Objective To analyze the multi-target mechanism of Paeoniflorin in the intervention of oral submucosal fibrosis(OSF)systematically,based on molecular dynamics simulation and network pharmacology.Methods Identify potential targets of Paeoniflorin were predicted by using database.OSF-related disease targets and identified drug-disease intersecting targets were screened.Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis were conducted to validate the molecular binding capabilities between Paeoniflorin and core targets.Finally,molecular dynamics simulations were performed to verify binding stability.Results A total of 20 overlapping targets were identified,including key genes such as transforming growth factor(TGF)-β1,interleukin(IL)-6,and tumor necrosis factor(TNF)-α.TGF-β1,IL-6,and TNF formed the core hub.The enrichment analysis revealed that the target molecules were significantly enriched in the TGF-β1,phosphatidylinositol 3-kinease-actin(PI3K-Akt),and nuclear factor κB(NF-κB)signaling pathways.Molecular docking confirmed high affinity binding of Paeoniflorin to targets including TGF-β1,while molecular dynamics simulations verified stable interactions between Paeoniflorin and both TGF-β1 and B-cell lymphoma-2 targets.Conclusion This study revealed that Paeoniflorin inhibits the inflammatory-fibrotic cascade of OSF through synergistic regulation of TGF-β1/Smad,PI3K-Akt and NF-κB pathways.

BACKGROUND: The American Heart Association (AHA) introduced the concept of cardiovascular-kidney-metabolic (CKM) health and stage, reflecting the interaction among metabolism, chronic kidney disease (CKD), and the cardiovascular system. However, the association between CKM stage and the long-term risk of cardiovascular disease (CVD) has not been validated. This study aimed to evaluate the long-term CVD risk associated with CKM health metrics and CKM stage using data from a population-based cohort study. METHODS: In total, 5293 CVD-free participants were followed up to around 13 years in the Chinese Multi-provincial Cohort Study (CMCS). Considering the pathophysiologic progression of CKM health metrics abnormalities (comprising obesity, central adiposity, prediabetes, diabetes, hypertriglyceridemia, CKD, and metabolic syndrome), participants were divided into CKM stages 0, 1, and 2. The time-dependent Cox regression models were used to estimate the cardiovascular risk associated with CKM health metrics and stage. Additionally, broader CVD outcomes were examined, with a specific assessment of the impact of stage 3 in 2581 participants from the CMCS-Beijing subcohort. RESULTS: Among participants, 91.2% (4825/5293) had at least one abnormal CKM health metric, 8.8% (468/5293), 13.3% (704/5293), and 77.9% (4121/5293) were in CKM stages 0, 1, and 2, respectively; and 710 incident CVD cases occurred during a median follow-up time of 13.3 years (interquartile range: 12.1 to 13.6 years). Participants with each poor CKM health metric exhibited significantly higher CVD risk. Compared with stage 0, the hazard ratio (HR) (95% confidence interval [CI]) for CVD incidence was 1.31 (0.84-2.04) in stage 1 and 2.27 (1.57-3.28) in stage 2. Significant interactive impacts existed between CKM stage and age or sex, with higher CVD risk related to increased CKM stages in participants aged <60 years or females. CONCLUSION These findings highlight the contribution of CKM health metrics and CKM stage to the long-term risk of CVD, suggesting the importance of multi-component recognition and management of poor CKM health in CVD prevention.
Humans ; Female ; Male ; Cardiovascular Diseases/etiology* ; Middle Aged ; Adult ; Cohort Studies ; Renal Insufficiency, Chronic/metabolism* ; Aged ; Risk Factors ; Metabolic Syndrome/metabolism* ; China ; East Asian People

Objective To analyze the multi-target mechanism of Paeoniflorin in the intervention of oral submucosal fibrosis(OSF)systematically,based on molecular dynamics simulation and network pharmacology.Methods Identify potential targets of Paeoniflorin were predicted by using database.OSF-related disease targets and identified drug-disease intersecting targets were screened.Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis were conducted to validate the molecular binding capabilities between Paeoniflorin and core targets.Finally,molecular dynamics simulations were performed to verify binding stability.Results A total of 20 overlapping targets were identified,including key genes such as transforming growth factor(TGF)-β1,interleukin(IL)-6,and tumor necrosis factor(TNF)-α.TGF-β1,IL-6,and TNF formed the core hub.The enrichment analysis revealed that the target molecules were significantly enriched in the TGF-β1,phosphatidylinositol 3-kinease-actin(PI3K-Akt),and nuclear factor κB(NF-κB)signaling pathways.Molecular docking confirmed high affinity binding of Paeoniflorin to targets including TGF-β1,while molecular dynamics simulations verified stable interactions between Paeoniflorin and both TGF-β1 and B-cell lymphoma-2 targets.Conclusion This study revealed that Paeoniflorin inhibits the inflammatory-fibrotic cascade of OSF through synergistic regulation of TGF-β1/Smad,PI3K-Akt and NF-κB pathways.

Objective:To explore the etiological rules of multifactorial refractory infertility patients by association analysis.Methods:A total of 283 patients with refractory infertility met the inclusion criteria from January 2019 to December 2021 in Nanping People's Hospital Affiliated to Fujian University of Traditional Chinese Medicine,were analyzed retrospectively.Using the Apriori algorithm,association rule analysis was performed on 7 etiological fac-tors:fallopian tube obstruction(FTO),intrauterine adhesions(IUA),ovarian dysfunction[diminished ovarian re-serve(DOR),premature ovarian insufficiency(POI)],polycystic ovary syndrome(PCOS),endometriosis(EMT),adenomyosis(AM)and thin endometrium(TE).Further stratified analysis was performed to assess the combina-tions of causes based on the severity of 4 major factors(EMT,FTO,IUA and DOR/POI).Results:①Among 283 patients,EMT(59.0%)and FTO(50.5%)were identified as the most frequent etiological factors,significantly more prevalent than the other causes(P=0.0000,P＜α').②The 5 most common etiological combinations were:FTO with EMT,PCOS with EMT,AM with FTO,DOR/POI with EMT,and AM with EMT.③After stratified analysis,it was found that the following combination of causes was ranked in the top three:with EMT stages I-IV being highly associated with FTO;the degree of merger between low stage with PCOS is high,while the degree of merger be-tween high stage with AM and DOR/POI is high.Different degrees of IUA are highly associated with EMT,FTO and DOR/POI,while severe IUA also being highly associated with TE.Both unilateral and bilateral FTO have a high degree of merger with EMT and AM.DOR and POI have a high degree of merger with EMT,FTO and AM.Conclusions:EMT and FTO are the main causes of refractory infertility.There are correlations among the causes combinations.The etiological factors combined with different stages of endometriosis are also different.These findings underscore the importance of a comprehensive diagnostic framework to address multifactorial etiologies and reduce missed diagnoses.

Objective:To explore the etiological rules of multifactorial refractory infertility patients by association analysis.Methods:A total of 283 patients with refractory infertility met the inclusion criteria from January 2019 to December 2021 in Nanping People's Hospital Affiliated to Fujian University of Traditional Chinese Medicine,were analyzed retrospectively.Using the Apriori algorithm,association rule analysis was performed on 7 etiological fac-tors:fallopian tube obstruction(FTO),intrauterine adhesions(IUA),ovarian dysfunction[diminished ovarian re-serve(DOR),premature ovarian insufficiency(POI)],polycystic ovary syndrome(PCOS),endometriosis(EMT),adenomyosis(AM)and thin endometrium(TE).Further stratified analysis was performed to assess the combina-tions of causes based on the severity of 4 major factors(EMT,FTO,IUA and DOR/POI).Results:①Among 283 patients,EMT(59.0%)and FTO(50.5%)were identified as the most frequent etiological factors,significantly more prevalent than the other causes(P=0.0000,P＜α').②The 5 most common etiological combinations were:FTO with EMT,PCOS with EMT,AM with FTO,DOR/POI with EMT,and AM with EMT.③After stratified analysis,it was found that the following combination of causes was ranked in the top three:with EMT stages I-IV being highly associated with FTO;the degree of merger between low stage with PCOS is high,while the degree of merger be-tween high stage with AM and DOR/POI is high.Different degrees of IUA are highly associated with EMT,FTO and DOR/POI,while severe IUA also being highly associated with TE.Both unilateral and bilateral FTO have a high degree of merger with EMT and AM.DOR and POI have a high degree of merger with EMT,FTO and AM.Conclusions:EMT and FTO are the main causes of refractory infertility.There are correlations among the causes combinations.The etiological factors combined with different stages of endometriosis are also different.These findings underscore the importance of a comprehensive diagnostic framework to address multifactorial etiologies and reduce missed diagnoses.

Objective:To explore the etiological rules of multifactorial refractory infertility patients by association analysis.Methods:A total of 283 patients with refractory infertility met the inclusion criteria from January 2019 to December 2021 in Nanping People's Hospital Affiliated to Fujian University of Traditional Chinese Medicine,were analyzed retrospectively.Using the Apriori algorithm,association rule analysis was performed on 7 etiological fac-tors:fallopian tube obstruction(FTO),intrauterine adhesions(IUA),ovarian dysfunction[diminished ovarian re-serve(DOR),premature ovarian insufficiency(POI)],polycystic ovary syndrome(PCOS),endometriosis(EMT),adenomyosis(AM)and thin endometrium(TE).Further stratified analysis was performed to assess the combina-tions of causes based on the severity of 4 major factors(EMT,FTO,IUA and DOR/POI).Results:①Among 283 patients,EMT(59.0%)and FTO(50.5%)were identified as the most frequent etiological factors,significantly more prevalent than the other causes(P=0.0000,P＜α').②The 5 most common etiological combinations were:FTO with EMT,PCOS with EMT,AM with FTO,DOR/POI with EMT,and AM with EMT.③After stratified analysis,it was found that the following combination of causes was ranked in the top three:with EMT stages I-IV being highly associated with FTO;the degree of merger between low stage with PCOS is high,while the degree of merger be-tween high stage with AM and DOR/POI is high.Different degrees of IUA are highly associated with EMT,FTO and DOR/POI,while severe IUA also being highly associated with TE.Both unilateral and bilateral FTO have a high degree of merger with EMT and AM.DOR and POI have a high degree of merger with EMT,FTO and AM.Conclusions:EMT and FTO are the main causes of refractory infertility.There are correlations among the causes combinations.The etiological factors combined with different stages of endometriosis are also different.These findings underscore the importance of a comprehensive diagnostic framework to address multifactorial etiologies and reduce missed diagnoses.

Objective:To explore the etiological rules of multifactorial refractory infertility patients by association analysis.Methods:A total of 283 patients with refractory infertility met the inclusion criteria from January 2019 to December 2021 in Nanping People's Hospital Affiliated to Fujian University of Traditional Chinese Medicine,were analyzed retrospectively.Using the Apriori algorithm,association rule analysis was performed on 7 etiological fac-tors:fallopian tube obstruction(FTO),intrauterine adhesions(IUA),ovarian dysfunction[diminished ovarian re-serve(DOR),premature ovarian insufficiency(POI)],polycystic ovary syndrome(PCOS),endometriosis(EMT),adenomyosis(AM)and thin endometrium(TE).Further stratified analysis was performed to assess the combina-tions of causes based on the severity of 4 major factors(EMT,FTO,IUA and DOR/POI).Results:①Among 283 patients,EMT(59.0%)and FTO(50.5%)were identified as the most frequent etiological factors,significantly more prevalent than the other causes(P=0.0000,P＜α').②The 5 most common etiological combinations were:FTO with EMT,PCOS with EMT,AM with FTO,DOR/POI with EMT,and AM with EMT.③After stratified analysis,it was found that the following combination of causes was ranked in the top three:with EMT stages I-IV being highly associated with FTO;the degree of merger between low stage with PCOS is high,while the degree of merger be-tween high stage with AM and DOR/POI is high.Different degrees of IUA are highly associated with EMT,FTO and DOR/POI,while severe IUA also being highly associated with TE.Both unilateral and bilateral FTO have a high degree of merger with EMT and AM.DOR and POI have a high degree of merger with EMT,FTO and AM.Conclusions:EMT and FTO are the main causes of refractory infertility.There are correlations among the causes combinations.The etiological factors combined with different stages of endometriosis are also different.These findings underscore the importance of a comprehensive diagnostic framework to address multifactorial etiologies and reduce missed diagnoses.

Objective:To explore the etiological rules of multifactorial refractory infertility patients by association analysis.Methods:A total of 283 patients with refractory infertility met the inclusion criteria from January 2019 to December 2021 in Nanping People's Hospital Affiliated to Fujian University of Traditional Chinese Medicine,were analyzed retrospectively.Using the Apriori algorithm,association rule analysis was performed on 7 etiological fac-tors:fallopian tube obstruction(FTO),intrauterine adhesions(IUA),ovarian dysfunction[diminished ovarian re-serve(DOR),premature ovarian insufficiency(POI)],polycystic ovary syndrome(PCOS),endometriosis(EMT),adenomyosis(AM)and thin endometrium(TE).Further stratified analysis was performed to assess the combina-tions of causes based on the severity of 4 major factors(EMT,FTO,IUA and DOR/POI).Results:①Among 283 patients,EMT(59.0%)and FTO(50.5%)were identified as the most frequent etiological factors,significantly more prevalent than the other causes(P=0.0000,P＜α').②The 5 most common etiological combinations were:FTO with EMT,PCOS with EMT,AM with FTO,DOR/POI with EMT,and AM with EMT.③After stratified analysis,it was found that the following combination of causes was ranked in the top three:with EMT stages I-IV being highly associated with FTO;the degree of merger between low stage with PCOS is high,while the degree of merger be-tween high stage with AM and DOR/POI is high.Different degrees of IUA are highly associated with EMT,FTO and DOR/POI,while severe IUA also being highly associated with TE.Both unilateral and bilateral FTO have a high degree of merger with EMT and AM.DOR and POI have a high degree of merger with EMT,FTO and AM.Conclusions:EMT and FTO are the main causes of refractory infertility.There are correlations among the causes combinations.The etiological factors combined with different stages of endometriosis are also different.These findings underscore the importance of a comprehensive diagnostic framework to address multifactorial etiologies and reduce missed diagnoses.

Objective:To explore the etiological rules of multifactorial refractory infertility patients by association analysis.Methods:A total of 283 patients with refractory infertility met the inclusion criteria from January 2019 to December 2021 in Nanping People's Hospital Affiliated to Fujian University of Traditional Chinese Medicine,were analyzed retrospectively.Using the Apriori algorithm,association rule analysis was performed on 7 etiological fac-tors:fallopian tube obstruction(FTO),intrauterine adhesions(IUA),ovarian dysfunction[diminished ovarian re-serve(DOR),premature ovarian insufficiency(POI)],polycystic ovary syndrome(PCOS),endometriosis(EMT),adenomyosis(AM)and thin endometrium(TE).Further stratified analysis was performed to assess the combina-tions of causes based on the severity of 4 major factors(EMT,FTO,IUA and DOR/POI).Results:①Among 283 patients,EMT(59.0%)and FTO(50.5%)were identified as the most frequent etiological factors,significantly more prevalent than the other causes(P=0.0000,P＜α').②The 5 most common etiological combinations were:FTO with EMT,PCOS with EMT,AM with FTO,DOR/POI with EMT,and AM with EMT.③After stratified analysis,it was found that the following combination of causes was ranked in the top three:with EMT stages I-IV being highly associated with FTO;the degree of merger between low stage with PCOS is high,while the degree of merger be-tween high stage with AM and DOR/POI is high.Different degrees of IUA are highly associated with EMT,FTO and DOR/POI,while severe IUA also being highly associated with TE.Both unilateral and bilateral FTO have a high degree of merger with EMT and AM.DOR and POI have a high degree of merger with EMT,FTO and AM.Conclusions:EMT and FTO are the main causes of refractory infertility.There are correlations among the causes combinations.The etiological factors combined with different stages of endometriosis are also different.These findings underscore the importance of a comprehensive diagnostic framework to address multifactorial etiologies and reduce missed diagnoses.

Objective:To explore the etiological rules of multifactorial refractory infertility patients by association analysis.Methods:A total of 283 patients with refractory infertility met the inclusion criteria from January 2019 to December 2021 in Nanping People's Hospital Affiliated to Fujian University of Traditional Chinese Medicine,were analyzed retrospectively.Using the Apriori algorithm,association rule analysis was performed on 7 etiological fac-tors:fallopian tube obstruction(FTO),intrauterine adhesions(IUA),ovarian dysfunction[diminished ovarian re-serve(DOR),premature ovarian insufficiency(POI)],polycystic ovary syndrome(PCOS),endometriosis(EMT),adenomyosis(AM)and thin endometrium(TE).Further stratified analysis was performed to assess the combina-tions of causes based on the severity of 4 major factors(EMT,FTO,IUA and DOR/POI).Results:①Among 283 patients,EMT(59.0%)and FTO(50.5%)were identified as the most frequent etiological factors,significantly more prevalent than the other causes(P=0.0000,P＜α').②The 5 most common etiological combinations were:FTO with EMT,PCOS with EMT,AM with FTO,DOR/POI with EMT,and AM with EMT.③After stratified analysis,it was found that the following combination of causes was ranked in the top three:with EMT stages I-IV being highly associated with FTO;the degree of merger between low stage with PCOS is high,while the degree of merger be-tween high stage with AM and DOR/POI is high.Different degrees of IUA are highly associated with EMT,FTO and DOR/POI,while severe IUA also being highly associated with TE.Both unilateral and bilateral FTO have a high degree of merger with EMT and AM.DOR and POI have a high degree of merger with EMT,FTO and AM.Conclusions:EMT and FTO are the main causes of refractory infertility.There are correlations among the causes combinations.The etiological factors combined with different stages of endometriosis are also different.These findings underscore the importance of a comprehensive diagnostic framework to address multifactorial etiologies and reduce missed diagnoses.