Metabolic dysfunction-associated steatotic liver disease(MASLD)has become the most prevalent chronic liver disease worldwide,affecting approximately 32%-38%of the adult population and posing a growing public health bu...Metabolic dysfunction-associated steatotic liver disease(MASLD)has become the most prevalent chronic liver disease worldwide,affecting approximately 32%-38%of the adult population and posing a growing public health burden.MASLD represents a continuous disease spectrum ranging from simple steatosis to metabolic dysfunction-associated steatohepatitis(MASH),progressive hepatic fibrosis,cirrhosis,and ultimately hepatocellular carcinoma(HCC).The pathological core of MASLD lies in disruption of hepatic lipid metabolic homeostasis,characterized by an imbalance among de novo lipogenesis,fatty acidβ-oxidation,and very-low-density lipoprotein(VLDL)-mediated lipid export.This metabolic disequilibrium subsequently drives inflammatory injury and fibrotic progression.Among the multiple regulatory pathways involved,thyroid hormone(TH)signaling has emerged as a central regulator of hepatic metabolic homeostasis.The liver is a major peripheral target organ of TH action,where TH predominantly exerts its metabolic effects through thyroid hormone receptorβ(TRβ).Large-scale epidemiological studies and metaanalyses have demonstrated that hypothyroidism is significantly associated with increased MASLD prevalence,more severe histological injury,and advanced hepatic fibrosis,suggesting that dysregulation of TH signaling may participate throughout the entire MASLD disease spectrum.At the molecular level,TH regulates hepatic lipid metabolism by coordinating suppression of lipogenesis,enhancement of mitochondrial fatty acid oxidation,and promotion of VLDL assembly and secretion through integrated genomic actions of the T3-TRβaxis and non-genomic signaling pathways.Across different stages of MASLD,TH signaling exerts stagedependent protective effects.In the steatosis stage,TH improves metabolic flexibility by modulating insulin sensitivity,glucose metabolism,and lipid droplet clearance,thereby alleviating early lipotoxic stress.During progression to MASH,TH attenuates inflammatory amplification by improving mitochondrial homeostasis,suppressing activation of the NOD-like receptor family pyrin domain containing 3(NLRP3)inflammasome,and modulating the gut-liver axis microenvironment.In advanced stages,TH signaling influences hepatic stellate cell activation and extracellular matrix deposition,partly through interaction with the transforming growth factor-β(TGF-β)/SMAD pathway,while alterations in intrahepatic TH availability,mediated by dynamic changes in iodothyronine deiodinase 1(DIO1),contribute to fibrosis progression and hepatocellular dedifferentiation.In hepatocellular carcinoma,coordinated downregulation of TRβand DIO1 establishes a tumor-associated hypothyroid state that promotes metabolic reprogramming and tumor progression.The clinical relevance of TH signaling in MASLD has been underscored by the recent approval of Resmetirom,a liver-targeted TRβ-selective agonist,for the treatment of non-cirrhotic MASH with moderate-to-severe fibrosis(F2-F3).This approval represents a landmark transition from mechanistic understanding to metabolismcentered precision therapy in MASLD.Clinical trials have demonstrated that Resmetirom not only improves key histological endpoints,including MASH resolution and fibrosis regression,but also favorably modulates atherogenic lipid profiles,highlighting the therapeutic potential of selectively targeting hepatic TH pathways.This review systematically summarizes the multidimensional regulatory roles of TH across the MASLD disease spectrum and discusses emerging diagnostic and therapeutic implications of THbased interventions,aiming to inform future mechanistic research and optimize clinical management strategies.展开更多
OBJECTIVE To investigate the role and mechanism of G protein-coupled receptor kinase 2(GRK2)involving in hepatocel ular carcinoma(HCC)progression.METHODS Cel Counting Kit 8 and tumor colony formation assay were design...OBJECTIVE To investigate the role and mechanism of G protein-coupled receptor kinase 2(GRK2)involving in hepatocel ular carcinoma(HCC)progression.METHODS Cel Counting Kit 8 and tumor colony formation assay were designed to detect HCC cell proliferation,wound healing assay was to detect HCC migration.The correlation between GRK2 and early growth response-1(EGR1)were detected by RT-PCR and real-time PCR assays.Co-immunoprecipitation and Western blot assay were adopted to detect the relationship between GRK2and insulin-like growth factor 1 receptor(IGF-1R)signaling pathway.RESULTS In this study we find that GRK2plays an inhibition role in IGF1-induced HCC cell proliferation and migration.Overexpression of GRK2 causes a decrease in EGR1 expression,while knockdown of GRK2 leads to the dramatically increase in EGR1 expression in the treatment of IGF1.Through co-immunoprecipitation and Western blot assay,we confirm that GRK2can interact with IGF-1R and inhibiting IGF1-induced activation of IGF1R signaling pathway.Silencing EGR1attenuates GRK2 overexpression-caused inhibition of cell proliferation,tumor colony number and migrationactivity,while overexpressing of EGR1 restores the antiproliferative and migratory effect by GRK2 overexpression in HCCLM3 cells.CONCLUSION Taken together,these results suggest that GRK2 may inhibit IGF1-induced HCC cell growth and migration through down-regulation of EGR1 and indicate that enforced GRK2 may offer a potential therapeutic approach against HCC.展开更多
OBJECTIVE To explore the mechanism of action of Danshen-Gegen on coronary heart disease.METHODS First using network pharmacology,according to oral bioavailability and drug-like properties,taking Danshen-Gegen as the r...OBJECTIVE To explore the mechanism of action of Danshen-Gegen on coronary heart disease.METHODS First using network pharmacology,according to oral bioavailability and drug-like properties,taking Danshen-Gegen as the research object,obtaining its active ingredients and targets in the pharmacological analysis platform of Chinese medicine system,using TTD,DrugBank and Disgenet database to obtain coronary heart disease targets,the active componentcoronary heart disease target network was constructed by CytosCape3.6.1 software,and the target protein interaction network was constructed by String database,Finally,GO and KEGG enrichment analysis was performed on the target in the DAVID database.RESULTS 61 active ingredients were screened from Danshen-Gegen,and 68 targets related to coronary heart disease were selected.GO analysis showed that Danshen-Gegen is involved in many biological processes such as transcription and inflammation of RNA polymeraseⅡpromoter.The target of treating coronary heart disease is mainly concentrated in extracellular space,plasma membrane and nucleus to treat coronary heart disease.The main effects of treatment of coronary heart disease are zinc ion binding,cytokine activity and sequence-specific DNA binding.The results of KEGG analysis showed that the regulation of Danshen-Gegen includes signaling pathways such as HIF-10,PI3K-Akt,TNF and Jak-STAT.CONCLUSION The combination of Danshen-Gegen has 61 active ingredients to play a role in the treatment of coronary heart disease through 68 targets and Jak-STAT,PI3K-Akt and other signaling path⁃ways.The results of this study provide a reference for further study of the pharmacological effects of Danshen-Gegen.展开更多
Objective:This paper aims to study the mutation of epidermal growth factor receptor(EGFR)gene in fresh cytological specimens from patients with lung adenocarcinoma,and to determine the prognosis of positive patients b...Objective:This paper aims to study the mutation of epidermal growth factor receptor(EGFR)gene in fresh cytological specimens from patients with lung adenocarcinoma,and to determine the prognosis of positive patients by tyrosine kinase inhibitor(TKI).Methods:A total of 313 specimens from needle aspiration and pleural effusion were collected in the Cancer Detection Center of the Fourth Hospital of Hebei Medical University.After HE and immunocytochemistry stainings,the specimens were diagnosed as lung adenocarcinoma by two cytology pathologists.The mutation of 18-21 exon was detectied using ARMS to observe mutations situation.Then,the objective response rate(ORR)and the progressionfree survival(PFS)between the targeted group and the chemotherapy group of patients were comparedith.Results:Among 313 cases,293 cases of lung adenocarcinoma were diagnosed,and DNA specimens were extracted from 288 cases.The success rate was about 98.3%.130 mutations were found and the rate was 45.1%.EGFR mutation of adenocarcinoma patients mainly occurred to females,nonsmokers,but had nothing to do with age.The ORR was statistically different between the targeted group with chemotherapy(P<0.01),and PFS curve of targeted group was on chemotherapy group.The efficacy and the survival time of targeted group and targeted and chemotherapy group were superior to that of chemotherapy group.The results of the EGFR mutation and the prognosis of the tested positive patients in the fresh cytology samples were consistent with that from previous literatures.Conclusion:The results of the test were accurate,and fresh cytological specimens can be used as a replacement for tumor tissue specimens.展开更多
文摘Metabolic dysfunction-associated steatotic liver disease(MASLD)has become the most prevalent chronic liver disease worldwide,affecting approximately 32%-38%of the adult population and posing a growing public health burden.MASLD represents a continuous disease spectrum ranging from simple steatosis to metabolic dysfunction-associated steatohepatitis(MASH),progressive hepatic fibrosis,cirrhosis,and ultimately hepatocellular carcinoma(HCC).The pathological core of MASLD lies in disruption of hepatic lipid metabolic homeostasis,characterized by an imbalance among de novo lipogenesis,fatty acidβ-oxidation,and very-low-density lipoprotein(VLDL)-mediated lipid export.This metabolic disequilibrium subsequently drives inflammatory injury and fibrotic progression.Among the multiple regulatory pathways involved,thyroid hormone(TH)signaling has emerged as a central regulator of hepatic metabolic homeostasis.The liver is a major peripheral target organ of TH action,where TH predominantly exerts its metabolic effects through thyroid hormone receptorβ(TRβ).Large-scale epidemiological studies and metaanalyses have demonstrated that hypothyroidism is significantly associated with increased MASLD prevalence,more severe histological injury,and advanced hepatic fibrosis,suggesting that dysregulation of TH signaling may participate throughout the entire MASLD disease spectrum.At the molecular level,TH regulates hepatic lipid metabolism by coordinating suppression of lipogenesis,enhancement of mitochondrial fatty acid oxidation,and promotion of VLDL assembly and secretion through integrated genomic actions of the T3-TRβaxis and non-genomic signaling pathways.Across different stages of MASLD,TH signaling exerts stagedependent protective effects.In the steatosis stage,TH improves metabolic flexibility by modulating insulin sensitivity,glucose metabolism,and lipid droplet clearance,thereby alleviating early lipotoxic stress.During progression to MASH,TH attenuates inflammatory amplification by improving mitochondrial homeostasis,suppressing activation of the NOD-like receptor family pyrin domain containing 3(NLRP3)inflammasome,and modulating the gut-liver axis microenvironment.In advanced stages,TH signaling influences hepatic stellate cell activation and extracellular matrix deposition,partly through interaction with the transforming growth factor-β(TGF-β)/SMAD pathway,while alterations in intrahepatic TH availability,mediated by dynamic changes in iodothyronine deiodinase 1(DIO1),contribute to fibrosis progression and hepatocellular dedifferentiation.In hepatocellular carcinoma,coordinated downregulation of TRβand DIO1 establishes a tumor-associated hypothyroid state that promotes metabolic reprogramming and tumor progression.The clinical relevance of TH signaling in MASLD has been underscored by the recent approval of Resmetirom,a liver-targeted TRβ-selective agonist,for the treatment of non-cirrhotic MASH with moderate-to-severe fibrosis(F2-F3).This approval represents a landmark transition from mechanistic understanding to metabolismcentered precision therapy in MASLD.Clinical trials have demonstrated that Resmetirom not only improves key histological endpoints,including MASH resolution and fibrosis regression,but also favorably modulates atherogenic lipid profiles,highlighting the therapeutic potential of selectively targeting hepatic TH pathways.This review systematically summarizes the multidimensional regulatory roles of TH across the MASLD disease spectrum and discusses emerging diagnostic and therapeutic implications of THbased interventions,aiming to inform future mechanistic research and optimize clinical management strategies.
基金The project supported by National Natural Science Foundation of China(81502123,81330081,81202596)Natural Science Foundation of Anhui Province(1308085QH130)+3 种基金Anhui Province Natural Science Foundation in University(KJ2014A119)Grants for Scientific Research of BSKY from Anhui Medical University(XJ201212)Specialized Research Fund for the Doctoral Program of Higher Education(20113420120006,20123420110003)Program for Tackling Key Problems in Science and Technology by Anhui Province(1301042098)
文摘OBJECTIVE To investigate the role and mechanism of G protein-coupled receptor kinase 2(GRK2)involving in hepatocel ular carcinoma(HCC)progression.METHODS Cel Counting Kit 8 and tumor colony formation assay were designed to detect HCC cell proliferation,wound healing assay was to detect HCC migration.The correlation between GRK2 and early growth response-1(EGR1)were detected by RT-PCR and real-time PCR assays.Co-immunoprecipitation and Western blot assay were adopted to detect the relationship between GRK2and insulin-like growth factor 1 receptor(IGF-1R)signaling pathway.RESULTS In this study we find that GRK2plays an inhibition role in IGF1-induced HCC cell proliferation and migration.Overexpression of GRK2 causes a decrease in EGR1 expression,while knockdown of GRK2 leads to the dramatically increase in EGR1 expression in the treatment of IGF1.Through co-immunoprecipitation and Western blot assay,we confirm that GRK2can interact with IGF-1R and inhibiting IGF1-induced activation of IGF1R signaling pathway.Silencing EGR1attenuates GRK2 overexpression-caused inhibition of cell proliferation,tumor colony number and migrationactivity,while overexpressing of EGR1 restores the antiproliferative and migratory effect by GRK2 overexpression in HCCLM3 cells.CONCLUSION Taken together,these results suggest that GRK2 may inhibit IGF1-induced HCC cell growth and migration through down-regulation of EGR1 and indicate that enforced GRK2 may offer a potential therapeutic approach against HCC.
文摘OBJECTIVE To explore the mechanism of action of Danshen-Gegen on coronary heart disease.METHODS First using network pharmacology,according to oral bioavailability and drug-like properties,taking Danshen-Gegen as the research object,obtaining its active ingredients and targets in the pharmacological analysis platform of Chinese medicine system,using TTD,DrugBank and Disgenet database to obtain coronary heart disease targets,the active componentcoronary heart disease target network was constructed by CytosCape3.6.1 software,and the target protein interaction network was constructed by String database,Finally,GO and KEGG enrichment analysis was performed on the target in the DAVID database.RESULTS 61 active ingredients were screened from Danshen-Gegen,and 68 targets related to coronary heart disease were selected.GO analysis showed that Danshen-Gegen is involved in many biological processes such as transcription and inflammation of RNA polymeraseⅡpromoter.The target of treating coronary heart disease is mainly concentrated in extracellular space,plasma membrane and nucleus to treat coronary heart disease.The main effects of treatment of coronary heart disease are zinc ion binding,cytokine activity and sequence-specific DNA binding.The results of KEGG analysis showed that the regulation of Danshen-Gegen includes signaling pathways such as HIF-10,PI3K-Akt,TNF and Jak-STAT.CONCLUSION The combination of Danshen-Gegen has 61 active ingredients to play a role in the treatment of coronary heart disease through 68 targets and Jak-STAT,PI3K-Akt and other signaling path⁃ways.The results of this study provide a reference for further study of the pharmacological effects of Danshen-Gegen.
文摘Objective:This paper aims to study the mutation of epidermal growth factor receptor(EGFR)gene in fresh cytological specimens from patients with lung adenocarcinoma,and to determine the prognosis of positive patients by tyrosine kinase inhibitor(TKI).Methods:A total of 313 specimens from needle aspiration and pleural effusion were collected in the Cancer Detection Center of the Fourth Hospital of Hebei Medical University.After HE and immunocytochemistry stainings,the specimens were diagnosed as lung adenocarcinoma by two cytology pathologists.The mutation of 18-21 exon was detectied using ARMS to observe mutations situation.Then,the objective response rate(ORR)and the progressionfree survival(PFS)between the targeted group and the chemotherapy group of patients were comparedith.Results:Among 313 cases,293 cases of lung adenocarcinoma were diagnosed,and DNA specimens were extracted from 288 cases.The success rate was about 98.3%.130 mutations were found and the rate was 45.1%.EGFR mutation of adenocarcinoma patients mainly occurred to females,nonsmokers,but had nothing to do with age.The ORR was statistically different between the targeted group with chemotherapy(P<0.01),and PFS curve of targeted group was on chemotherapy group.The efficacy and the survival time of targeted group and targeted and chemotherapy group were superior to that of chemotherapy group.The results of the EGFR mutation and the prognosis of the tested positive patients in the fresh cytology samples were consistent with that from previous literatures.Conclusion:The results of the test were accurate,and fresh cytological specimens can be used as a replacement for tumor tissue specimens.
