Sophorae Flavescentis Radix(SFR)is a medicinal herb with many functions that are involved in anti-inflammation,antinociception,and anticancer.SFR is also used to treat a variety of itching diseases.Matrine(MT)is one o...Sophorae Flavescentis Radix(SFR)is a medicinal herb with many functions that are involved in anti-inflammation,antinociception,and anticancer.SFR is also used to treat a variety of itching diseases.Matrine(MT)is one of the main constituents in SFR and also has the effect of relieving itching,but the antipruritic mechanism is still unclear.Here,we investigated the effect of MT on antipruritus.In acute and chronic itch models,MT significantly inhibited the scratching behavior not only in acute itching induced by histamine(His),chloroquine(CQ)and compound 48/80 with a dose-depended manner,but also in the chronic pruritus models of Atopic dermatitis(AD)and Acetone-ether-water(AEW)in mice.Furthermore,MT can be detected in the blood after intraperitoneal injection(i.p.)and subcutaneous injection(s.c.).Finally,electrophysiological and calcium image results show that MT inhibits the excitatory synaptic transmission from dorsal root ganglion(DRG)to the dorsal horn of the spinal cord by suppressing presynaptic N-type calcium channels.Taken together,we believe that MT is a novel drug candidate in treating pruritus diseases,especially for histamine-independent and chronic pruritus,which might be attributed to inhibition of presynaptic N-type calcium channels.展开更多
Attention-deficit hyperactivity disorder(ADHD) is a neurodevelopmental disorder prevalent in schoolage children. At present, however, its etiologies and risk factors are unknown. Transmembrane α-amino-3-hydroxy-5-met...Attention-deficit hyperactivity disorder(ADHD) is a neurodevelopmental disorder prevalent in schoolage children. At present, however, its etiologies and risk factors are unknown. Transmembrane α-amino-3-hydroxy-5-methyl-4-isoxazolepropionicacid(AMPA) receptor regulatory protein γ-8(TARP γ-8,also known as calcium voltage-gated channel auxiliary subunit gamma 8(CACNG8)) is an auxiliary AMPA receptor(AMPAR) subunit. Here, we report an association between TARP γ-8 and ADHD,whereby adolescent TARP γ-8 knockout(KO) mice exhibitedADHD-likebehaviors,including hyperactivity, impulsivity, anxiety, impaired cognition,and memory deficits. Human single-nucleotide polymorphism(SNP) analysis also revealed strong associations between intronic alleles in CACNG8genes and ADHD susceptibility. In addition,synaptosomal proteomic analysis revealed dysfunction of the AMPA glutamate receptor complex in the hippocampi of TARP γ-8 KO mice.Proteomic analysis also revealed dysregulation of dopaminergic and glutamatergic transmissions in the prefrontal cortices of TARP γ-8 KO mice.Methylphenidate(MPH), which is commonly used to treat ADHD, significantly rescued the major behavioral deficits and abnormal synaptosomal proteins in TARP γ-8 KO mice. Notably, MPH significantly reversed the up-regulation of Grik2 and Slc6a3 in the prefrontal cortex. MPH also significantly improved synaptic AMPAR complex function by up-regulating other AMPAR auxiliary proteins in hippocampal synaptosomes. Taken together, our results suggest that TARP γ-8 is involved in the development of ADHD in humans.This study provides a useful alternative animal model with ADHD-like phenotypes related to TARP γ-8deficiency, which has great potential for the development of new therapies.展开更多
Dear Editor,Tetralogy of Fallot(TOF)is the most common complex congenital heart disease.Besides gene mutations and copy number variants,altered protein function induced by posttranscriptional or translational regulati...Dear Editor,Tetralogy of Fallot(TOF)is the most common complex congenital heart disease.Besides gene mutations and copy number variants,altered protein function induced by posttranscriptional or translational regulation also contributes to the onset of TOF.1 MiRNAs are short noncoding RNAs that bind to the 3’-UTR of target mRNAs to repress protein production.However,the causal link between miRNAs and TOF and the underlying mechanism has not been established.展开更多
Body weight regain often causes failure of obesity therapies while the underlying mechanism remains largely unknown.In this study,we report that immune cells,especially CD4+T cells,mediate the‘memory’of previous obe...Body weight regain often causes failure of obesity therapies while the underlying mechanism remains largely unknown.In this study,we report that immune cells,especially CD4+T cells,mediate the‘memory’of previous obese status.In a weight gain-loss-regain model,we found that C57BL/6J mice with an obesity history showed a much faster rate of body weight regain.This obesity memory could last for at least 2 months after previously obese mice were kept at the same body weight as non-obese mice.Surprisingly,such obesity memory was abrogated by dexamethasone treatment,whereas immunodeficient Rag1−/−and H2A−/−mice failed to establish such memory.Rag1−/−mice repossessed the obesity memory when immune cells or CD4+T cells isolated from previously obese mice were transferred.Furthermore,depletion of CD4+T cells led to obesity memory ablation.Taken together,we conclude that CD4+T cells mediate obesity memory and promote weight regain.展开更多
Owing to its remarkable benefits on metabolic health and its demonstrated presence in adult humans,beige or‘brite'adipocytes holdgreatpromiseto combat obesity and metabolic diseases.Delineation of the mechanisms ...Owing to its remarkable benefits on metabolic health and its demonstrated presence in adult humans,beige or‘brite'adipocytes holdgreatpromiseto combat obesity and metabolic diseases.Delineation of the mechanisms involved inadipocyte‘beiging'or‘browning'is thus of particular interest.展开更多
Hedgehog(Hh)signalling plays conserved roles in controlling embryonic development;its dysregulation causes many diseases including cancers.The G protein-coupled receptor Smoothened(Smo)is the key signal transducer of ...Hedgehog(Hh)signalling plays conserved roles in controlling embryonic development;its dysregulation causes many diseases including cancers.The G protein-coupled receptor Smoothened(Smo)is the key signal transducer of the Hh pathway,whose posttranslational regulation has been shown to be critical for its accumulation and activation.Ubiquitination has been reported an essential posttranslational regulation of Smo.Here,we identify a novel E3 ligase of Smo,Herc4,which binds to Smo,and regulates Hh signalling by controlling Smo ubiquitination and degradation.Interestingly,our data suggest that Herc4-mediated Smo degradation is regulated by Hh in PKA-primed phosphorylation-dependent and independent manners.展开更多
Characterized by multicellular migratory behavior and cooperative ability,collective cell migration plays critical roles in developmental,physiological and pathological processes,such as organogenesis,wound healing an...Characterized by multicellular migratory behavior and cooperative ability,collective cell migration plays critical roles in developmental,physiological and pathological processes,such as organogenesis,wound healing and tumor metastasis (Friedl and Gilmour,2009).Molecular features of collective cell migration including collective polarization,coordinated cytoskeletal activity,and guidance signaling have been recently investigated in a variety of in vivo and in vitro model systems (Scarpa and Mayor,2016),but many other aspects of regulatory mechanisms remain unexplored.展开更多
文摘Sophorae Flavescentis Radix(SFR)is a medicinal herb with many functions that are involved in anti-inflammation,antinociception,and anticancer.SFR is also used to treat a variety of itching diseases.Matrine(MT)is one of the main constituents in SFR and also has the effect of relieving itching,but the antipruritic mechanism is still unclear.Here,we investigated the effect of MT on antipruritus.In acute and chronic itch models,MT significantly inhibited the scratching behavior not only in acute itching induced by histamine(His),chloroquine(CQ)and compound 48/80 with a dose-depended manner,but also in the chronic pruritus models of Atopic dermatitis(AD)and Acetone-ether-water(AEW)in mice.Furthermore,MT can be detected in the blood after intraperitoneal injection(i.p.)and subcutaneous injection(s.c.).Finally,electrophysiological and calcium image results show that MT inhibits the excitatory synaptic transmission from dorsal root ganglion(DRG)to the dorsal horn of the spinal cord by suppressing presynaptic N-type calcium channels.Taken together,we believe that MT is a novel drug candidate in treating pruritus diseases,especially for histamine-independent and chronic pruritus,which might be attributed to inhibition of presynaptic N-type calcium channels.
基金supported by the National Natural Science Foundation of China (81872848, 81803509)National Major Special Project on New Drug Innovation grant(2018ZX09711001-004-003)+3 种基金CAMS Innovation Fund for Medical Sciences (2019-I2M-5-055)Hebei Natural Science Foundation(H2019206038)National Key R&D Program of China(2019YFA0801603)Natural Science Foundation of Jiangsu Province (BE2019707)。
文摘Attention-deficit hyperactivity disorder(ADHD) is a neurodevelopmental disorder prevalent in schoolage children. At present, however, its etiologies and risk factors are unknown. Transmembrane α-amino-3-hydroxy-5-methyl-4-isoxazolepropionicacid(AMPA) receptor regulatory protein γ-8(TARP γ-8,also known as calcium voltage-gated channel auxiliary subunit gamma 8(CACNG8)) is an auxiliary AMPA receptor(AMPAR) subunit. Here, we report an association between TARP γ-8 and ADHD,whereby adolescent TARP γ-8 knockout(KO) mice exhibitedADHD-likebehaviors,including hyperactivity, impulsivity, anxiety, impaired cognition,and memory deficits. Human single-nucleotide polymorphism(SNP) analysis also revealed strong associations between intronic alleles in CACNG8genes and ADHD susceptibility. In addition,synaptosomal proteomic analysis revealed dysfunction of the AMPA glutamate receptor complex in the hippocampi of TARP γ-8 KO mice.Proteomic analysis also revealed dysregulation of dopaminergic and glutamatergic transmissions in the prefrontal cortices of TARP γ-8 KO mice.Methylphenidate(MPH), which is commonly used to treat ADHD, significantly rescued the major behavioral deficits and abnormal synaptosomal proteins in TARP γ-8 KO mice. Notably, MPH significantly reversed the up-regulation of Grik2 and Slc6a3 in the prefrontal cortex. MPH also significantly improved synaptic AMPAR complex function by up-regulating other AMPAR auxiliary proteins in hippocampal synaptosomes. Taken together, our results suggest that TARP γ-8 is involved in the development of ADHD in humans.This study provides a useful alternative animal model with ADHD-like phenotypes related to TARP γ-8deficiency, which has great potential for the development of new therapies.
基金supported by grants from the National Key R&D Program of China(2021YFC2701101,H.W.)the National Natural Science Foundation of China(81930036 and 82150008,H.W.)the Commission for Science and Technology of Shanghai Municipality(20JC1418500,H.W.).
文摘Dear Editor,Tetralogy of Fallot(TOF)is the most common complex congenital heart disease.Besides gene mutations and copy number variants,altered protein function induced by posttranscriptional or translational regulation also contributes to the onset of TOF.1 MiRNAs are short noncoding RNAs that bind to the 3’-UTR of target mRNAs to repress protein production.However,the causal link between miRNAs and TOF and the underlying mechanism has not been established.
基金This work was supported by the National Natural Science Foundation of China(Grant 31301217)the Ministry of Science and Technology of China(Grants 2015BAI08B02 and 2014BAI02B01).
文摘Body weight regain often causes failure of obesity therapies while the underlying mechanism remains largely unknown.In this study,we report that immune cells,especially CD4+T cells,mediate the‘memory’of previous obese status.In a weight gain-loss-regain model,we found that C57BL/6J mice with an obesity history showed a much faster rate of body weight regain.This obesity memory could last for at least 2 months after previously obese mice were kept at the same body weight as non-obese mice.Surprisingly,such obesity memory was abrogated by dexamethasone treatment,whereas immunodeficient Rag1−/−and H2A−/−mice failed to establish such memory.Rag1−/−mice repossessed the obesity memory when immune cells or CD4+T cells isolated from previously obese mice were transferred.Furthermore,depletion of CD4+T cells led to obesity memory ablation.Taken together,we conclude that CD4+T cells mediate obesity memory and promote weight regain.
基金This work was supported by grants from the National Natural Science Foundation of China(31922033,91857105,32071136,32100922,and 32100942)the Natural Science Foundation of Jiangsu Province(BK20170014 and SWYY-002)+1 种基金the China Postdoctoral Science Foundation(2021M691524)the Fundamental Research Funds for the Central Universities(021414380511)。
文摘Owing to its remarkable benefits on metabolic health and its demonstrated presence in adult humans,beige or‘brite'adipocytes holdgreatpromiseto combat obesity and metabolic diseases.Delineation of the mechanisms involved inadipocyte‘beiging'or‘browning'is thus of particular interest.
基金This work was supported by grants from the National Basic Research Program of China (2011CB943902), the National Natural Science Foundation of China (30971679, 31071264, and 31271531), and the Fundamental Research Funds for the Central Universities (090314380019).
基金grants from the National Key Scientific Program of China(2011CB943902)the National Natural Science Foundation of China(30971679,3107126A,31271531,and 31771615)the Fundamental Research Funds for the Central Universities(090314380019).
文摘Hedgehog(Hh)signalling plays conserved roles in controlling embryonic development;its dysregulation causes many diseases including cancers.The G protein-coupled receptor Smoothened(Smo)is the key signal transducer of the Hh pathway,whose posttranslational regulation has been shown to be critical for its accumulation and activation.Ubiquitination has been reported an essential posttranslational regulation of Smo.Here,we identify a novel E3 ligase of Smo,Herc4,which binds to Smo,and regulates Hh signalling by controlling Smo ubiquitination and degradation.Interestingly,our data suggest that Herc4-mediated Smo degradation is regulated by Hh in PKA-primed phosphorylation-dependent and independent manners.
基金supported by grants from the National Natural Science Foundation of China(31171335 and 31271488)
文摘Characterized by multicellular migratory behavior and cooperative ability,collective cell migration plays critical roles in developmental,physiological and pathological processes,such as organogenesis,wound healing and tumor metastasis (Friedl and Gilmour,2009).Molecular features of collective cell migration including collective polarization,coordinated cytoskeletal activity,and guidance signaling have been recently investigated in a variety of in vivo and in vitro model systems (Scarpa and Mayor,2016),but many other aspects of regulatory mechanisms remain unexplored.