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
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
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
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
Schwann cells in peripheral nerves react to traumatic nerve injury by attempting to grow and regenerate.Howeve r,it is unclear what factors play a role in this process.In this study,we searched a GEO database and foun...Schwann cells in peripheral nerves react to traumatic nerve injury by attempting to grow and regenerate.Howeve r,it is unclear what factors play a role in this process.In this study,we searched a GEO database and found that expression of platelet factor 4 was markedly up-regulated after sciatic nerve injury.Platelet factor is an important molecule in cell apoptosis,diffe rentiation,survival,and proliferation.Further,polymerase chain reaction and immunohistochemical staining confirmed the change in platelet factor 4 in the sciatic nerve at different time points after injury.Enzyme-linked immunosorbent assay confirmed that platelet factor 4 was secreted by Schwann cells.We also found that silencing platelet factor 4 decreased the proliferation and migration of primary cultured Schwann cells,while exogenously applied platelet factor 4 stimulated Schwann cell prolife ration and migration and neuronal axon growth.Furthermore,knocking out platelet factor 4 inhibited the prolife ration of Schwann cells in injured rat sciatic nerve.These findings suggest that Schwann cell-secreted platelet factor 4 may facilitate peripheral nerve repair and regeneration by regulating Schwann cell activation and axon growth.Thus,platelet factor 4 may be a potential therapeutic target for traumatic peripheral nerve injury.展开更多
Pregnancy in women with monogenic diabetes is potentially complex,with significant implications for both maternal and fetal health.Among these,maturity-onset diabetes of the young(MODY)stands out as a prevalent monoge...Pregnancy in women with monogenic diabetes is potentially complex,with significant implications for both maternal and fetal health.Among these,maturity-onset diabetes of the young(MODY)stands out as a prevalent monogenic diabetes subtype frequently encountered in clinical practice.Each subtype of MODY requires a distinct approach tailored to the pregnancy,diverging from management strategies in non-pregnant individuals.Glucokinase MODY(GCK-MODY)typically does not require treatment outside of pregnancy,but special considerations arise when a woman with GCK-MODY becomes pregnant.The glycemic targets in GCK-MODY pregnancies are not exclusively dictated by the maternal/paternal MODY genotype but are also influenced by the genotype of the developing fetus.During pregnancy,the choice between sulfonylurea or insulin for treating hepatocyte nuclear factor 1-alpha(HNF1A)-MODY and HNF4A-MODY depends on the mother’s specific circumstances and the available expertise.Management of other rarer MODY subtypes is individu-alized,with decisions made on a case-by-case basis.Therefore,a collaborative approach involving expert diabetes and obstetric teams is crucial for the compre-hensive management of MODY pregnancies.展开更多
Non-alcoholic fatty liver disease (NAFLD) has become a global issue and a severe threat to public health.However, to date, no approved therapeutic drugs have been developed. Dietary interventions with naturalproducts ...Non-alcoholic fatty liver disease (NAFLD) has become a global issue and a severe threat to public health.However, to date, no approved therapeutic drugs have been developed. Dietary interventions with naturalproducts have shown promise in preventing and treating NAFLD. Sulforaphane (SFN) is a phytocompoundwith antioxidant and anti-inflammatory properties, and previous research has demonstrated that SFN canameliorate hepatic lipid accumulation and inflammation. However, the molecular mechanisms underlying thesebeneficial effects remain unclear. In this study, we confirmed the protective effects of SFN on excessive lipidaccumulation and inflammatory injury in a high-fat, high-fructose diet-induced non-alcoholic steatohepatitis(NASH) mouse model. We found that SFN attenuates the inflammatory injury in a macrophage cell line andthe liver of NASH mice, owing to the promotion of M1-type macrophage polarization toward the M2-type andthe regulation of inflammatory mediators. Further analysis demonstrated that this SFN-induced macrophageM2-type polarization occurs in a Krüppel-like factor 4 (KLF4)-dependent manner. In summary, we uncovereda new mechanism of action underlying SFN activity and provide evidence that dietary intervention with SFNmight be protective against NASH.展开更多
Objective Hepatic stellate cells(HSCs)play a crucial role in liver fibrosis.Early-stage liver fibrosis is reversible and intimately associated with the state of HSCs.Kruppel-like factor 4(KLF4)plays a pivotal role in ...Objective Hepatic stellate cells(HSCs)play a crucial role in liver fibrosis.Early-stage liver fibrosis is reversible and intimately associated with the state of HSCs.Kruppel-like factor 4(KLF4)plays a pivotal role in a wide array of physiological and pathological processes.This study aimed to investigate the effect of KLF4 on the proliferation,apoptosis and phenotype of quiescent HSCs Methods We designed a KLF4 lentiviral vector and a KLF4 siRNA lentiviral vector,to upregulate and silence KLF4 expression in human HSC LX-2 cells via transfection.Cell proliferation was assessed using the CCK-8 assay.Flow cytometry was used to detect the cell cycle distribution and apoptosis rate.Western blotting was used to determine the levels of some quiescence and activation markers of HSCs Results Overexpression of KLF4 significantly increased the levels of E-cadherin and ZO-1,which are quiescent HSC markers,while significantly decreased the levels of N-cadherin and a-SMA,known activated HSC markers.In contrast,cell proliferation and apoptosis rates were elevated in LX-2 cells in which KLF4 expression was silenced Conclusion KLF4 inhibits the proliferation and activation of human LX-2 HSCs.It might be a key regulatory protein in the maintenance of HSC quiescence and may serve as a target for the inhibition of hepatic fibrosis.展开更多
Hepatocyte nuclear factor 1 alpha(HNF1A),hepatocyte nuclear factor 4 alpha(HNF4A),and forkhead box protein A2(FOXA2)are key transcription factors that regulate a complex gene network in the liver,cre-ating a regulator...Hepatocyte nuclear factor 1 alpha(HNF1A),hepatocyte nuclear factor 4 alpha(HNF4A),and forkhead box protein A2(FOXA2)are key transcription factors that regulate a complex gene network in the liver,cre-ating a regulatory transcriptional loop.The Encode and ChIP-Atlas databases identify the recognition sites of these transcription factors in many glycosyltransferase genes.Our in silico analysis of HNF1A,HNF4A.and FOXA2 binding to the ten candidate glyco-genes studied in this work confirms a significant enrich-ment of these transcription factors specifically in the liver.Our previous studies identified HNF1A as a master regulator of fucosylation,glycan branching,and galactosylation of plasma glycoproteins.Here,we aimed to functionally validate the role of the three transcription factors on downstream glyco-gene transcriptional expression and the possible effect on glycan phenotype.We used the state-of-the-art clus-tered regularly interspaced short palindromic repeats/dead Cas9(CRISPR/dCas9)molecular tool for the downregulation of the HNF1A,HNF4A,and FOXA2 genes in HepG2 cells-a human liver cancer cell line.The results show that the downregulation of all three genes individually and in pairs affects the transcrip-tional activity of many glyco-genes,although downregulation of glyco-genes was not always followed by an unambiguous change in the corresponding glycan structures.The effect is better seen as an overall change in the total HepG2 N-glycome,primarily due to the extension of biantennary glycans.We propose an alternative way to evaluate the N-glycome composition via estimating the overall complexity of the glycome by quantifying the number of monomers in each glycan structure.We also propose a model showing feedback loops with the mutual activation of HNF1A-FOXA2 and HNF4A-FOXA2 affecting glyco-genes and protein glycosylation in HepG2 cells.展开更多
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(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 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.
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.
基金supported by the National Natural Science Foundation of China,Nos.31730031,32130060the National Natural Science Foundation of China,No.31971276(to JH)+1 种基金the Natural Science Foundation of Jiangsu Province,No.BK20202013(to XG)the Natural Science Foundation of Jiangsu Higher Education Institutions of China(Major Program),No.19KJA320005(to JH)。
文摘Schwann cells in peripheral nerves react to traumatic nerve injury by attempting to grow and regenerate.Howeve r,it is unclear what factors play a role in this process.In this study,we searched a GEO database and found that expression of platelet factor 4 was markedly up-regulated after sciatic nerve injury.Platelet factor is an important molecule in cell apoptosis,diffe rentiation,survival,and proliferation.Further,polymerase chain reaction and immunohistochemical staining confirmed the change in platelet factor 4 in the sciatic nerve at different time points after injury.Enzyme-linked immunosorbent assay confirmed that platelet factor 4 was secreted by Schwann cells.We also found that silencing platelet factor 4 decreased the proliferation and migration of primary cultured Schwann cells,while exogenously applied platelet factor 4 stimulated Schwann cell prolife ration and migration and neuronal axon growth.Furthermore,knocking out platelet factor 4 inhibited the prolife ration of Schwann cells in injured rat sciatic nerve.These findings suggest that Schwann cell-secreted platelet factor 4 may facilitate peripheral nerve repair and regeneration by regulating Schwann cell activation and axon growth.Thus,platelet factor 4 may be a potential therapeutic target for traumatic peripheral nerve injury.
文摘Pregnancy in women with monogenic diabetes is potentially complex,with significant implications for both maternal and fetal health.Among these,maturity-onset diabetes of the young(MODY)stands out as a prevalent monogenic diabetes subtype frequently encountered in clinical practice.Each subtype of MODY requires a distinct approach tailored to the pregnancy,diverging from management strategies in non-pregnant individuals.Glucokinase MODY(GCK-MODY)typically does not require treatment outside of pregnancy,but special considerations arise when a woman with GCK-MODY becomes pregnant.The glycemic targets in GCK-MODY pregnancies are not exclusively dictated by the maternal/paternal MODY genotype but are also influenced by the genotype of the developing fetus.During pregnancy,the choice between sulfonylurea or insulin for treating hepatocyte nuclear factor 1-alpha(HNF1A)-MODY and HNF4A-MODY depends on the mother’s specific circumstances and the available expertise.Management of other rarer MODY subtypes is individu-alized,with decisions made on a case-by-case basis.Therefore,a collaborative approach involving expert diabetes and obstetric teams is crucial for the compre-hensive management of MODY pregnancies.
基金supported by the Science and Technology project of Henan Province(202102310142)the National Natural Science Foundation of China(32001806)。
文摘Non-alcoholic fatty liver disease (NAFLD) has become a global issue and a severe threat to public health.However, to date, no approved therapeutic drugs have been developed. Dietary interventions with naturalproducts have shown promise in preventing and treating NAFLD. Sulforaphane (SFN) is a phytocompoundwith antioxidant and anti-inflammatory properties, and previous research has demonstrated that SFN canameliorate hepatic lipid accumulation and inflammation. However, the molecular mechanisms underlying thesebeneficial effects remain unclear. In this study, we confirmed the protective effects of SFN on excessive lipidaccumulation and inflammatory injury in a high-fat, high-fructose diet-induced non-alcoholic steatohepatitis(NASH) mouse model. We found that SFN attenuates the inflammatory injury in a macrophage cell line andthe liver of NASH mice, owing to the promotion of M1-type macrophage polarization toward the M2-type andthe regulation of inflammatory mediators. Further analysis demonstrated that this SFN-induced macrophageM2-type polarization occurs in a Krüppel-like factor 4 (KLF4)-dependent manner. In summary, we uncovereda new mechanism of action underlying SFN activity and provide evidence that dietary intervention with SFNmight be protective against NASH.
基金supported by the National Natural Science Foundation of China(No.81071541).
文摘Objective Hepatic stellate cells(HSCs)play a crucial role in liver fibrosis.Early-stage liver fibrosis is reversible and intimately associated with the state of HSCs.Kruppel-like factor 4(KLF4)plays a pivotal role in a wide array of physiological and pathological processes.This study aimed to investigate the effect of KLF4 on the proliferation,apoptosis and phenotype of quiescent HSCs Methods We designed a KLF4 lentiviral vector and a KLF4 siRNA lentiviral vector,to upregulate and silence KLF4 expression in human HSC LX-2 cells via transfection.Cell proliferation was assessed using the CCK-8 assay.Flow cytometry was used to detect the cell cycle distribution and apoptosis rate.Western blotting was used to determine the levels of some quiescence and activation markers of HSCs Results Overexpression of KLF4 significantly increased the levels of E-cadherin and ZO-1,which are quiescent HSC markers,while significantly decreased the levels of N-cadherin and a-SMA,known activated HSC markers.In contrast,cell proliferation and apoptosis rates were elevated in LX-2 cells in which KLF4 expression was silenced Conclusion KLF4 inhibits the proliferation and activation of human LX-2 HSCs.It might be a key regulatory protein in the maintenance of HSC quiescence and may serve as a target for the inhibition of hepatic fibrosis.
基金the European Structural and Investment Funded Grant"Cardio Metabolic"(#KK.01.2.1.02.0321)the Croatian National Centre of Research Excellence in Personalized Healthcare Grant(#KK.01.1.1.01.0010)+2 种基金the European Regional Development Fund Grant,project"CRISPR/Cas9-CasMouse"(#KK.01.1.1.04.0085)the European Structural and Investment Funded Project of Centre of Competence in Molecular Diagnostics(#KK.01.2.2.03.0006)the Croatian National Centre of Research Excellence in Personalized Healthcare Grant(#KK.01.1.1.01.0010).
文摘Hepatocyte nuclear factor 1 alpha(HNF1A),hepatocyte nuclear factor 4 alpha(HNF4A),and forkhead box protein A2(FOXA2)are key transcription factors that regulate a complex gene network in the liver,cre-ating a regulatory transcriptional loop.The Encode and ChIP-Atlas databases identify the recognition sites of these transcription factors in many glycosyltransferase genes.Our in silico analysis of HNF1A,HNF4A.and FOXA2 binding to the ten candidate glyco-genes studied in this work confirms a significant enrich-ment of these transcription factors specifically in the liver.Our previous studies identified HNF1A as a master regulator of fucosylation,glycan branching,and galactosylation of plasma glycoproteins.Here,we aimed to functionally validate the role of the three transcription factors on downstream glyco-gene transcriptional expression and the possible effect on glycan phenotype.We used the state-of-the-art clus-tered regularly interspaced short palindromic repeats/dead Cas9(CRISPR/dCas9)molecular tool for the downregulation of the HNF1A,HNF4A,and FOXA2 genes in HepG2 cells-a human liver cancer cell line.The results show that the downregulation of all three genes individually and in pairs affects the transcrip-tional activity of many glyco-genes,although downregulation of glyco-genes was not always followed by an unambiguous change in the corresponding glycan structures.The effect is better seen as an overall change in the total HepG2 N-glycome,primarily due to the extension of biantennary glycans.We propose an alternative way to evaluate the N-glycome composition via estimating the overall complexity of the glycome by quantifying the number of monomers in each glycan structure.We also propose a model showing feedback loops with the mutual activation of HNF1A-FOXA2 and HNF4A-FOXA2 affecting glyco-genes and protein glycosylation in HepG2 cells.
