(IM)is a prevalent complication affecting up to 80%of cancer patients undergoing treatment.Current therapies focus on symptomatic relief rather than addressing the underlying mechanism.Recent advances in integrative medicine highlight the potential of traditional Chinese medicine formulations as alternatives or adjuncts to existing therapies.In this context,this editorial discusses the recent results of a study published by Qiu et al,which investigates the multifaceted potential of modified Pulsatilla decoction(PD),a formulation of PD with licorice(Glycyrrhiza uralensis)and Ejiao(Colla corii asini),on 5-fluorouracil-induced IM in mice to alleviate clinical symptoms including diarrhea,weight loss,and intestinal damage.A series of histological,biochemical,bioinformatic,and microbiological assays evaluated body weight,diarrhea scores,inflammatory cytokine profiles,oxidative stress modulation,and microbiota composition.The findings indicated a reduction in diarrhea and oxidative stress,as well as an improvement in body weight and intestinal histopathology.Furthermore,the modified PD suppressed the TLR4/MyD88/nuclear factor kappa-B inflammatory pathway and down-regulated key proinflammatory cytokines.Moreover,the study underscores the role of gut microbiota in IM pathogenesis.Modified PD treatment reshaped microbial diversity by promoting beneficial genera such as Bacteroides acidifaciens while suppressing pathogenic species like Salmonella.These findings suggest that the therapeutic effects of the modified PD extend beyond inflammation modulation to encompass microbiome reprogramming and mucosal barrier repair.Although the study provides significant insights,several limitations still prevail.The broader implications of modified PD in gastrointestinal disorders and integrative oncology need further exploration.
文摘Objective: To study the prognostic value of the pathological margin and molecular margin marked by eIF4E and P53 protein in laryngeal carcinoma. Methods: The prognostic value of pathological and molecular margin was studied in 253 cases and 67 cases respectively, the latter were pathological negative margin chosen from the former. Immunohistochemisty was used to detect the expression of eIF4E and p53 proteins. Results: The rate of pathological, p53 and eIF4E positive margins was 20.2%, 19.4% and 32.8% respectively. The recurrent rate of those with positive margins was higher than that of negative margins, which including pathological margin (70.6% vs 35.1%, P =0.0000), p53 margin (69.2% vs 33.3%, P =0.018) and eIF4E margin (63.6% vs 28.9%, P =0.018); The survival rate of those with negative margins was higher than those with positive margins, including pathological margin (the 5-year cumulative survival rate was 37.52% and 64.37% respectively, P =0.0023), p53 margin (the 5-year cumulative survival rate was 24.62% and 75.69% respectively, P =0.0012) and eIF4E margin (the 5-year cumulative survival rate was 43.31% and 77.52% respectively, P =0.0006). Conclusion: The prognosis of those with both pathological and molecular positive margins was worse than that of the negative margins; Both the eIF4E and p53 were useful markers to pick out the poor prognostic patients from those with pathological negative margin, and the former seemed to be more potential.
基金supported by grants from National Institutes of Health (HL093429 and HL107526 to S.-Y.C.)
文摘Vascular smooth muscle cell （VSMC） differentiation and proliferation are two important physiological proc- esses during vascular development. The phenotypic alteration from differentiated to proliferative VSMC contrib- utes to the development of several major cardiovascular diseases including atherosclerosis, hypertension, resteno- sis after angioplasty or bypass, diabetic vascular complications, and transplantation arteriopathy. Since the VSMC phenotype in these pathological conditions resembles that of developing VSMC during embryonic development, understanding of the molecular mechanisms that control VSMC differentiation will provide fundamental insights into the pathological processes of these cardiovascular diseases. Although VSMC differentiation is usually ac- companied by an irreversible cell cycle exit, VSMC proliferation and differentiation occur concurrently during embryonic development. The molecular mechanisms simultaneously regulating these two processes, however, remain largely unknown. Our recent study demonstrates that cell division cycle 7, a key regulator of cell cycle, promotes both VSMC differentiation and proliferation through different mechanisms during the initial phase of VSMC differentiation. Conversely, Kriappel-like factor 4 appears to be a repressor for both VSMC differentia- tion and proliferation. This review attempts to highlight the novel role of cell division cycle 7 in TGF-β-induced VSMC differentiation and proliferation. The role of K141ppel-like factor 4 in suppressing these two processes will also be discussed.
