BACKGROUND The transforming growth factor β(TGFβ) signaling pathway plays a crucial role in the development of liver fibrosis by activating TGFβ type Ⅱ receptor(TGFβR2), followed by the recruitment of TGFβR1 fin...BACKGROUND The transforming growth factor β(TGFβ) signaling pathway plays a crucial role in the development of liver fibrosis by activating TGFβ type Ⅱ receptor(TGFβR2), followed by the recruitment of TGFβR1 finally triggering downstream signaling pathway.AIM To find drugs targeting TGFβR2 that inhibit TGFβR1/TGFβR2 complex formation, theoretically inhibit TGFβ signaling pathway, and thereby ameliorate liver fibrosis.METHODS Food and Drug Administration-approved drugs were screened for binding affinity with TGFβR2 by virtual molecular docking. We identified 6 candidates and further explored their potential by Cell Counting Kit-8(CCK-8) cell cytotoxic experiment to validate toxicity and titrated the best cellular working concentrations. Next, we further demonstrated the detailed molecular working mechanisms using mutagenesis analysis. Finally, we used a mouse model to investigate its potential anti-liver fibrosis effect.RESULTS We identified 6 drug candidates. Among these 6 drugs, dihydroergotamine(DHE) shows great ability in reducing fibrotic gene expressions such as collagen, p-SMAD3, and α-SMA in TGFβ induced cellular model of liver fibrosis in LX-2 cells. Furthermore, we demonstrated that DHE binds to TGFβR2. Moreover, mutation of Leu27, Phe30, Thr51, Ser52, Ile53, and Glu55 of TGFβR2 disrupted the binding of TGFβR2 with DHE. In addition, DHE significantly improved liver fibrosis, as evidenced by Masson’s trichrome staining of liver sections. This is further supported by the width and the velocity of the portal vein, and serum markers of liver function. In line with those observations, DHE also decreased macrophages infiltration and extracellular matrix deposition in the liver.CONCLUSION DHE alleviates liver fibrosis by binding to TGFβR2 thereby suppressing TGFβ signaling pathway. We show here that as far as drug repurposing, DHE has great potential to treat liver fibrosis.展开更多
It has been recognized that salinity variability in the tropical Pacific is closely related to the Interdecadal Pacific Oscillation(IPO).Here,we use model simulations from 1900 to 2017 to illustrate obvious asymmetrie...It has been recognized that salinity variability in the tropical Pacific is closely related to the Interdecadal Pacific Oscillation(IPO).Here,we use model simulations from 1900 to 2017 to illustrate obvious asymmetries of salinity variability in the tropical Pacific during positive and negative IPO phases.The amplitude of salinity variability in the tropical Pacific during positive IPO phases is larger than that during negative IPO phases,with a more westward shift of a large Sea Surface Salinity(SSS)anomaly along the equator.Salinity budget analyses show that the asymmetry of salinity variability during positive and negative IPO phases is dominated by the difference in the surface forcing associated with the freshwater flux[FWF,precipitation(P)minus evaporation(E)],with a contribution of 40%–50%near the dateline on the equator.Moreover,the relationships between the salinity variability and its budget terms also show differences in their leadlag correlations during positive and negative IPO phases.These differences in salinity variability during different IPO phases produce asymmetric effects on seawater density which can reduce or enhance upper-ocean stratification.Therefore,the salinity effects may modulate the intensity of El Nino-Southern Oscillation(ENSO),resulting in an enhanced(reduced)El Nino but a reduced(enhanced)La Ni?a during positive(negative)IPO phases by 1.6℃psu^(-1)(1.3℃psu^(-1)),respectively.It is suggested that the asymmetry of salinity variability may be related to the recent change in ENSO amplitude associated with the IPO,which can help elucidate ENSO diversity.展开更多
Ocean salinity is an important variable that affects the ocean stratification.We compared the salinity and ocean stratification in the tropical Pacific derived from the Argo(Array for Real-time Geostrophic Oceanograph...Ocean salinity is an important variable that affects the ocean stratification.We compared the salinity and ocean stratification in the tropical Pacific derived from the Argo(Array for Real-time Geostrophic Oceanography data),EN4(Ensemble 4 analysis),SODA(the Simple Ocean Data Assimilation reanalysis),IAP(Institute of Atmospheric Physics data),and ORAS4(Ocean Reanalysis System 4)over 2005–2017.Results show that the spatial distribution of climatological mean of sea surface salinity(SSS)in all the products is consistent,and the low salinity region showed large deviation and strong dispersion.The Argo has the smallest RMSE and the highest correlation with the ensemble mean,while the IAP shows a high-salinity deviations relative to other datasets.All the products show high positive correlations between the sea surface density(SSD)and SSS with respect to the deviations of climatological mean from ensemble mean,suggesting that the SSD deviation may be mainly influenced by the SSS deviation.In the aspect of the ocean stratification,the mixed layer depth(MLD)climatological mean in the Argo shows the highest correlation with the ensemble mean,followed by EN4,IAP,ORAS4,and SODA.The Argo and EN4 show thicker barrier layer(BL)relative to the ensemble mean while the SODA displays the largest negative deviation in the tropical western Pacific.Furthermore,the EN4,ORAS4,and IAP underestimate the stability in the upper ocean at the depths of 20–140 m,while Argo overestimates ocean stability.The salinity fronts in the western-central equatorial Pacific from Argo,EN4,and ORAS4 are consistent,while those from SODA and IAP show large deviations with a westward position in amplitude of 0°–6°and 0°–10°,respectively.The SSS trend patterns from all the products are consistent in having ensemble mean with high spatial correlations of 0.95–0.97.展开更多
Polycystic ovary syndrome(PCOS)is an endocrine disorder caused by hypothalamic-pituitary-ovarian(HPO)axis dysfunction.In the field of gynecology and reproduction,PCOS has emerged as both a research hot spot and a chal...Polycystic ovary syndrome(PCOS)is an endocrine disorder caused by hypothalamic-pituitary-ovarian(HPO)axis dysfunction.In the field of gynecology and reproduction,PCOS has emerged as both a research hot spot and a challenging area of study.According to Chinese medicine,this disease is related to kidney deficiency,phlegm and dampness obstruction,blood stasis and interconnection,Chong pulse impassability,the lack of Ren pulse,and the loss of uterine nourishment,all of which affect the normal development and maturation of eggs as well as the duration at which menstrual blood stores.In this paper,based on the theoretical basis of“liver collects blood,regulates the flow of qi,and is the master of drainage,”we explore the rationality of the treatment of this disease from the perspective of“liver and kidney have the same origin”and the development of PCOS-related infertility in relation to dysfunctional internal organs.We also explore the feasibility of treatment from the perspective of“liver and kidney homology,”expand the ideas for treatment,as well as develop and innovate the application of organ identification in PCOS in relation to infertility.展开更多
Objective:To investigate the mechanism of action and efficacy of Shi-Pi-San(SPS)in the treatment of cirrhotic ascites based on intestinal flora and to provide new ideas for clinical research.Methods:We searched PubMed...Objective:To investigate the mechanism of action and efficacy of Shi-Pi-San(SPS)in the treatment of cirrhotic ascites based on intestinal flora and to provide new ideas for clinical research.Methods:We searched PubMed,CNKI,Wanfang and Wipu Chinese journal databases to collect randomized controlled trials of SPS in the treatment of cirrhotic ascites,extracted relevant data,and summarized them to analyze the relationship between intestinal flora and cirrhotic ascites.Results:The disorder of intestinal flora can lead to cirrhotic ascites,and the treatment of cirrhotic ascites with SPS has good efficacy,and SPS has positive effects in improving the status of intestinal flora,increasing the abundance of flora and inhibiting the growth of pathogenic bacteria.Conclusion:SPS has good long-term efficacy in the treatment of cirrhotic ascites,but the side effects and dosage criteria have not been extensively studied in clinical practice.展开更多
基金Supported by the Special Research Project for Capital Health Development,No.2022-2-2174the Beijing Municipal Science and Technology Commission,No.Z191100007619037.
文摘BACKGROUND The transforming growth factor β(TGFβ) signaling pathway plays a crucial role in the development of liver fibrosis by activating TGFβ type Ⅱ receptor(TGFβR2), followed by the recruitment of TGFβR1 finally triggering downstream signaling pathway.AIM To find drugs targeting TGFβR2 that inhibit TGFβR1/TGFβR2 complex formation, theoretically inhibit TGFβ signaling pathway, and thereby ameliorate liver fibrosis.METHODS Food and Drug Administration-approved drugs were screened for binding affinity with TGFβR2 by virtual molecular docking. We identified 6 candidates and further explored their potential by Cell Counting Kit-8(CCK-8) cell cytotoxic experiment to validate toxicity and titrated the best cellular working concentrations. Next, we further demonstrated the detailed molecular working mechanisms using mutagenesis analysis. Finally, we used a mouse model to investigate its potential anti-liver fibrosis effect.RESULTS We identified 6 drug candidates. Among these 6 drugs, dihydroergotamine(DHE) shows great ability in reducing fibrotic gene expressions such as collagen, p-SMAD3, and α-SMA in TGFβ induced cellular model of liver fibrosis in LX-2 cells. Furthermore, we demonstrated that DHE binds to TGFβR2. Moreover, mutation of Leu27, Phe30, Thr51, Ser52, Ile53, and Glu55 of TGFβR2 disrupted the binding of TGFβR2 with DHE. In addition, DHE significantly improved liver fibrosis, as evidenced by Masson’s trichrome staining of liver sections. This is further supported by the width and the velocity of the portal vein, and serum markers of liver function. In line with those observations, DHE also decreased macrophages infiltration and extracellular matrix deposition in the liver.CONCLUSION DHE alleviates liver fibrosis by binding to TGFβR2 thereby suppressing TGFβ signaling pathway. We show here that as far as drug repurposing, DHE has great potential to treat liver fibrosis.
基金supported by the National Natural Science Foundation of China(NSFCGrant No.42030410)+3 种基金the Laoshan Laboratory(Grant No.LSKJ202202403)the National Key Research and Development Program on Monitoring,Early Warning and Prevention of Major Natural Disaster(Grant Nos.2019YFC1510004,2020YFA0608902)supported by the NSFC(Grant No.41976026)supported by the Startup Foundation for Introducing Talent of NUIST。
文摘It has been recognized that salinity variability in the tropical Pacific is closely related to the Interdecadal Pacific Oscillation(IPO).Here,we use model simulations from 1900 to 2017 to illustrate obvious asymmetries of salinity variability in the tropical Pacific during positive and negative IPO phases.The amplitude of salinity variability in the tropical Pacific during positive IPO phases is larger than that during negative IPO phases,with a more westward shift of a large Sea Surface Salinity(SSS)anomaly along the equator.Salinity budget analyses show that the asymmetry of salinity variability during positive and negative IPO phases is dominated by the difference in the surface forcing associated with the freshwater flux[FWF,precipitation(P)minus evaporation(E)],with a contribution of 40%–50%near the dateline on the equator.Moreover,the relationships between the salinity variability and its budget terms also show differences in their leadlag correlations during positive and negative IPO phases.These differences in salinity variability during different IPO phases produce asymmetric effects on seawater density which can reduce or enhance upper-ocean stratification.Therefore,the salinity effects may modulate the intensity of El Nino-Southern Oscillation(ENSO),resulting in an enhanced(reduced)El Nino but a reduced(enhanced)La Ni?a during positive(negative)IPO phases by 1.6℃psu^(-1)(1.3℃psu^(-1)),respectively.It is suggested that the asymmetry of salinity variability may be related to the recent change in ENSO amplitude associated with the IPO,which can help elucidate ENSO diversity.
基金Supported by the National Key Research and Development Program on MonitoringEarly Warning and Prevention of Major Natural Disaster (No.2019YFC1510004)the Laoshan Laboratory (No.LSKJ202202403)。
文摘Ocean salinity is an important variable that affects the ocean stratification.We compared the salinity and ocean stratification in the tropical Pacific derived from the Argo(Array for Real-time Geostrophic Oceanography data),EN4(Ensemble 4 analysis),SODA(the Simple Ocean Data Assimilation reanalysis),IAP(Institute of Atmospheric Physics data),and ORAS4(Ocean Reanalysis System 4)over 2005–2017.Results show that the spatial distribution of climatological mean of sea surface salinity(SSS)in all the products is consistent,and the low salinity region showed large deviation and strong dispersion.The Argo has the smallest RMSE and the highest correlation with the ensemble mean,while the IAP shows a high-salinity deviations relative to other datasets.All the products show high positive correlations between the sea surface density(SSD)and SSS with respect to the deviations of climatological mean from ensemble mean,suggesting that the SSD deviation may be mainly influenced by the SSS deviation.In the aspect of the ocean stratification,the mixed layer depth(MLD)climatological mean in the Argo shows the highest correlation with the ensemble mean,followed by EN4,IAP,ORAS4,and SODA.The Argo and EN4 show thicker barrier layer(BL)relative to the ensemble mean while the SODA displays the largest negative deviation in the tropical western Pacific.Furthermore,the EN4,ORAS4,and IAP underestimate the stability in the upper ocean at the depths of 20–140 m,while Argo overestimates ocean stability.The salinity fronts in the western-central equatorial Pacific from Argo,EN4,and ORAS4 are consistent,while those from SODA and IAP show large deviations with a westward position in amplitude of 0°–6°and 0°–10°,respectively.The SSS trend patterns from all the products are consistent in having ensemble mean with high spatial correlations of 0.95–0.97.
文摘Polycystic ovary syndrome(PCOS)is an endocrine disorder caused by hypothalamic-pituitary-ovarian(HPO)axis dysfunction.In the field of gynecology and reproduction,PCOS has emerged as both a research hot spot and a challenging area of study.According to Chinese medicine,this disease is related to kidney deficiency,phlegm and dampness obstruction,blood stasis and interconnection,Chong pulse impassability,the lack of Ren pulse,and the loss of uterine nourishment,all of which affect the normal development and maturation of eggs as well as the duration at which menstrual blood stores.In this paper,based on the theoretical basis of“liver collects blood,regulates the flow of qi,and is the master of drainage,”we explore the rationality of the treatment of this disease from the perspective of“liver and kidney have the same origin”and the development of PCOS-related infertility in relation to dysfunctional internal organs.We also explore the feasibility of treatment from the perspective of“liver and kidney homology,”expand the ideas for treatment,as well as develop and innovate the application of organ identification in PCOS in relation to infertility.
文摘Objective:To investigate the mechanism of action and efficacy of Shi-Pi-San(SPS)in the treatment of cirrhotic ascites based on intestinal flora and to provide new ideas for clinical research.Methods:We searched PubMed,CNKI,Wanfang and Wipu Chinese journal databases to collect randomized controlled trials of SPS in the treatment of cirrhotic ascites,extracted relevant data,and summarized them to analyze the relationship between intestinal flora and cirrhotic ascites.Results:The disorder of intestinal flora can lead to cirrhotic ascites,and the treatment of cirrhotic ascites with SPS has good efficacy,and SPS has positive effects in improving the status of intestinal flora,increasing the abundance of flora and inhibiting the growth of pathogenic bacteria.Conclusion:SPS has good long-term efficacy in the treatment of cirrhotic ascites,but the side effects and dosage criteria have not been extensively studied in clinical practice.
