ObjectiveTo investigate the mechanism of liver injury induced by tripterygium glycosides tablets （TG） and the molecular mechanism of compound glycyrrhizin tablets （CG） in alleviating the abnormalities of cholesterol metabolism caused by TG via cholesterol metabolism. MethodsAccording to the body weights， male Sprague-Dawley （SD） rats were randomly grouped as follows： control （pure water）， low-dose TG （TG-L， 189.0 mg·kg^-1·d^-1）， high-dose TG （TG-H， 472.5 mg·kg^-1·d^-1）， TG-L+CG （189.0 mg·kg^-1·d^-1 TG + 20.25 mg·kg^-1·d^-1 CG）， and TG-H+CG （472.5 mg·kg^-1·d^-1 TG + 20.25 mg·kg^-1·d^-1 CG）， with 6 rats in each group. Rats were administrated with corresponding drugs once daily for 3 weeks. At the end of the last administration， the mRNA and protein levels of liver X receptor-alpha （LXR-α）， low-density lipoprotein receptor （LDLR）， adenosine triphosphate-binding cassette transporter A1 （ABCA1）， adenosine triphosphate-binding cassette transporter G1 （ABCG1）， 3-hydroxy-3-methylglutaryl coenzyme A reductase （HMGCR）， cholesterol 7α-hydroxylase （CYP7A1）， cholesterol 12α-hydroxylase （CYP8B1）， and sterol 27-hydroxylase （CYP27A1） in the liver tissue were determined by Real-time PCR and Western blotting， respectively. The level of 3-hydroxy-3-methylglutaryl coenzyme A reductase （HMG-CoAR）， a regulatory enzyme of cholesterol synthesis， was measured by enzyme-linked immunosorbent assay （ELISA）. HepG2 cells were used to observe the effect of TG on the cell proliferation in vitro. Specifically， HepG2 cells were grouped as follows： Low-dose TG （TG-l， 15 mg·L^-1）， medium-dose TG （TG-m， 45 mg·L^-1）， high-dose TG （TG-h， 135 mg·L^-1）， fenofibrate （FB， 10 μmol·L^-1）， CG extract， TG-h+FB （135 mg·L^-1 TG + 10 μmol·L^-1 FB）， TG-m+FB （45 mg·L^-1 TG + 10 μmol·L^-1 FB）， TG-l+FB （15 mg·L^-1 TG + 10 μmol·L^-1 FB）， TG-h+CG （135 mg·L^-1 TG + 60 μmol·L^-1 CG）， TG-m+CG （45 mg·L^-1 TG + 60 μmol·L^-1 CG）， and TG-l+CG （15 mg·L^-1 TG + 60 μmol·L^-1 CG）. The mRNA and protein levels of LXR-α， ABCG1， LDLR， CYP7A1， CYP8B1， and CYP27A1 in HepG2 cells were determined by Real-time PCR and Western blotting， respectively. ResultsThe rat experiment showed that compared with the control group， the TG-H group showed down-regulated mRNA levels of CYP7A1， CYP8B1， and CYP27A1 in the liver tissue （P<0.05， P<0.01）， which were up-regulated by the application of CG （P<0.05， P<0.01）， and the TG-H+CG group showed up-regulated mRNA level of LDLR （P<0.01）. Compared with the control group， the TG-L and TG-H groups showed down-regulated protein levels of LDLR， CYP7A1， and CYP8B1 in the liver tissue （P<0.05， P<0.01）. In addition， the protein levels of ABCG1 and LXR-α were down-regulated in the TG-H and TG-L groups， respectively （P<0.05）. Compared with TG alone， TG+CG up-regulated the protein levels of ABCG1 and LDLR （P<0.05， P<0.01）， and the protein levels of CYP7A1 and CYP8B1 in the TG-H+CG group were up-regulated （P<0.05， P<0.01）. The cell experiment showed that compared with the control group， the TG-h group presented up-regulated mRNA level of LXR-α （P<0.01）， and the TG-m and TG-h groups showcased down-regulated mRNA levels of LDLR and CYP7A1 （P<0.01） and up-regulated mRNA level of CYP27A1 （P<0.01） in HepG2 cells. The combination of CG with TG restored the above changes （P<0.01）. Western blotting results showed that compared with the control group， the TG-m and TG-h groups showed down-regulated protein levels of LXR-α， ABCG1， LDLR， CYP7A1， CYP8B1， and CYP27A1 in HepG2 cells （P<0.01）. Compared with the TG-h group， the TG-h+CG group showed up-regulated protein level of LDLR （P<0.05）. Compared with the TG-m group， the TG-m+CG group showcased up-regulated protein levels of LDLR， ABCG1， CYP7A1， and CYP27A1 （P<0.05， P<0.01）. ConclusionThe administration of TG at 189.0， 472.5 mg·kg^-1 for 3 weeks could modulate the signaling pathways associated with cholesterol efflux， endocytosis， and cholesterol biotransformation in hepatocytes， leading to the accumulation of cholesterol and subsequent liver injury in rats. CG could ameliorate the liver injury induced by lipid metabolism disorders caused by TG by up-regulating the expression of LXR-α， LDLR， ABCG1， CYP7A1， CYP8B1， and CYP27A1 to promote cholesterol biotransformation.

OBJECTIVE: To analyze the acupoint selection patterns and core prescriptions of acupuncture for polycystic ovary syndrome (PCOS) using data mining, and to explore the molecular mechanisms of core acupoints through network acupuncture medicine. METHODS: The randomized controlled trials (RCTs) on acupuncture for PCOS published from January 1, 2004 to July 21, 2024 were retrieved from CNKI, VIP, Wanfang, PubMed, and Web of Science databases. R software (version 4.4.0) was used for acupoint frequency and association rule analysis to identify core acupoint prescriptions. Potential targets were predicted via the STITCH and Swiss Target Prediction databases, and a "core prescription-active compounds-targets- PCOS" network was constructed. Cytoscape 3.7.1 was applied to build protein-protein interaction (PPI) networks of potential targets of core acupoint prescriptions. Key therapeutic targets were subjected to gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analyses using the DAVID and Microbioinformatics platforms. RESULTS: A total of 176 RCTs were included, covering 208 prescriptions and 89 acupoints. The five most frequently used acupoints were Guanyuan (CV4), Sanyinjiao (SP6), Zigong (EX-CA1), Zusanli (ST36) and Zhongji (CV3). Association rule analysis yielded 13 core acupoint combinations, with Guanyuan (CV4), Sanyinjiao (SP6), Zigong (EX-CA1) and Zusanli (ST36) as the core prescription. Twenty-seven active compounds were involved, with 852 potential therapeutic targets, among which 208 targets overlapped with PCOS-related targets. Network acupuncture medicine analysis suggested that the core prescription may act through targets such as estrogen receptor 1 (ESR1), proto-oncogene tyrosine-protein kinase Src (SRC), signal transducer and activator of transcription 3 (STAT3), peroxisome proliferator-activated receptor gamma (PPARG), and RAC-alpha serine/threonine-protein kinase (AKT1). GO and KEGG analyses indicated that the main pathways included the hypoxia-inducible factor 1 (HIF-1) signaling pathway, phosphatidylinositol 3-kinase-protein kinase B (PI3K-AKT) signaling pathway, and advanced glycation end products-receptor for advanced glycation end products (AGE-RAGE) signaling pathway, involving processes such as signal transduction, receptor complex formation, and cytokine activity. CONCLUSION The core acupoint prescription for PCOS might exert therapeutic effects through multiple targets and pathways, providing a theoretical basis for mechanistic research on acupoint prescriptions.
Humans ; Acupuncture Therapy ; Data Mining ; Acupuncture Points ; Polycystic Ovary Syndrome/metabolism* ; Female ; Protein Interaction Maps ; Randomized Controlled Trials as Topic

Proteolysis-targeting chimeras (PROTACs) represent a promising class of drugs that can target disease-causing proteins more effectively than traditional small molecule inhibitors can, potentially revolutionizing drug discovery and treatment strategies. However, the links between in vitro and in vivo data are poorly understood, hindering a comprehensive understanding of the absorption, distribution, metabolism, and excretion (ADME) of PROTACs. In this work, ¹⁴C-labeled vepdegestrant (ARV-471), which is currently in phase III clinical trials for breast cancer, was synthesized as a model PROTAC to characterize its preclinical ADME properties and simulate its clinical pharmacokinetics (PK) by establishing a physiologically based pharmacokinetics (PBPK) model. For in vitro-in vivo extrapolation (IVIVE), hepatocyte clearance correlated more closely with in vivo rat PK data than liver microsomal clearance did. PBPK models, which were initially developed and validated in rats, accurately simulate ARV-471's PK across fed and fasted states, with parameters within 1.75-fold of the observed values. Human models, informed by in vitro ADME data, closely mirrored postoral dose plasma profiles at 30 mg. Furthermore, no human-specific metabolites were identified in vitro and the metabolic profile of rats could overlap that of humans. This work presents a roadmap for developing future PROTAC medications by elucidating the correlation between in vitro and in vivo characteristics.

ObjectiveTo explore the characteristics and regulatory mechanisms of cholestatic liver injury （CLI） caused by traditional Chinese medicine based on data mining， network pharmacology， and molecular docking. MethodChina National Knowledge Infrastructure and PubMed were searched for the relevant literature on CLI caused by traditional Chinese medicine from inception to 2024， and the information was standardized， summarized， and analyzed by cluster analysis. The Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform （TCMSP）， Integrative Pharmacology-based Research Platform of Traditional Chinese Medicine （TCMIP）， GeneCards， Online Mendelian Inheritance in Man （OMIM）， and DisGeNET were used to retrieve the active ingredients and targets of core medicines. The Venn diagram was established to map the common targets shared by the core medicines and CLI. Cytoscape 3.10.2 was used to construct the protein-protein interaction （PPI） network of the common targets. DAVID was used for gene ontology （GO） and Kyoto Encyclopedia of Genes and Genomes （KEGG） enrichment of the core targets. Finally， molecular docking was performed by AutoDock Vina. ResultA total of 849 eligible articles were included in this study， from which 64 active ingredients of 39 herbal medicines that can cause cholestasis were counted and categorized according to the 2020 edition of the Pharmacopoeia of the People's Republic of China. The frequency of the medidicnes followed a descending order of heat-clearing medicines， exterior-releasing medicines， blood-activating and stasis-resolving medicines， purgative medicines， phlegm-resolving and cough- and dyspnea-relieving medicines， tonics， wind- and dampness-expelling medicines， interior-warming medicines， urination-promoting and dampness-draining medicines， Qi movement-regulating medicines， hemostatics， toxin-removing， worm-killing， and itch-relieving medicines， astringent medicines， dampness-eliminating medicines， and tranquiling medicines. The cluster analysis revealed that the reports of CLI caused by heat-clearing medicines accounted for the highest proportion of 39.69%. Among the heat-clearing medicines， Gardeniae Fructus （92 articles， accounting for 10.84%）， Scutellariae Radix （76 articles， 8.95%）， and Sophorae Flavescentis Radix （69 articles， 6.95%） were frequently reported. The core targets of cholestasis induced by Chinese herbal medicines reported to cause CLI mainly included tumor necrosis factor （TNF）， peroxisome proliferator activated receptor alpha （PPARA）， farnesoid X receptor （FXR）， glutamic-pyruvic transaminase 2 （GPT2）， superoxide dismutase 1 （SOD1）， interferon gamma （IFN-γ）， interleukin-6（IL-6）， CD36， Apolipoprotein A1（APOA1）， Angiotensin converting enzyme（ACE）， Cytochrome P450 3A4 enzyme（CYP3A4）， Protein kinase B1（Akt1）， APOB， albumin（ALB）， ATP binding cassette transporter A4（ABCB4）， SLC10A1， Estrogen Receptor alpha （ESR1）， signal transducer and activator of transcription1（STAT1）， β-actin（ACTB）， Endothelin 1（EDN1）， ABCG2， and peroxisome proliferator activated receptor gamma（PPARG）. The signaling pathways involved included bile secretion， ABC transporter， steroid biosynthesis， DNA adducts， drug metabolism， cytochrome P450， peroxisomes， primary bile acid biosynthesis， retinol metabolism， and Toll-like receptor. The molecular docking results showed that the active ingredients （e.g.， baicalin and berberine） of the heat-clearing medicines reported by high frequency to cause CLI had high binding affinity to the targets including ABCG2， IFN-γ， EDN1， IL-6 and SOD1， with the binding energy in the range of -13 kcal·mol^-1 to -9 kcal·mol^-1， and the regulatory pathways were highly correlated with transporters， microvascular function regulation， inflammation， and oxidative stress， which was consistent with the cluster analysis. ConclusionThe available reports about the Chinese herbal medicines causing CLI mainly focused on heat-clearing medicines， and the core targets included ABCG2， IFN-γ， EDN1， IL-6， and SOD1. The regulatory pathways were mainly related to transporters， microvascular function regulation， inflammation， and oxidative stress.

Objective:To evaluate the immunogenicity, safety, and immune persistence of the sequential booster with the recombinant protein-based COVID-19 vaccine (CHO cell) in healthy people aged 18-84 years.Methods:An open-label, multi-center trial was conducted in October 2021. The eligible healthy individuals, aged 18-84 years who had completed primary immunization with the inactivated COVID-19 vaccine 3 to 9 months before, were recruited from Shangyu district of Shaoxing and Kaihua county of Quzhou, Zhejiang province. All participants were divided into three groups based on the differences in prime-boost intervals: Group A (3-4 months), Group B (5-6 months) and Group C (7-9 months), with 320 persons per group. All participants received the recombinant COVID-19 vaccine (CHO cell). Blood samples were collected before the vaccination and after receiving the booster at 14 days, 30 days, and 180 days for analysis of GMTs, antibody positivity rates, and seroconversion rates. All adverse events were collected within one month and serious adverse events were collected within six months. The incidences of adverse reactions were analyzed after the booster.Results:The age of 960 participants was (52.3±11.5) years old, and 47.4% were males (455). The GMTs of Groups B and C were 65.26 (54.51-78.12) and 60.97 (50.61-73.45) at 14 days after the booster, both higher than Group A′s 44.79 (36.94-54.30) ( P value<0.05). The GMTs of Groups B and C were 23.95 (20.18-28.42) and 27.98 (23.45-33.39) at 30 days after the booster, both higher than Group A′s 15.71 (13.24-18.63) ( P value <0.05). At 14 days after the booster, the antibody positivity rates in Groups A, B, and C were 91.69% (276/301), 94.38% (302/320), and 93.95% (295/314), respectively. The seroconversion rates in the three groups were 90.37% (272/301), 93.75% (300/320), and 93.31% (293/314), respectively. There was no significant difference among these rates in the three groups (all P values >0.05). At 30 days after the booster, antibody positivity rates in Groups A, B, and C were 79.60% (238/299), 87.74% (279/318), and 90.48% (285/315), respectively. The seroconversion rates in the three groups were 76.92% (230/299), 85.85% (273/318), and 88.25% (278/315), respectively. There was a significant difference among these rates in the three groups (all P values <0.001). During the sequential booster immunization, the incidence of adverse events in 960 participants was 15.31% (147/960), with rates of about 14.38% (46/320), 17.50% (56/320), and 14.06% (45/320) in Groups A, B, and C, respectively. The incidence of adverse reactions was 8.02% (77/960), with rates of about 7.50% (24/320), 6.88% (22/320), and 9.69% (31/320) in Groups A, B, and C, respectively. No serious adverse events related to the booster were reported. Conclusion:Healthy individuals aged 18-84 years, who had completed primary immunization with the inactivated COVID-19 vaccine 3 to 9 months before, have good immunogenicity and safety profiles following the sequential booster with the recombinant COVID-19 vaccine (CHO cell).

【Objective】 To examine risk factors for acute pancreatitis (AP) in individuals with chronic alcohol consumption habits. 【Methods】 The study incorporated participants from the initial survey (2006-2010) and subsequent follow-ups (2014+) taken from the UK Biobank database, with the observation period ending on November 30, 2022. During this period, 176 individuals were newly diagnosed with AP, while 59,512 remained unaffected. Vital characteristics of the target population, such as their medical histories, surgical experiences and dietary patterns, were collected during the enrolment phase (2006-2010). The Cox proportional hazard model was employed to ascertain whether these characteristics were potent risk factors for AP. Concurrently, a subgroup from the target population with documented drinking behavior was selected. The multivariate Cox proportional hazard model was utilized to analyze the relationship of the established factors, variances in alcohol consumption, and increased alcohol intake (Δ) with the onset of AP, and whether the additional alcohol intake served as a risk factor. 【Results】 Multivariate analysis revealed that consumption quantity of cooked vegetables inversely correlated with AP risk (HR=0.44, 0.39, 0.42 and 0.41 for one, two, three and four+ tablespoons per day, respectively, as compared to non-consumers). Coffee consumption (2-3 cups per day) also reduced AP risk (HR=0.45 for 2 cups/day; HR=0.39 for 3 cups/day as compared to non-coffee drinkers). However, those with biliary disease without cholecystectomy exhibited a marked increase in AP risk (HR=7.82), which reduced albeit remained elevated for those with biliary disease post-cholecystectomy (HR=2.15). Subgroup analysis showed minimal impact of alcohol intake levels on AP incidence. Yet, increased alcohol consumption (Δ of 1 bottle/week) was linked to a heightened AP risk (HR=1.05, 95% CI:1.02-1.09, P<0.05). 【Conclusion】 Among longstanding alcohol consumers, a diet rich in cooked vegetables and moderate coffee consumption offers protective effects against AP. Conversely, biliary disease (particularly without cholecystectomy) and elevated alcohol intake present considerable risk factors for the development of this condition.

Objective:To study the effect of first drainage failure on the prognosis of perihilar cholangiocarcinoma (PHCC).Methods:The clinical data of 68 patients with PHCC undergoing surgery in the Department of Pancreatic and Metabolic Surgery of Nanjing Drum Tower Hospital, Affiliated to the Medical School of Nanjing University, from April 2014 to December 2022 were retrospectively analyzed, including 46 males and 22 females, aged (63±9) (range, 39-80) years old. The patients were divided into two groups based on whether the first drainage was successful: successful group ( n=34) and failed group ( n=34). The patient's age, gender, first drainage, complications and other clinical data were collected. Patients were followed up by outpatient or telephone review. Kaplan-Meier method was used for survival analysis, and log-rank test was used for survival comparison. Results:Compared to the successful group, the drainage time [41(28, 52) d vs. 20(14, 28) d], the drainage tube adjustment rate [32.4%(11/34) vs. 0(0/34)], and the incidence of complications after drainage [88.2% (30/34) vs. 0(0/34)] were all increased in the failed group, with the adjustment rate of drainage position decreased [82.4%(28/34) vs. 100%(34/34)] (all P<0.05). Compared to the successful group, the incidence of abdominal infection was higher [70.6%(24/34) vs. 44.1%(15/34)] in the failed group ( P=0.027). The 5-year cumulative survival rates of the failed group and the successful group were 61.4% and 44.1%, respectively ( P>0.05). Conclusion:Compared to the patients of PHCC with first successful drainage, the risk of abdominal infection is increased when first drainage failed, while the incidence of postoperative complications, in-hospital mortality and long-term survival rate are comparable.

OBJECTIVE To study the improvement effect of total flavonoids from Rosa multiflora root on vascular injury in rheumatoid arthritis （RA） model rats and its potential mechanism. METHODS Female Wistar rats were randomly divided into normal control group， model group， aspirin group （positive control， 30 mg/kg）， low-dose and high-dose groups of total flavonoids from R. multiflora root （4.15， 8.30 g/kg， by crude drug）， with 10 rats in each group. Except for the normal control group， the RA model was induced in other groups by collagen induction and high-fat diet. After 14 days of modeling， they were given corresponding drug solution/0.5% sodium carboxymethyl cellulose solution intragastrically， once a day， for 36 consecutive days. The total body score， arthritis index （AI） and swollen joint count （SJC） of the rats were evaluated regularly. After the last medication， serum levels of interleukin-6 （IL-6）， intercellular adhesion molecule-1 （ICAM-1） and vascular cell adhesion molecule- 1 （VCAM-1） were determined. The pathological morphological changes in the vascular tissue of thoracic aorta were observed； the protein expression of Toll-like receptor 4 （TLR4） and the protein phosphorylation levels of Janus kinase 2 （JAK2） and signal transduction and activator of transcription 3 （STAT3） in vascular tissue of thoracic aorta were measured. RESULTS Compared with the normal control group， serum levels of IL-6， ICAM-1 and VCAM-1， protein expression of TLR4， and the protein phosphorylation levels of JAK2 and STAT3 in vascular tissue of thoracic aorta were increased significantly in model group （P＜ 0.01）. The atherosclerotic plaque （atheroma）， cholesterol crystal， lymphocyte infiltration and a small number of unbroken foam cell aggregation could be seen in the vascular tissue of thoracic aorta. Compared with the model group， total body score （except for the low-dose group）， AI and SJC were decreased significantly in groups of total flavonoids from R. multiflora root on the 28th day （P＜0.05 or P＜0.01）； total body score，AI and SJC were decreased significantly in low-dose group of total flavonoids from R. multiflora root on the 49th day （P＜0.05 or P＜0.01）； the other quantitative indicators in serum and vascular tissue were significantly reversed in groups of total flavonoids from R. multiflora root （P＜0.05 or P＜0.01）， and pathological damage of vascular tissue was significantly relieved. CONCLUSIONS Total flavonoids from R. multiflora root can significantly improve vascular injury in RA model rats， and its mechanism may be related to reducing the protein expression of TLR4 in vascular tissue and inhibiting the activation of IL-6/JAK2/ STAT3 signaling pathway.

Background According to the Classification and Catalogue of Occupational Diseases, brucellosis is one of the notifiable occupational infectious diseases, which occurs from time to time in the occupational population. Objective To compare the work-related injury appraisal process and results of 13 cases of brucellosis at both provincial and municipal levels, analyze and summarize the bias in the practical work of labor capacity identification for occupational diseases such as brucellosis by appraisal management departments and experts, and propose suggestions for optimizing appraisal work. Methods A comparative study was conducted on the objective examination results and labor capacity appraisal conclusions based on the occupational contact history, clinical diagnosis, occupational disease diagnosis staging, and labor capacity appraisal of 13 patients with brucellosis. The reasons for the inconsistency between the initial appraisal conclusion by institutions at the municipal level and the final appraisal conclusion by institutions at the provincial level were compared and analyzed. Results All of the 13 patients with brucellosis applied for municipal-level labor capacity identification after being identified as work-related injuries, 11 of which did not receive a disability level, and 2 were rated as level 10 disability. Four of those who did not receive the disability rate applied for provincial-level labor capacity identification. As a result, 2 cases were maintained original appraisal conclusions, while the other 2 changed the conclusions to level 9 disability and level 10 disability respectively. It was the first time in Shijiangzhuang municipal-level primary labor capacity appraisal and Hebei provincial-level labor capacity re-appraisal that the work-related injury caused by occupational brucellosis was rated as level 9 disability or level 10 disability. Hence, the lessons learned from this comparative analysis are that the degree of target organ damage and (or) organ dysfunction are the direct basis for work-related injury appraisal; an objective and scientific labor capacity identification for occupational brucellosis should base on the each case of disability evaluation, identify the relevant target organ damage and the degree of dysfunction, and rate the disability level after a comprehensive appraisal. Conclusion This analysis would be a guidance to the identification of labor capacity for occupational brucellosis in Hebei Province and the whole country. There is a hysteresis issue in the occupational disease provisions in the national standard GB/T 16180—2014 Standard for identify work ability—Gradation of disability caused by work-related injuries and occupatiaonal diseases. In current situation, appraisal experts should not only search for clauses that directly correspond to the occupational diseases and injuries, but also target conditions not covered in the clauses and conduct assessment based on the characteristics of occupational diseases, with scientific, accurate, and flexible application of the clauses in the standard and appendix, so as to make fair, just, and professional appraisal conclusions.