Nonalcoholic fatty liver disease(NAFLD)is a global health concern associated with significant morbidity and mortality.NAFLD is a spectrum of diseases originating from simple steatosis,progressing through nonalcoholic ...Nonalcoholic fatty liver disease(NAFLD)is a global health concern associated with significant morbidity and mortality.NAFLD is a spectrum of diseases originating from simple steatosis,progressing through nonalcoholic steatohepatitis(NASH),fibrosis,and cirrhosis that may lead to hepatocellular carcinoma(HCC).The pathogenesis of NAFLD is mediated by the triglyceride accumulation followed by proinflam-matory cytokines expression leading to inflammation,oxidative stress,and mitochondrial dysfunction de-noted as“two-hit hypothesis”,advancing with a“third hit”of insufficient hepatocyte proliferation,lead-ing to the increase in hepatic progenitor cells contributing to fibrosis and HCC.Wnt/β-catenin signaling is responsible for normal liver development,regeneration,hepatic metabolic zonation,ammonia and drug detoxification,hepatobiliary development,etc.,maintaining the overall liver homeostasis.The key regula-tors of canonical Wnt signaling such as LRP6,Wnt1,Wnt3a,β-catenin,GSK-3β,and APC are abnormally regulated in NAFLD.Many experimental studies have shown the aberrated Wnt/β-catenin signaling dur-ing the NAFLD progression and NASH to hepatic fibrosis and HCC.Therefore,in this review,we have em-phasized the role of Wnt/β-catenin signaling and its modulators that can potentially aid in the inhibition of NAFLD.展开更多
Diabetic cardiomyopathy(DCM)is one of the major heart complications of diabetic patients.Hydrogen sulfide(H2S)is now recognized as an important signaling molecule and has been shown to attenuate the development of dia...Diabetic cardiomyopathy(DCM)is one of the major heart complications of diabetic patients.Hydrogen sulfide(H2S)is now recognized as an important signaling molecule and has been shown to attenuate the development of diabetic cardiomyopathy.However,the underlying mechanisms linking H2S and the development of DCM have not been fully elucidated.In the present study,we therefore sought to explore the role and mechanism of H2S in the pathogenesis of DCM by establishing high glucose-induced injury model in neonatal rat cardiomyocytes(NRCMs)and H9c2 cells.Using cystathionine gamma-lyase(CSE)overexpression and CSE interference vectors transfection,the cell viability,cell apoptosis,and oxidative stress were determined and compared between the treatment of high glucose induction and exgenous NaHS administration.Meanwhile,the relationship between the CSE/H2S system and Wnt/beta-catenin pathway was analyzed and discussed in the high glucose-induced cardiomyocytes.Our results indicated that H2S played an important protective role in high glucose-induced apoptosis and oxidative stress in cardiomyocytes,as shown by the decreased reactive oxygen species and malondialdehyde levels,and the increased activities of superoxide dismutase,catalase and glutathione peroxidase.Moreover,H:S could attenuate the Wnt/p-catenin signalling pathway and up-regulate the expression of haem oxygenase-1(HO-1)and NAD(P)H:quinone oxidoreductase 1(NQOl)in the diabetic myocardium cells.Together,these results demonstrated that H2S could attenuate high glucoseinduced myocardial injury in rat cardiomyocytes by suppressing Wnt/p-catenin pathway.展开更多
The Author Reply:We sincerely appreciated the interest of Polyzos et al.,in our review article and sharing their improvised thoughts regarding the Wnt signaling modulators for the treatment of postmenopausal women wit...The Author Reply:We sincerely appreciated the interest of Polyzos et al.,in our review article and sharing their improvised thoughts regarding the Wnt signaling modulators for the treatment of postmenopausal women with osteoporosis and nonalcoholic fatty liver disease(NAFLD).Several experimental studies have showed that the aberrant Wnt/β-catenin signaling promotes the development and/or progression of a variety of chronic liver diseases including NAFLD[1,2].Therefore,our review emphasized on the modulation of Wnt/β-catenin signaling and the role of its mediators in NAFLD progression.Given that NAFLD prevalence is constantly increas-ing,and that osteoporosis is associated with women over 50 years of age with NAFLD[3],there is an unmet need for an effective treatment.Sclerostin blocks the canonical Wnt signaling pathway of bone formation.Therefore,romosozumab,a humanized anti-sclerostin monoclonal antibody,was approved for the treatment of osteoporosis.Romosozumab binds to sclerostin,permitting the en-gagement of Wnt ligands with their co-receptors,resulting in an increase in bone formation and bone mineral density.展开更多
Skeletal muscles are essential for locomotion,posture,and metabolic regulation.To understand physiological processes,exercise adaptation,and muscle-related disorders,it is critical to understand the molecular pathways...Skeletal muscles are essential for locomotion,posture,and metabolic regulation.To understand physiological processes,exercise adaptation,and muscle-related disorders,it is critical to understand the molecular pathways that underlie skeletal muscle function.The process of muscle contra ction,orchestrated by a complex interplay of molecular events,is at the core of skeletal muscle function.Muscle contraction is initiated by an action potential and neuromuscular transmission requiring a neuromuscular junction.Within muscle fibers,calcium ions play a critical role in mediating the interaction between actin and myosin filaments that generate force.Regulation of calcium release from the sarcoplasmic reticulum plays a key role in excitation-contraction coupling.The development and growth of skeletal muscle are regulated by a network of molecular pathways collectively known as myogenesis.Myogenic regulators coordinate the diffe rentiation of myoblasts into mature muscle fibers.Signaling pathways regulate muscle protein synthesis and hypertrophy in response to mechanical stimuli and nutrient availability.Seve ral muscle-related diseases,including congenital myasthenic disorders,sarcopenia,muscular dystrophies,and metabolic myopathies,are underpinned by dys regulated molecular pathways in skeletal muscle.Therapeutic interventions aimed at preserving muscle mass and function,enhancing regeneration,and improving metabolic health hold promise by targeting specific molecular pathways.Other molecular signaling pathways in skeletal muscle include the canonical Wnt signaling pathway,a critical regulator of myogenesis,muscle regeneration,and metabolic function,and the Hippo signaling pathway.In recent years,more details have been uncovered about the role of these two pathways during myogenesis and in developing and adult skeletal muscle fibers,and at the neuromuscular junction.In fact,research in the last few years now suggests that these two signaling pathways are interconnected and that they jointly control physiological and pathophysiological processes in muscle fibers.In this review,we will summarize and discuss the data on these two pathways,focusing on their concerted action next to their contribution to skeletal muscle biology.However,an in-depth discussion of the noncanonical Wnt pathway,the fibro/a dipogenic precursors,or the mechanosensory aspects of these pathways is not the focus of this review.展开更多
Liver cancer,and in particular hepatocellular carcinoma(HCC)is a disease of rising prevalence and incidence.To date,definitive treatment options include either surgical excision or ablation of the affected area.With i...Liver cancer,and in particular hepatocellular carcinoma(HCC)is a disease of rising prevalence and incidence.To date,definitive treatment options include either surgical excision or ablation of the affected area.With increasing research on several pathways that could be involved in the progression of HCC,new elements within these pathways emerge as potential targets for novel therapies.The WNT/β-catenin pathway favors the presence of M2 tumor-associated macrophages which in turn promote tumor growth and metastasis.The inhibition of this pathway is considered a good candidate for such targeted therapeutic interventions.Interestingly,as Huang et al show in their recently published article,Calculus bovis which is used in traditional Chinese medicine can exert an inhibitory effect on theβ-catenin pathway and become a potential candidate for targeted pharmacotherapy against liver cancer.展开更多
目的探讨甲基转移酶5(methyltransferase-like 5,METTL5)在三阴乳腺癌(triple-negative breast cancer,TNBC)中的作用和潜在机制。方法采用免疫组织化学方法和Western blot检测TNBC肿瘤组织和细胞系中METTL5的表达情况。用靶向METTL5的s...目的探讨甲基转移酶5(methyltransferase-like 5,METTL5)在三阴乳腺癌(triple-negative breast cancer,TNBC)中的作用和潜在机制。方法采用免疫组织化学方法和Western blot检测TNBC肿瘤组织和细胞系中METTL5的表达情况。用靶向METTL5的shRNA(shRNA-METTL5)转染TNBC细胞后,用CCK-8、集落形成、伤口愈合以及Transwell实验分别检测细胞增殖活性、迁移与侵袭,Western blot检测Wnt/β-catenin信号关键蛋白的表达。构建异种移植瘤模型,验证敲降METTL5对TNBC细胞在体内生长以及Wnt/β-catenin信号活性的影响。结果METTL5在TNBC肿瘤组织和细胞系中表达上调(P<0.01)。敲降METTL5可抑制TNBC细胞的增殖、迁移和侵袭并降低了Wnt/β-catenin信号分子β-catenin、细胞周期蛋白(Cyclin)D1、基质金属蛋白酶(MMP)-2和MMP-7的表达(均P<0.01)。体内实验显示,敲降METTL5减缓了移植瘤生长和Wnt/β-catenin信号活性。结论敲降METTL5能抑制TNBC细胞的增殖、迁移与侵袭,其作用可能与抑制Wnt/β-catenin信号通路有关。展开更多
基金supported by a grant from the Extramural Re-search Project,Indian Council of Medical Research,New Delhi,In-dia(58/30/2020/PHA/BMS dtd 9.11.2021).
文摘Nonalcoholic fatty liver disease(NAFLD)is a global health concern associated with significant morbidity and mortality.NAFLD is a spectrum of diseases originating from simple steatosis,progressing through nonalcoholic steatohepatitis(NASH),fibrosis,and cirrhosis that may lead to hepatocellular carcinoma(HCC).The pathogenesis of NAFLD is mediated by the triglyceride accumulation followed by proinflam-matory cytokines expression leading to inflammation,oxidative stress,and mitochondrial dysfunction de-noted as“two-hit hypothesis”,advancing with a“third hit”of insufficient hepatocyte proliferation,lead-ing to the increase in hepatic progenitor cells contributing to fibrosis and HCC.Wnt/β-catenin signaling is responsible for normal liver development,regeneration,hepatic metabolic zonation,ammonia and drug detoxification,hepatobiliary development,etc.,maintaining the overall liver homeostasis.The key regula-tors of canonical Wnt signaling such as LRP6,Wnt1,Wnt3a,β-catenin,GSK-3β,and APC are abnormally regulated in NAFLD.Many experimental studies have shown the aberrated Wnt/β-catenin signaling dur-ing the NAFLD progression and NASH to hepatic fibrosis and HCC.Therefore,in this review,we have em-phasized the role of Wnt/β-catenin signaling and its modulators that can potentially aid in the inhibition of NAFLD.
基金the Natural Science Foundation of Hubei Province of China(No.2011CDC146).
文摘Diabetic cardiomyopathy(DCM)is one of the major heart complications of diabetic patients.Hydrogen sulfide(H2S)is now recognized as an important signaling molecule and has been shown to attenuate the development of diabetic cardiomyopathy.However,the underlying mechanisms linking H2S and the development of DCM have not been fully elucidated.In the present study,we therefore sought to explore the role and mechanism of H2S in the pathogenesis of DCM by establishing high glucose-induced injury model in neonatal rat cardiomyocytes(NRCMs)and H9c2 cells.Using cystathionine gamma-lyase(CSE)overexpression and CSE interference vectors transfection,the cell viability,cell apoptosis,and oxidative stress were determined and compared between the treatment of high glucose induction and exgenous NaHS administration.Meanwhile,the relationship between the CSE/H2S system and Wnt/beta-catenin pathway was analyzed and discussed in the high glucose-induced cardiomyocytes.Our results indicated that H2S played an important protective role in high glucose-induced apoptosis and oxidative stress in cardiomyocytes,as shown by the decreased reactive oxygen species and malondialdehyde levels,and the increased activities of superoxide dismutase,catalase and glutathione peroxidase.Moreover,H:S could attenuate the Wnt/p-catenin signalling pathway and up-regulate the expression of haem oxygenase-1(HO-1)and NAD(P)H:quinone oxidoreductase 1(NQOl)in the diabetic myocardium cells.Together,these results demonstrated that H2S could attenuate high glucoseinduced myocardial injury in rat cardiomyocytes by suppressing Wnt/p-catenin pathway.
基金supported by a grant from the Extramural Re-search Project-Indian Council of Medical Research,New Delhi,In-dia(58/30/2020/PHA/BMS dtd.9.11.2021).
文摘The Author Reply:We sincerely appreciated the interest of Polyzos et al.,in our review article and sharing their improvised thoughts regarding the Wnt signaling modulators for the treatment of postmenopausal women with osteoporosis and nonalcoholic fatty liver disease(NAFLD).Several experimental studies have showed that the aberrant Wnt/β-catenin signaling promotes the development and/or progression of a variety of chronic liver diseases including NAFLD[1,2].Therefore,our review emphasized on the modulation of Wnt/β-catenin signaling and the role of its mediators in NAFLD progression.Given that NAFLD prevalence is constantly increas-ing,and that osteoporosis is associated with women over 50 years of age with NAFLD[3],there is an unmet need for an effective treatment.Sclerostin blocks the canonical Wnt signaling pathway of bone formation.Therefore,romosozumab,a humanized anti-sclerostin monoclonal antibody,was approved for the treatment of osteoporosis.Romosozumab binds to sclerostin,permitting the en-gagement of Wnt ligands with their co-receptors,resulting in an increase in bone formation and bone mineral density.
基金supported by the German Research Council(Deutsche Forschungsgemeinschaft,HA3309/3-1/2,HA3309/6-1,HA3309/7-1)。
文摘Skeletal muscles are essential for locomotion,posture,and metabolic regulation.To understand physiological processes,exercise adaptation,and muscle-related disorders,it is critical to understand the molecular pathways that underlie skeletal muscle function.The process of muscle contra ction,orchestrated by a complex interplay of molecular events,is at the core of skeletal muscle function.Muscle contraction is initiated by an action potential and neuromuscular transmission requiring a neuromuscular junction.Within muscle fibers,calcium ions play a critical role in mediating the interaction between actin and myosin filaments that generate force.Regulation of calcium release from the sarcoplasmic reticulum plays a key role in excitation-contraction coupling.The development and growth of skeletal muscle are regulated by a network of molecular pathways collectively known as myogenesis.Myogenic regulators coordinate the diffe rentiation of myoblasts into mature muscle fibers.Signaling pathways regulate muscle protein synthesis and hypertrophy in response to mechanical stimuli and nutrient availability.Seve ral muscle-related diseases,including congenital myasthenic disorders,sarcopenia,muscular dystrophies,and metabolic myopathies,are underpinned by dys regulated molecular pathways in skeletal muscle.Therapeutic interventions aimed at preserving muscle mass and function,enhancing regeneration,and improving metabolic health hold promise by targeting specific molecular pathways.Other molecular signaling pathways in skeletal muscle include the canonical Wnt signaling pathway,a critical regulator of myogenesis,muscle regeneration,and metabolic function,and the Hippo signaling pathway.In recent years,more details have been uncovered about the role of these two pathways during myogenesis and in developing and adult skeletal muscle fibers,and at the neuromuscular junction.In fact,research in the last few years now suggests that these two signaling pathways are interconnected and that they jointly control physiological and pathophysiological processes in muscle fibers.In this review,we will summarize and discuss the data on these two pathways,focusing on their concerted action next to their contribution to skeletal muscle biology.However,an in-depth discussion of the noncanonical Wnt pathway,the fibro/a dipogenic precursors,or the mechanosensory aspects of these pathways is not the focus of this review.
文摘Liver cancer,and in particular hepatocellular carcinoma(HCC)is a disease of rising prevalence and incidence.To date,definitive treatment options include either surgical excision or ablation of the affected area.With increasing research on several pathways that could be involved in the progression of HCC,new elements within these pathways emerge as potential targets for novel therapies.The WNT/β-catenin pathway favors the presence of M2 tumor-associated macrophages which in turn promote tumor growth and metastasis.The inhibition of this pathway is considered a good candidate for such targeted therapeutic interventions.Interestingly,as Huang et al show in their recently published article,Calculus bovis which is used in traditional Chinese medicine can exert an inhibitory effect on theβ-catenin pathway and become a potential candidate for targeted pharmacotherapy against liver cancer.
