Nicotinamide adenine dinucleotide(NAD+)plays an essential role in cellular metabolism,mitochondrial homeostasis,inflammation,and senescence.However,the role of NAD+-regulated genes,including coding and long non-coding...Nicotinamide adenine dinucleotide(NAD+)plays an essential role in cellular metabolism,mitochondrial homeostasis,inflammation,and senescence.However,the role of NAD+-regulated genes,including coding and long non-coding genes in cancer development is poorly understood.We constructed a prediction model based on the expression level of NAD+metabolism-related genes(NMRGs).Furthermore,we validated the expression of NMRGs in gastric cancer(GC)tissues and cell lines;additionally,β-nicotinamide mononucleotide(NMN),a precursor of NAD+,was used to treat the GC cell lines to analyze its effects on the expression level of NMRGs lncRNAs and cellular proliferation,cell cycle,apoptosis,and senescence-associated secretory phenotype(SASP).A total of 13 NMRGs-related lncRNAs were selected to construct prognostic risk signatures,and patients with high-risk scores had a poor prognosis.Some immune checkpoint genes were upregulated in the high-risk group.In addition,cell cycle,epigenetics,and senescence were significantly downregulated in the high-risk group.Notably,we found that the levels of immune cell infiltration,including CD8 T cells,CD4 naïve T cells,CD4 memory-activated T cells,B memory cells,and naïve B cells,were significantly associated with risk scores.Furthermore,the treatment of NMN showed increased proliferation of AGS and MKN45 cells.In addition,the expression of SASP factors(IL6,IL8,IL10,TGF-β,and TNF-α)was significantly decreased after NMN treatment.We conclude that the lncRNAs associated with NAD+metabolism can potentially be used as biomarkers for predicting clinical outcomes of GC patients.展开更多
Background:Nonalcoholic fatty liver disease(NAFLD)is one of the most common chronic liver diseases globally.Hepatic stellate cells(HSCs)are the major effector cells of liver fibrosis.HSCs contain abundant lipid drople...Background:Nonalcoholic fatty liver disease(NAFLD)is one of the most common chronic liver diseases globally.Hepatic stellate cells(HSCs)are the major effector cells of liver fibrosis.HSCs contain abundant lipid droplets(LDs)in their cytoplasm during quiescence.Perilipin 5(PLIN 5)is a LD surface-associated protein that plays a crucial role in lipid homeostasis.However,little is known about the role of PLIN 5 in HSC activation.Methods:PLIN 5 was overexpressed in HSCs of Sprague–Dawley rats by lentivirus transfection.At the same time,PLIN 5 gene knockout mice were constructed and fed with a high-fat diet(HFD)for 20 weeks to study the role of PLIN 5 in NAFLD.The corresponding reagent kits were used to measure TG,GSH,Caspase 3 activity,ATP level,and mitochondrial DNA copy number.Metabolomic analysis of mice liver tissue metabolism was performed based on UPLC-MS/MS.AMPK,mitochondrial function,cell proliferation,and apoptosis-related genes and proteins were detected by western blotting and qPCR.Results:Overexpression of PLIN 5 in activated HSCs led to a decrease in ATP levels in mitochondria,inhibition of cell proliferation,and a significant increase in cell apoptosis through AMPK activation.In addition,compared with the HFD-fed C57BL/6J mice,PLIN 5 knockout mice fed with HFD showed reduced liver fat deposition,decreased LD abundance and size,and reduced liver fibrosis.Conclusion:These findings highlight the unique regulatory role of PLIN 5 in HSCs and the role of PLIN 5 in the fibrosis process of NAFLD.展开更多
The activation of some oncogenes promote cancer cell proliferation and growth,facilitate cancer progression and metastasis by induce DNA replication stress,even genome instability.Activation of the cyclic GMP-AMP synt...The activation of some oncogenes promote cancer cell proliferation and growth,facilitate cancer progression and metastasis by induce DNA replication stress,even genome instability.Activation of the cyclic GMP-AMP synthase(cGAS)mediates classical DNA sensing,is involved in genome instability,and is linked to various tumor development or therapy.However,the function of cGAS in gastric cancer remains elusive.In this study,the TCGA database and retrospective immunohistochemical analyses revealed substantially high cGAS expression in gastric cancer tissues and cell lines.By employing cGAS high-expression gastric cancer cell lines,including AGS and MKN45,ectopic silencing of cGAS caused a significant reduction in the proliferation of the cells,tumor growth,and mass in xenograft mice.Mechanistically,database analysis predicted a possible involvement of cGAS in the DNA damage response(DDR),further data through cells revealed protein interactions of the cGAS and MRE11-RAD50-NBN(MRN)complex,which activated cell cycle checkpoints,even increased genome instability in gastric cancer cells,thereby contributing to gastric cancer progression and sensitivity to treatment with DNA damaging agents.Furthermore,the upregulation of cGAS significantly exacerbated the prognosis of gastric cancer patients while improving radiotherapeutic outcomes.Therefore,we concluded that cGAS is involved in gastric cancer progression by fueling genome instability,implying that intervening in the cGAS pathway could be a practicable therapeutic approach for gastric cancer.展开更多
Helicobacter pylori infection,affecting over 4.4 billion individuals globally,is a leading cause of chronic gastritis,peptic ulcers and gastric cancer.At present,the standard therapeutic approach for H.pylori infectio...Helicobacter pylori infection,affecting over 4.4 billion individuals globally,is a leading cause of chronic gastritis,peptic ulcers and gastric cancer.At present,the standard therapeutic approach for H.pylori infection continues to rely on high-dose antibiotic regimens,despite growing concerns about antibiotic resistance and treatment-associated dysbiosis.Probiotics,particularly Lactobacillus species,have emerged as promising adjuncts due to their multifaceted anti-H.pylori mechanisms.However,only a limited number of existing strains have demonstrated efficacy in treating H.pylori infections.This study investigated the effects of Lactiplantibacillus plantarum HCS03-001(LP-HCS03)and Lacticaseibacillus paracasei HCS17-040(LPC-HCS17)against H.pylori using a mousemodel.In infected mice,administration of the combined probiotics with 1×10^(9) CFU each significantly decreased mRNA expression levels of ureA/ureB(P<0.001),increased the level of IL-10,and decreased the levels of IL-17 and TNF-α(P<0.001),which indicates that the intervention reduced gastric colonization,alleviated inflammation and promoted the restoration of the gastric mucosal barrier.The microbiota in both the stomach and intestines were reconstructed,with particularly pronounced effects observed in the stomach.These findings highlight LP-HCS03 and LPC-HCS17 as promising probiotics to augment H.pylori eradication while preserving microbial homeostasis.展开更多
基金supported by Zhengzhou Major Collaborative Innovation Project(No.18XTZX12003)Key Projects of Discipline Construction in Zhengzhou University(No.XKZDJC202001)+1 种基金National Key Research and Development Program in China(No.2020YFC2006100)Medical Service Capacity Improvement Project of Henan Province in China(Grant Number Yu Wei Medicine[2017]No.66).
文摘Nicotinamide adenine dinucleotide(NAD+)plays an essential role in cellular metabolism,mitochondrial homeostasis,inflammation,and senescence.However,the role of NAD+-regulated genes,including coding and long non-coding genes in cancer development is poorly understood.We constructed a prediction model based on the expression level of NAD+metabolism-related genes(NMRGs).Furthermore,we validated the expression of NMRGs in gastric cancer(GC)tissues and cell lines;additionally,β-nicotinamide mononucleotide(NMN),a precursor of NAD+,was used to treat the GC cell lines to analyze its effects on the expression level of NMRGs lncRNAs and cellular proliferation,cell cycle,apoptosis,and senescence-associated secretory phenotype(SASP).A total of 13 NMRGs-related lncRNAs were selected to construct prognostic risk signatures,and patients with high-risk scores had a poor prognosis.Some immune checkpoint genes were upregulated in the high-risk group.In addition,cell cycle,epigenetics,and senescence were significantly downregulated in the high-risk group.Notably,we found that the levels of immune cell infiltration,including CD8 T cells,CD4 naïve T cells,CD4 memory-activated T cells,B memory cells,and naïve B cells,were significantly associated with risk scores.Furthermore,the treatment of NMN showed increased proliferation of AGS and MKN45 cells.In addition,the expression of SASP factors(IL6,IL8,IL10,TGF-β,and TNF-α)was significantly decreased after NMN treatment.We conclude that the lncRNAs associated with NAD+metabolism can potentially be used as biomarkers for predicting clinical outcomes of GC patients.
基金Discipline Key Special ProjectGrant/Award Number:XKZDQY202001+7 种基金Henan Provincial Key R&D and Promotion Special ProjectGrant/Award Number:212102310033Henan Provincial Medical Science and Technology Tackling ProgramGrant/Award Number:LHGJ20220557Key R&D Program of ChinaGrant/Award Number:2020YFC2006100,2020YFC2009000 and 2020YFC2009006National Natural Science Foundation of ChinaGrant/Award Number:31471330 and 81870408。
文摘Background:Nonalcoholic fatty liver disease(NAFLD)is one of the most common chronic liver diseases globally.Hepatic stellate cells(HSCs)are the major effector cells of liver fibrosis.HSCs contain abundant lipid droplets(LDs)in their cytoplasm during quiescence.Perilipin 5(PLIN 5)is a LD surface-associated protein that plays a crucial role in lipid homeostasis.However,little is known about the role of PLIN 5 in HSC activation.Methods:PLIN 5 was overexpressed in HSCs of Sprague–Dawley rats by lentivirus transfection.At the same time,PLIN 5 gene knockout mice were constructed and fed with a high-fat diet(HFD)for 20 weeks to study the role of PLIN 5 in NAFLD.The corresponding reagent kits were used to measure TG,GSH,Caspase 3 activity,ATP level,and mitochondrial DNA copy number.Metabolomic analysis of mice liver tissue metabolism was performed based on UPLC-MS/MS.AMPK,mitochondrial function,cell proliferation,and apoptosis-related genes and proteins were detected by western blotting and qPCR.Results:Overexpression of PLIN 5 in activated HSCs led to a decrease in ATP levels in mitochondria,inhibition of cell proliferation,and a significant increase in cell apoptosis through AMPK activation.In addition,compared with the HFD-fed C57BL/6J mice,PLIN 5 knockout mice fed with HFD showed reduced liver fat deposition,decreased LD abundance and size,and reduced liver fibrosis.Conclusion:These findings highlight the unique regulatory role of PLIN 5 in HSCs and the role of PLIN 5 in the fibrosis process of NAFLD.
基金supported by Zhengzhou Major Collaborative Innovation Project(No.18XTZX12003)Key Projects of Discipline Construction in Zhengzhou University(No.XKZDJC202001)+2 种基金National Key Research and Development Program in China(No.2020YFC2006100)Excellent Foreign Scientist Studio of Henan Province in China(No.GZS2018001)Medical Service Capacity Improvement Project of Henan Province in China(Grant No.Yu Wei Medicine[2017]No.66).
文摘The activation of some oncogenes promote cancer cell proliferation and growth,facilitate cancer progression and metastasis by induce DNA replication stress,even genome instability.Activation of the cyclic GMP-AMP synthase(cGAS)mediates classical DNA sensing,is involved in genome instability,and is linked to various tumor development or therapy.However,the function of cGAS in gastric cancer remains elusive.In this study,the TCGA database and retrospective immunohistochemical analyses revealed substantially high cGAS expression in gastric cancer tissues and cell lines.By employing cGAS high-expression gastric cancer cell lines,including AGS and MKN45,ectopic silencing of cGAS caused a significant reduction in the proliferation of the cells,tumor growth,and mass in xenograft mice.Mechanistically,database analysis predicted a possible involvement of cGAS in the DNA damage response(DDR),further data through cells revealed protein interactions of the cGAS and MRE11-RAD50-NBN(MRN)complex,which activated cell cycle checkpoints,even increased genome instability in gastric cancer cells,thereby contributing to gastric cancer progression and sensitivity to treatment with DNA damaging agents.Furthermore,the upregulation of cGAS significantly exacerbated the prognosis of gastric cancer patients while improving radiotherapeutic outcomes.Therefore,we concluded that cGAS is involved in gastric cancer progression by fueling genome instability,implying that intervening in the cGAS pathway could be a practicable therapeutic approach for gastric cancer.
基金supported by the Overseas Training Program for Scientific and Technological Talents in Health and Family Planning of Henan Province(2018125)the 2022 Major Science and Technology Special Project of Henan Province(221100310200)the National Natural Science Foundation of China(81870408).
文摘Helicobacter pylori infection,affecting over 4.4 billion individuals globally,is a leading cause of chronic gastritis,peptic ulcers and gastric cancer.At present,the standard therapeutic approach for H.pylori infection continues to rely on high-dose antibiotic regimens,despite growing concerns about antibiotic resistance and treatment-associated dysbiosis.Probiotics,particularly Lactobacillus species,have emerged as promising adjuncts due to their multifaceted anti-H.pylori mechanisms.However,only a limited number of existing strains have demonstrated efficacy in treating H.pylori infections.This study investigated the effects of Lactiplantibacillus plantarum HCS03-001(LP-HCS03)and Lacticaseibacillus paracasei HCS17-040(LPC-HCS17)against H.pylori using a mousemodel.In infected mice,administration of the combined probiotics with 1×10^(9) CFU each significantly decreased mRNA expression levels of ureA/ureB(P<0.001),increased the level of IL-10,and decreased the levels of IL-17 and TNF-α(P<0.001),which indicates that the intervention reduced gastric colonization,alleviated inflammation and promoted the restoration of the gastric mucosal barrier.The microbiota in both the stomach and intestines were reconstructed,with particularly pronounced effects observed in the stomach.These findings highlight LP-HCS03 and LPC-HCS17 as promising probiotics to augment H.pylori eradication while preserving microbial homeostasis.
