ObjectiveTo investigate the mechanisms by which Mahuang Lianqiao Chixiaodoutang （MLC） improves obesity-type polycystic ovary syndrome （PCOS） through the phosphatidylinositol 3-kinase （PI3K）/protein kinase B （Akt） signaling pathway. MethodsThirty-six female Sprague-Dawley （SD） rats were randomly divided into a blank control group （Con） and an obesity-type PCOS model preparation group. The model was induced by gavage with letrozole （1 mg·kg^-1） combined with a high-fat diet （HFD）. After model establishment， the obesity-type PCOS model preparation group was further divided into the model group （Mod， normal saline）， metformin group （Met， 0.3 g·kg^-1）， low-dose MLC group （MLC-L， 4.3 g·kg^-1）， medium-dose MLC group （MLC-M， 8.6 g·kg^-1）， and high-dose MLC group （MLC-H， 17.2 g·kg^-1）. Active components of MLC and targets of obesity-type PCOS were screened from databases， a protein-protein interaction （PPI） network was constructed， and gene ontology（GO）and Kyoto Encyclopedia of Genes and Genomes （KEGG） pathway enrichment analysis was performed. The gut microbiota structure was analyzed based on 16S rRNA sequencing and correlated with network pharmacology pathways. Body weight and estrous cycle were dynamically monitored. Ovarian morphology was observed by hematoxylin-eosin （HE） staining. Cell apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling （TUNEL）. Enzyme-linked immunosorbent assay （ELISA） was used to detect levels of follicle-stimulating hormone （FSH）， luteinizing hormone （LH）， anti-Müllerian hormone （AMH）， testosterone （T）， and estradiol （E₂）. Western blot was used to detect the protein expression levels of phosphorylated PI3K/PI3K （p-PI3K/PI3K）， phosphorylated Akt/Akt （p-Akt/Akt）， B-cell lymphoma-2 （Bcl-2）， and Bcl-2-associated X protein （Bax）. ResultsNetwork pharmacology screening identified 124 active components of MLC and 408 overlapping targets between the herbal formula and the disease. Core targets such as Akt1 and Bcl-2 were revealed. As indicated by 16S rRNA sequencing， the abundances of Lachnospiraceae， Lachnoclostridium， and Dorea were increased in the MLC groups （P<0.05）， while the abundance of Veillonella was decreased （P<0.05）. KEGG correlation analysis integrating network pharmacology and gut microbiota data showed significant enrichment of the PI3K/Akt signaling pathway. Animal experiments showed that， compared with the Mod group， body weight decreased to normal levels in the Met， MLC-M， and MLC-H groups. The estrous cycle became regular. The number of corpora lutea increased and cystic follicles decreased. Serum levels of T， FSH， and LH/FSH were reduced （P<0.05， P<0.01）， while the E₂ level was increased （P<0.01）. Ovarian cell apoptosis was reduced （P<0.01）， and the protein expression levels of p-PI3K/PI3K， p-Akt/Akt， and Bcl-2 in ovarian tissue were significantly increased， whereas Bax protein expression was significantly decreased （P<0.05， P<0.01）. ConclusionMLC can regulate gut microbiota structure， effectively improve ovarian pathology in rats with obesity-type PCOS， and inhibit ovarian granulosa cell apoptosis. The mechanism may be associated with upregulation of the PI3K/Akt signaling pathway.

ObjectiveTo investigate the mechanisms by which Mahuang Lianqiao Chixiaodoutang （MLC） improves obesity-type polycystic ovary syndrome （PCOS） through the phosphatidylinositol 3-kinase （PI3K）/protein kinase B （Akt） signaling pathway. MethodsThirty-six female Sprague-Dawley （SD） rats were randomly divided into a blank control group （Con） and an obesity-type PCOS model preparation group. The model was induced by gavage with letrozole （1 mg·kg^-1） combined with a high-fat diet （HFD）. After model establishment， the obesity-type PCOS model preparation group was further divided into the model group （Mod， normal saline）， metformin group （Met， 0.3 g·kg^-1）， low-dose MLC group （MLC-L， 4.3 g·kg^-1）， medium-dose MLC group （MLC-M， 8.6 g·kg^-1）， and high-dose MLC group （MLC-H， 17.2 g·kg^-1）. Active components of MLC and targets of obesity-type PCOS were screened from databases， a protein-protein interaction （PPI） network was constructed， and gene ontology（GO）and Kyoto Encyclopedia of Genes and Genomes （KEGG） pathway enrichment analysis was performed. The gut microbiota structure was analyzed based on 16S rRNA sequencing and correlated with network pharmacology pathways. Body weight and estrous cycle were dynamically monitored. Ovarian morphology was observed by hematoxylin-eosin （HE） staining. Cell apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling （TUNEL）. Enzyme-linked immunosorbent assay （ELISA） was used to detect levels of follicle-stimulating hormone （FSH）， luteinizing hormone （LH）， anti-Müllerian hormone （AMH）， testosterone （T）， and estradiol （E₂）. Western blot was used to detect the protein expression levels of phosphorylated PI3K/PI3K （p-PI3K/PI3K）， phosphorylated Akt/Akt （p-Akt/Akt）， B-cell lymphoma-2 （Bcl-2）， and Bcl-2-associated X protein （Bax）. ResultsNetwork pharmacology screening identified 124 active components of MLC and 408 overlapping targets between the herbal formula and the disease. Core targets such as Akt1 and Bcl-2 were revealed. As indicated by 16S rRNA sequencing， the abundances of Lachnospiraceae， Lachnoclostridium， and Dorea were increased in the MLC groups （P<0.05）， while the abundance of Veillonella was decreased （P<0.05）. KEGG correlation analysis integrating network pharmacology and gut microbiota data showed significant enrichment of the PI3K/Akt signaling pathway. Animal experiments showed that， compared with the Mod group， body weight decreased to normal levels in the Met， MLC-M， and MLC-H groups. The estrous cycle became regular. The number of corpora lutea increased and cystic follicles decreased. Serum levels of T， FSH， and LH/FSH were reduced （P<0.05， P<0.01）， while the E₂ level was increased （P<0.01）. Ovarian cell apoptosis was reduced （P<0.01）， and the protein expression levels of p-PI3K/PI3K， p-Akt/Akt， and Bcl-2 in ovarian tissue were significantly increased， whereas Bax protein expression was significantly decreased （P<0.05， P<0.01）. ConclusionMLC can regulate gut microbiota structure， effectively improve ovarian pathology in rats with obesity-type PCOS， and inhibit ovarian granulosa cell apoptosis. The mechanism may be associated with upregulation of the PI3K/Akt signaling pathway.

Diabetic kidney disease（DKD） is a chronic kidney structural and functional disorder caused by diabetes. With the global prevalence of diabetes continuing to rise， DKD has gradually become a major cause of chronic kidney disease and end-stage renal disease（ESRD）， posing a serious threat to patients' quality of life and long-term health outcomes. Studies have shown that apoptosis plays a pivotal role in the development and progression of DKD， with its mechanisms involving abnormal activation of multiple signaling pathways such as Toll-like receptor 4（TLR4）/nuclear transcription factor-κB（NF-κB）/B-cell lymphoma-2（Bcl-2）/cysteinyl aspartate-specific proteinase（Caspase）-3， protein kinase R-like endoplasmic reticulum kinase（PERK）/eukaryotic initiation factor 2α（eIF2α）/activating transcript factor 4（ATF4）/CCAAT enhancer-binding protein homologous protein（CHOP）， phosphatidylinositol 3-kinase（PI3K）/protein kinase B（Akt）/glycogen synthase kinase-3β（GSK-3β）， Janus kinase 2（JAK2）/signal transducer and activator of transcription 3（STAT3）， adenosine monophosphate-activated protein kinase（AMPK）/mammalian target of rapamycin（mTOR） and silent information regulator 1（SIRT1）/tumor suppressor protein 53（p53）， thereby accelerating renal pathological damage in DKD. Extensive evidence-based medical studies have confirmed that traditional Chinese medicine（TCM）， leveraging its unique therapeutic advantages of multi-target， multi-component and multi-pathway approaches， has demonstrated remarkable efficacy and favorable safety profiles in treating DKD. Recent studies have demonstrated that active components of TCM can specifically target and modulate key effectors in apoptotic signaling pathways. Meanwhile， traditional compound formulations exert synergistic effects through multiple approaches such as replenishing deficiency and activating blood circulation， detoxifying and dredging collaterals， tonifying kidney essence， and removing stasis and purging turbidity， thereby comprehensively regulating critical pathological processes including endoplasmic reticulum stress and mitochondrial apoptosis pathways. This combined therapeutic approach of molecular targeting and holistic regulation provides novel strategies for delaying the progression of DKD. Based on this， this paper provides an in-depth analysis of key apoptotic signaling pathways and their regulatory mechanisms， while systematically summarizing recent research advances regarding the therapeutic effects of TCM active components， compound formulations， and proprietary Chinese medicines on DKD through modulation of these pathways， with particular emphasis on their underlying molecular mechanisms. These findings not only elucidate the modern scientific connotation and theoretical basis of TCM in treating DKD but also establish a solid theoretical and practical foundation for promoting the wider clinical application and further research of TCM in the field of DKD treatment.

Objective Exploring the therapeutic mechanism of Yishen Jiangzhuo Granules(YSJZG)on chronic kidney disease(CKD)based on mitochondrial dynamics and apoptosis of renal tubular epithelial cells.Methods The CKD model of rats with 5/6 nephrectomy was adopted and divided into 6 groups according to random number table:sham operation control group,model group,emodin group(500 mg/kg/d),Yishen Jiangzhuo granule low,middle and high dose groups.After 8 weeks of treatment with YSJZG,serum creatinine(SCR)and urea nitrogen(BUN),pathological changes of renal cortex,mitochondrial morphology and ultrastructure were detected,and mitochondrial kinetic protein in renal tubular epithelial cells was detected by immunohistochemistry(Drp1,Fis1)and fusion proteins(Opa1,Mfn1)were detected by Western blot,and apoptotic proteins(CytC,Bax)in cytoplasm and mitochondria were detected by real-time PCR.Results Renal injury:Compared with the model group,YSJZG groups significantly reduced the levels of SCR and BUN,renal tubular degeneration and necrosis,and mitochondrial structural damage in rats.Renal tubule mitochondrial dynamic protein:Compared with the model group,the expression of division proteins Drp1 and Fis1 was downregulated,the expression of fusion proteins Opa1 and Mfn1 was upregulated,and transmission electron microscopy observed that the mitochondrial fragmentation changes were relatively mild.Apoptosis related indicators and mtDNA copy number of renal tubular cells:Compared with the model group,the content of Bax protein in renal tubular epithelial cells of YSJZG groups increased significantly in cytoplasm(P<0.05)and decreased significantly in mitochondria(P<0.05).The content of CytC protein decreased significantly in cytoplasm(P<0.05)and increased significantly in mitochondria(P<0.05).The copy number of mtDNA increased significantly(P<0.05),and the total levels of SMAC,CytC and Bax mRNA decreased significantly(P<0.05).Correlation between mitochondrial dynamic protein and apoptosis in renal tubular cells:Pearson correlation analysis showed that the expression of Drp1 and Fis1 was negatively correlated with the expression of CytC in mitochondria,and positively correlated with the expression of CytC in cytoplasm.The expression levels of fusion proteins Opa1 and Mfn1 showed a significant positive correlation with CytC expression in mitochondria,and a significant negative correlation with CytC expression in cytoplasm.Conclusion YSJZG can significantly delay the progression of CKD,and its mechanism may be achieved by regulating mitochondrial dynamics of renal tubular epithelial cells,thereby inhibiting endogenous cell apoptosis pathway.

Background and Aims:Extrahepatic cholangiocarcinoma(ECCA)is a malignancy with insidious onset,strong invasiveness,and poor prognosis,characterized by a high postoperative recurrence rate and a 5-year overall survival of less than 20％.Most existing prognostic models are based on the Cox proportional hazards model,which is limited by the proportional hazards assumption and linearity constraints.The random survival forest(RSF)model,a novel machine learning algorithm,can capture complex interactions and nonlinear effects among variables;however,its application in ECCA remains scarce.Therefore,this study developed a prognostic model for ECCA patients after radical resection using the RSF algorithm,aiming to provide precise and individualized prognostic assessments and support clinical decision-making.Methods:A total of 515 postoperative ECCA patients from the SEER database(2016-2021)were retrospectively enrolled and randomly divided into a training set(n=361)and a test set(n=154).Demographic and clinical variables were collected.Cox models were developed using univariate and multivariate regression,while RSF models were constructed using variable importance(VIMP)and minimal depth methods.Model performance was evaluated using the concordance index(C-index),time-dependent area under the curve(AUC),Brier scores,calibration plots,and decision curve analysis.Survival differences were assessed using Kaplan-Meier analysis,and interpretability was enhanced through the use of SurvSHAP and SurvLIME.Results:Multivariate Cox regression identified seven independent prognostic factors:age,race,income,T stage,N stage,tumor size,and chemotherapy.The RSF model selected four key predictors:age,tumor size,lymph node positive rate,and chemotherapy.In the test cohort,the RSF model achieved a C-index of 0.751,outperforming the Cox model(0.711).The RSF model yielded AUCs of 0.843,0.749,and 0.814 at 1,2,and 3 years,respectively,with superior calibration,overall performance,and net clinical benefit.Nonlinear associations were observed for lymph node positive rate,age,and tumor size,while chemotherapy was associated with reduced mortality risk.Stratified survival curves indicated poorer prognosis in patients without chemotherapy,lymph node positive rate＞0.1,age＞70 years,or tumor size＞20 mm.Conclusion:The RSF model,based on only four readily available clinical variables,demonstrated superior predictive performance compared with the Cox model.It provides a reliable tool for individualized prognosis and postoperative management in ECCA patients.The integration of interpretability frameworks further enhances its clinical applicability,offering potential to improve survival outcomes and quality of life.

Objective To explore the distribution characteristics and development trend of TCM prevention and treatment for irritable bowel syndrome(IBS)by analyzing the clinical trials of TCM prevention and treatment for IBS registered in China Clinical Trial Registry(ChiCTR).Methods The ChiCTR database was retrieved to collect and organize clinical trials related to the TCM prevention and treatment of IBS from the establishment of the database to May 1,2024.Characteristics of the included trials were analyzed and summarized using SPSS 25.0 and Excel 2021.Results A total of 73 clinical trials were included,of which 65 were pre-registered.The registered research projects involved 14 provincial-level administrative regions,including Beijing,Jiangsu,Guangdong,Shanghai,and Sichuan,and 46 clinical trial institutions,among which Beijing University of Chinese Medicine(6 items,7.89%)registered a higher number.The top three sources of research funding were,in order,local finance(26 items,35.62%),state finance(20 items,27.40%),and hospital funding(10 items,13.70%).The types of studies were predominantly interventional(68 items,93.15%),and the study designs were predominantly randomized parallel controlled studies(64 items,87.67%),but only 27 studies(36.99%)used a blinded approach.The main interventions included acupuncture and moxibustion,Chinese patent medicines,classic prescriptions/hospital-prepared remedies,etc.Conclusion The number of clinical research registrations in this field has been gradually increasing in recent years,but there are problems such as uneven regional distribution,low use of blinding,and lack of standardization of registration information.

Objective To analyze the clinical trial projects of TCM treatment for psoriasis registered at the China Clinical Trial Registry(ChiCTR);To provide references for clinical research in this field.Methods Clinical trial studies on the TCM treatment for psoriasis were retrieved from the ChiCTR database from the establishment of the database to June 17,2024.Excel 2019 and GraphPad Prism 9.0 were used to organize and analyze the general characteristics included in registered clinical trials.Results Totally 65 TCM-related trials were included,of which 58(89.23%)were prospectively registered,and 55(84.62%)had undergone ethical review.The majority of trials were registered in Guangdong,Beijing and Shanghai,collectively accounting for 78.46%(n=51)of the total.The leading institution,Guangdong Provincial Hospital of Chinese Medicine,contributed 19 trials.Funding was predominantly sourced from governmental bodies,with 72.31%(n=47)supported by national or regional grants.Among the registered studies,interventional trials predominated(n=56),including 46 randomised parallel-controlled designs.Blinding was implemented in 23 trials,and biospecimen collection was reported in 48 studies.40 trials were single-centre studies,and a cumulative sample size was 17 695 participants.Common interventions included oral administration of classical TCM formulations or hospital-prepared remedies,alongside topical applications such as medicated baths and ointments.The primary outcome measure in most trials was the Psoriasis Area and Severity Index.Conclusion While the number of registered clinical trials on TCM for psoriasis in China demonstrates a fluctuating yet upward trend,the overall volume remains modest.Disparities in regional distribution,methodological variability,and incomplete trial registration details highlight areas for improvement.

Type Ⅳ cardiorenal syndrome(CRS)is a subtype of CRS characterized by cardiac structural damage and/or functional decline secondary to chronic kidney disease.Clinically,it often manifests as fatigue,shortness of breath,edema,oliguria,and difficulty lying flat at night,which align with the TCM pattern of"deficiency of primordial qi and excess of yin-pathogenic fire".Li Dongyuan proposed the theory that"yin-pathogenic fire and primordial qi are opposites",emphasizing the dynamic relationship of"mutual growth and decline"between primordial qi and yin fire.From this perspective,the development and progression of Type Ⅳ CRS are believed to correspond to the fluctuations in the balance of primordial qi and yin-pathogenic fire.Based on this theory,the core pathogenesis of Type Ⅳ CRS is summarized as"imbalance between qi and fire",where"deficiency of primordial qi"is the root cause,often attributed to damage to the heart,spleen,and kidney,while"exuberance of yin-pathogenic fire"represents the pathological manifestation.In clinical practice,the treatment should focus on reinforcing primordial qi and subduing yin-pathogenic fire,with tailored approaches according to the stages of disease progression.In the early stage,when primordial qi lacks a foundation for generation and yin-pathogenic fire begins to emerge,the treatment should aim to consolidate the root of primordial qi and suppress the budding of yin-pathogenic fire.In the middle stage,when primordial qi is insufficiently produced and yin-pathogenic fire becomes predominant,the treatment should focus on nourishing the source of primordial qi and curbing the exuberance of yin-pathogenic fire.In the late stage,when primordial qi becomes dispersed and yin-pathogenic fire is unconstrained,the treatment should prioritize consolidating the foundation of primordial qi and restraining the chaotic movement of yin-pathogenic fire.

Objective To establish a pediatric rare disease catalog,analyze the current status of therapeutic drugs and their coverage of the medical insurance in China,and propose strategies to enhance drug accessibility.Methods Pediatric rare diseases were identified from China's two national rare disease catalogs combined with the EU Orphanet database,US FDA orphan drug database,and the Diagnosis and Treatment Standards for Rare Diseases in Children.We created a specialized drug catalog for pediatric rare diseases,then analyzed drug types(ATC classification),pricing,and medical insurance coverage using descriptive statistics based on Yaozhi.com drug bidding prices and the 2024 Drug of List National Basic Medical Insurance(NBMIDL).Drug affordability was assessed through annual treatment cost calculations.Results The national catalogs included 151 pediatric rare diseases(72.95%of listed conditions),spanning 13 disease systems.We identified 94 dedicated orphan drugs(by generic name)for these conditions,among which 43 were approved internationally but unavailable in China.The average unit price per package was 6 113.53 yuan.Overall NBMIDL coverage was 68.83%,but drugs priced above 7 000 yuan per unit had only 7.69%coverage.Annual treatment costs reached 4.54 million for laronidase(mucopolysaccharidosis).Conclusions Critical gaps persist in China's pediatric rare disease treatment landscape,including catalog deficiencies,inadequate coverage for high-cost drugs and insufficient domestic innovation.It is recommended to establish a list of orphan drugs for pediatric rare diseases,accelerate the import of foreign drugs and the local innovative drugs through policy incentives,optimizing medical insurance reimbursement mechanisms for pediatric rare disease drugs to comprehensively improve therapeutic accessibility.

Background and Aims:Extrahepatic cholangiocarcinoma(ECCA)is a malignancy with insidious onset,strong invasiveness,and poor prognosis,characterized by a high postoperative recurrence rate and a 5-year overall survival of less than 20％.Most existing prognostic models are based on the Cox proportional hazards model,which is limited by the proportional hazards assumption and linearity constraints.The random survival forest(RSF)model,a novel machine learning algorithm,can capture complex interactions and nonlinear effects among variables;however,its application in ECCA remains scarce.Therefore,this study developed a prognostic model for ECCA patients after radical resection using the RSF algorithm,aiming to provide precise and individualized prognostic assessments and support clinical decision-making.Methods:A total of 515 postoperative ECCA patients from the SEER database(2016-2021)were retrospectively enrolled and randomly divided into a training set(n=361)and a test set(n=154).Demographic and clinical variables were collected.Cox models were developed using univariate and multivariate regression,while RSF models were constructed using variable importance(VIMP)and minimal depth methods.Model performance was evaluated using the concordance index(C-index),time-dependent area under the curve(AUC),Brier scores,calibration plots,and decision curve analysis.Survival differences were assessed using Kaplan-Meier analysis,and interpretability was enhanced through the use of SurvSHAP and SurvLIME.Results:Multivariate Cox regression identified seven independent prognostic factors:age,race,income,T stage,N stage,tumor size,and chemotherapy.The RSF model selected four key predictors:age,tumor size,lymph node positive rate,and chemotherapy.In the test cohort,the RSF model achieved a C-index of 0.751,outperforming the Cox model(0.711).The RSF model yielded AUCs of 0.843,0.749,and 0.814 at 1,2,and 3 years,respectively,with superior calibration,overall performance,and net clinical benefit.Nonlinear associations were observed for lymph node positive rate,age,and tumor size,while chemotherapy was associated with reduced mortality risk.Stratified survival curves indicated poorer prognosis in patients without chemotherapy,lymph node positive rate＞0.1,age＞70 years,or tumor size＞20 mm.Conclusion:The RSF model,based on only four readily available clinical variables,demonstrated superior predictive performance compared with the Cox model.It provides a reliable tool for individualized prognosis and postoperative management in ECCA patients.The integration of interpretability frameworks further enhances its clinical applicability,offering potential to improve survival outcomes and quality of life.