Metabolic Dysfunction-Associated Steatotic Liver Disease(MASLD)has emerged as a predominant cause of chronic liver disease globally,with its prevalence rising steadily each year.If left untreated,MASLD may progress to...Metabolic Dysfunction-Associated Steatotic Liver Disease(MASLD)has emerged as a predominant cause of chronic liver disease globally,with its prevalence rising steadily each year.If left untreated,MASLD may progress to metabolic dysfunction in associated steatohepatitis(MASH),a more severe condition that can irreversibly advance to liver fibrosis,cirrhosis,and even hepatocyte carcinoma(HCC).Recent studies have illuminated a pivotal link between dysregulated cholesterol metabolism and the pathogenesis and severity of MASLD.This underscores the critical need for a comprehensive exploration of the regulatory mechanisms underlying hepatic cholesterol metabolism in MASLD,as such insights could unveil new therapeutic targets and pave the way for early diagnosis and effective prevention strategies.Cyclocarya paliurus(Batal.)Iljinskaja,a plant known for both medicinal and dietary applications,has demonstrated diverse pharmacological properties,including hypoglycemic,lipid-regulating,and hepatoprotective effects.This study aimed to investigate the hypolipidemic and hepatoprotective activities of Cyclocarya paliurus extract(CCE)in a murine model of MASLD induced by a methionine-choline-deficient(MCD)diet.Simvastatin was employed as a positive control drug,while various doses of CCE were administered to assess its therapeutic potential.Meanwhile,the control and model groups received 0.5%sodium carboxymethyl cellulose(CMC-Na)once daily for 6 weeks.At the end of the treatment period,blood and liver samples were collected for biochemical analysis,histopathological assessment,and gene expression profiling.The findings revealed that CCE significantly reduced serum levels of aspartate aminotransferase(AST)and alanine aminotransferase(ALT)while enhancing the activities of cholinesterase(CHE)and high-density lipoprotein cholesterol(HDL-C).In liver tissues,CCE markedly decreased the levels of total cholesterol(TC)and triglycerides(TG),while simultaneously increasing hepatic HDL-C content.Histological analyses showed notable alleviation of pathological liver damage in CCE-treated mice.Molecular studies further demonstrated that CCE downregulated the expression of key genes and proteins involved in cholesterol synthesis,including SREBP2,LDLR,and HMGCR.Concurrently,it upregulated the expression of genes and proteins related to cholesterol transport,such as ABCG5 and ABCG8.Additionally,CCE mitigated inflammation by improving the expression levels of pro-inflammatory cytokines,including TNF-α and IL-6,and modulated oxidative stress markers,such as NRF2,KEAP1,and NQO1.Protein expression analyses revealed reduced levels of IL-6 and IL-1β,further corroborating its anti-inflammatory effects.In summary,C.paliurus exhibited potent hepatoprotective effects in MCD-induced MASLD mice.These protective mechanisms were closely linked to the upregulation of cholesterol transporters ABCG5/8 and the modulation of sterol regulatory element-binding protein 2(SREBP2).This study highlighted the therapeutic potential of C.paliurus as a promising intervention for MASLD and underscored its role in regulating cholesterol metabolism and mitigating inflammation and oxidative stress.展开更多
Cadmium(Cd)is a non-essential toxic heavy metal,seriously posing high environmental risks to human health.Digging genetic resources relevant to functional genes is important for understanding the metal absorption and ...Cadmium(Cd)is a non-essential toxic heavy metal,seriously posing high environmental risks to human health.Digging genetic resources relevant to functional genes is important for understanding the metal absorption and accumulation in crops and bioremediation of Cd-polluted environments.This study investigated a functionally uncharacterized ATP binding cassette transporter G family(ABCG)gene encoding a Pleiotropic Drug Resistance 20(PDR20)type metal transporter which is localized to the plasma membrane of rice.OsPDR20 was transcriptionally expressed in almost all tissues and organs in lifespan and was strongly induced in roots and shoots of young rice under Cd stress.Ectopic expression of OsPDR20 in a yeast mutant ycf1 sensitive to Cd conferred cellular tolerance with less Cd accumulation.Knockdown of OsPDR20 by RNA interference(RNAi)moderately attenuated root/shoot elongation and biomass,with reduced chlorophylls in rice grown under hydroponic medium with 2 and 10μmol/L Cd,but led to more Cd accumulation.A field trial of rice grown in a realistic Cd-contaminated soil(0.40 mg/kg)showed that RNAi plants growth and development were also compromised compared to wild-type(WT),with smaller panicles and lower spikelet fertility but little effect on yield of grains.However,OsPDR20 suppression resulted in unexpectedly higher levels of Cd accumulation in rice straw including lower leaves and culm and grain.These results suggest that OsPDR20 is actively involved in Cd accumulation and homeostasis in rice crops.The increased Cd accumulation in the RNAi plants has the potential application in phytoremediation of Cd-polluted wetland soils.展开更多
Background:Hyperuricemia is a metabolic disorder which is characterized by increased serum uric acid levels,which can contribute to serious health issues such as gout,cardiovascular disease,and kidney damage.Epigeneti...Background:Hyperuricemia is a metabolic disorder which is characterized by increased serum uric acid levels,which can contribute to serious health issues such as gout,cardiovascular disease,and kidney damage.Epigenetic modifications,for example,DNA methylation,exert a crucial function in gene regulation and have been implicated in various metabolic disorders.The ATP-Binding Cassette Subfamily G Member 2(ABCG2)gene is involved in uric acid excretion,and its expression can be influenced by methylation of its promoter region.Methods:This study involved the design of three guide RNA(gRNA)sequences targeting specific CpG sites within the ABCG2 promoter region.Using the Clustered Regularly Interspaced Short Palindromic Repeats/dead Cas9-Ten-Eleven Translocation 1(CRISPR/dCas9-TET1)system,these gRNAs were employed to guide targeted demethylation of the ABCG2 promoter in cell models.A non-targeting gRNA served as a negative control.The methylation status of the ABCG2 promoter and its effect on gene expression were assessed using bisulfite sequencing and qRT-PCR.Results:Among the gRNAs tested,gRNA2 and gRNA3 effectively guided the dCas9-TET1 complex to the ABCG2 promoter,resulting in significant demethylation.gRNA2 showed the most pronounced effect,leading to a substantial increase in ABCG2 expression.Clinical data analysis revealed that adolescents with hyperuricemia had higher uric acid levels compared to healthy controls,and a higher proportion of the hyperuricemia group reported a high-protein diet,suggesting a link between diet and ABCG2 methylation.Conclusion:The findings demonstrate that targeted demethylation of the ABCG2 promoter can significantly upregulate its expression,which may help modulate uric acid levels.These results indicate that dietary factors,such as a high-protein diet,could influence ABCG2 methylation and thus impact hyperuricemia.Advanced research is necessary to explore the therapeutic potential of aiming at epigenetic modifications for the treatment of hyperuricemia.展开更多
基金National Key Research and Development Program of China(Grant No.2022YFC3501700)the Beijing Municipal Natural Science Foundation(Grant No.7144219).
文摘Metabolic Dysfunction-Associated Steatotic Liver Disease(MASLD)has emerged as a predominant cause of chronic liver disease globally,with its prevalence rising steadily each year.If left untreated,MASLD may progress to metabolic dysfunction in associated steatohepatitis(MASH),a more severe condition that can irreversibly advance to liver fibrosis,cirrhosis,and even hepatocyte carcinoma(HCC).Recent studies have illuminated a pivotal link between dysregulated cholesterol metabolism and the pathogenesis and severity of MASLD.This underscores the critical need for a comprehensive exploration of the regulatory mechanisms underlying hepatic cholesterol metabolism in MASLD,as such insights could unveil new therapeutic targets and pave the way for early diagnosis and effective prevention strategies.Cyclocarya paliurus(Batal.)Iljinskaja,a plant known for both medicinal and dietary applications,has demonstrated diverse pharmacological properties,including hypoglycemic,lipid-regulating,and hepatoprotective effects.This study aimed to investigate the hypolipidemic and hepatoprotective activities of Cyclocarya paliurus extract(CCE)in a murine model of MASLD induced by a methionine-choline-deficient(MCD)diet.Simvastatin was employed as a positive control drug,while various doses of CCE were administered to assess its therapeutic potential.Meanwhile,the control and model groups received 0.5%sodium carboxymethyl cellulose(CMC-Na)once daily for 6 weeks.At the end of the treatment period,blood and liver samples were collected for biochemical analysis,histopathological assessment,and gene expression profiling.The findings revealed that CCE significantly reduced serum levels of aspartate aminotransferase(AST)and alanine aminotransferase(ALT)while enhancing the activities of cholinesterase(CHE)and high-density lipoprotein cholesterol(HDL-C).In liver tissues,CCE markedly decreased the levels of total cholesterol(TC)and triglycerides(TG),while simultaneously increasing hepatic HDL-C content.Histological analyses showed notable alleviation of pathological liver damage in CCE-treated mice.Molecular studies further demonstrated that CCE downregulated the expression of key genes and proteins involved in cholesterol synthesis,including SREBP2,LDLR,and HMGCR.Concurrently,it upregulated the expression of genes and proteins related to cholesterol transport,such as ABCG5 and ABCG8.Additionally,CCE mitigated inflammation by improving the expression levels of pro-inflammatory cytokines,including TNF-α and IL-6,and modulated oxidative stress markers,such as NRF2,KEAP1,and NQO1.Protein expression analyses revealed reduced levels of IL-6 and IL-1β,further corroborating its anti-inflammatory effects.In summary,C.paliurus exhibited potent hepatoprotective effects in MCD-induced MASLD mice.These protective mechanisms were closely linked to the upregulation of cholesterol transporters ABCG5/8 and the modulation of sterol regulatory element-binding protein 2(SREBP2).This study highlighted the therapeutic potential of C.paliurus as a promising intervention for MASLD and underscored its role in regulating cholesterol metabolism and mitigating inflammation and oxidative stress.
基金supported by the National Natural Science Foundation of China (No.21777072)。
文摘Cadmium(Cd)is a non-essential toxic heavy metal,seriously posing high environmental risks to human health.Digging genetic resources relevant to functional genes is important for understanding the metal absorption and accumulation in crops and bioremediation of Cd-polluted environments.This study investigated a functionally uncharacterized ATP binding cassette transporter G family(ABCG)gene encoding a Pleiotropic Drug Resistance 20(PDR20)type metal transporter which is localized to the plasma membrane of rice.OsPDR20 was transcriptionally expressed in almost all tissues and organs in lifespan and was strongly induced in roots and shoots of young rice under Cd stress.Ectopic expression of OsPDR20 in a yeast mutant ycf1 sensitive to Cd conferred cellular tolerance with less Cd accumulation.Knockdown of OsPDR20 by RNA interference(RNAi)moderately attenuated root/shoot elongation and biomass,with reduced chlorophylls in rice grown under hydroponic medium with 2 and 10μmol/L Cd,but led to more Cd accumulation.A field trial of rice grown in a realistic Cd-contaminated soil(0.40 mg/kg)showed that RNAi plants growth and development were also compromised compared to wild-type(WT),with smaller panicles and lower spikelet fertility but little effect on yield of grains.However,OsPDR20 suppression resulted in unexpectedly higher levels of Cd accumulation in rice straw including lower leaves and culm and grain.These results suggest that OsPDR20 is actively involved in Cd accumulation and homeostasis in rice crops.The increased Cd accumulation in the RNAi plants has the potential application in phytoremediation of Cd-polluted wetland soils.
基金supported by the Science and Technology Plan Program of Yantian District of Shenzhen(YTWS20200208)Project funding department is Shenzhen Yantian District Science and Technology Innovation Bureau。
文摘Background:Hyperuricemia is a metabolic disorder which is characterized by increased serum uric acid levels,which can contribute to serious health issues such as gout,cardiovascular disease,and kidney damage.Epigenetic modifications,for example,DNA methylation,exert a crucial function in gene regulation and have been implicated in various metabolic disorders.The ATP-Binding Cassette Subfamily G Member 2(ABCG2)gene is involved in uric acid excretion,and its expression can be influenced by methylation of its promoter region.Methods:This study involved the design of three guide RNA(gRNA)sequences targeting specific CpG sites within the ABCG2 promoter region.Using the Clustered Regularly Interspaced Short Palindromic Repeats/dead Cas9-Ten-Eleven Translocation 1(CRISPR/dCas9-TET1)system,these gRNAs were employed to guide targeted demethylation of the ABCG2 promoter in cell models.A non-targeting gRNA served as a negative control.The methylation status of the ABCG2 promoter and its effect on gene expression were assessed using bisulfite sequencing and qRT-PCR.Results:Among the gRNAs tested,gRNA2 and gRNA3 effectively guided the dCas9-TET1 complex to the ABCG2 promoter,resulting in significant demethylation.gRNA2 showed the most pronounced effect,leading to a substantial increase in ABCG2 expression.Clinical data analysis revealed that adolescents with hyperuricemia had higher uric acid levels compared to healthy controls,and a higher proportion of the hyperuricemia group reported a high-protein diet,suggesting a link between diet and ABCG2 methylation.Conclusion:The findings demonstrate that targeted demethylation of the ABCG2 promoter can significantly upregulate its expression,which may help modulate uric acid levels.These results indicate that dietary factors,such as a high-protein diet,could influence ABCG2 methylation and thus impact hyperuricemia.Advanced research is necessary to explore the therapeutic potential of aiming at epigenetic modifications for the treatment of hyperuricemia.
文摘目的通过动物实验和体外细胞实验探讨SAK-HV蛋白降胆固醇的机制。方法以0.5mg/kg浓度的SAK-HV蛋白治疗高脂喂养的Apo E-/-C57小鼠,酶法检测Apo E-/-C57小鼠血脂水平,定量PCR法(real-time quantitative PCR,q PCR)和蛋白质印迹(Western blot)法检测小肠ABCG5和ABCG8 m RNA和蛋白的表达水平。100μg/ml的SAK-HV蛋白作用caco-2细胞不同时间后,NBD胆固醇作为荧光探针检测SAK-HV蛋白对caco-2细胞胆固醇吸收的影响,q-PCR和Western blot法检测SAK-HV蛋白对caco-2细胞ABCG5和ABCG8 m RNA和蛋白表达水平的影响。结果 SAK-HV蛋白可以降低高脂喂养的Apo E-/-C57小鼠的血清胆固醇水平,同时上调小肠ABCG5和ABCG8 m RNA和蛋白的表达水平。体外实验表明,SAK-HV蛋白可以抑制caco-2细胞胆固醇的吸收,同时上调ABCG5和ABCG8 m RNA和蛋白的表达水平。结论 SAK-HV蛋白通过上调ABCG5和ABCG8的表达抑制小肠胆固醇的吸收从而降低血清胆固醇水平。
