ObjectiveThis paper aims to investigate the potential molecular biological mechanism of Buyang Huanwu Tongfeng decoction in treating hyperuricemia and gouty arthritis by network pharmacology and molecular docking technology and preliminarily verify the mechanism through animal experiments. MethodsThe active ingredients and targets in the Buyang Huanwu Tongfeng decoction were obtained by the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform （TCMSP） and ETCM databases. The DisGeNET and GeneCards databases were utilized to acquire disease targets associated with hyperuricemia and gouty arthritis. These disease targets were then intersected with drug targets to identify key targets. The R language ClusterProfiler package and Python were employed for conducting gene ontology（GO） enrichment analysis and Kyoto encyclopedia of genes and genomes（KEGG） enrichment analysis. The regulatory network diagram of the drug-key target-function-pathway was visualized using Cytoscape 3.9.1 software， and the protein-protein interaction （PPI） network for key targets was depicted. Finally， the hub gene was determined through topological analysis. Auto Dock， PyMOL， and other software were used for molecular docking to explore the possible therapeutic mechanism of Buyang Huanwu Tongfeng decoction for hyperuricemia and gouty arthritis. In animal experiments， a composite rat model of hyperuricemia induced by intraperitoneal injection of oteracil potassium combined with gouty arthritis induced by the modified Coderre method was established. Through hematoxylin-eosin（HE） staining， uric acid test， enzyme linked immunosorbent assay（ELISA）， Western blot， and real-time polymerase chain reaction（Real-time PCR）， the molecular mechanism and key targets of Buyang Huanwu Tongfeng decoction for treating hyperuricemia and gouty arthritis were observed. ResultsAfter screening and removing duplicate values， 76 active ingredients and 15 key targets were finally obtained. GO enrichment analysis yielded that the treatment of hyperuricemia and gouty arthritis with Buyang Huanwu Tongfeng decoction was significantly associated with acute inflammatory response， astrocyte activation， regulation of interleukin （IL）-8 production， nuclear receptor activity， and binding of growth factor receptor. KEGG pathway enrichment analysis obtained that the key target genes were significantly associated with the IL-17 signaling pathway， advanced glycosylation end/receptor of advanced glycation endproducts（AGE/RAGE） signaling pathway， anti-inflammatory， and other pathways. PPI network indicated that albumin（ALB）， peroxisome proliferator-activated receptor-γ （PPAR-γ）， IL-6， IL-1β， and C-reactive protein（CRP） were the key protein targets. The molecular docking results showed that ALB had the strongest binding force with beta-carotene （β-carotene）. Biochemical results showed that blood uric acid decreased in the Buyang Huanwu Tongfeng decoction groups. HE staining results showed that the low-dose （7.76 g·kg^-1·d^-1）， medium-dose （15.53 g·kg^-1·d^-1）， and high-dose （31.05 g·kg^-1·d^-1） groups of Buyang Huanwu Tongfeng decoction had different degrees of remission， and the remission of the high-dose group was the most obvious. Fibroblastic tissue hyperplasia in synovial joints accompanied with inflammatory cell infiltration， as well as inflammatory cell infiltration in renal tissue of the high-dose group was significantly reduced， followed by the medium-dose and low-dose groups， and the expression of ALB， PPAR-γ， IL-6， IL-1β， and CRP was down-regulated to different degrees. ConclusionBy regulating the targets such as ALB， PPAR-γ， IL-6， IL-1β， and CRP， inhibiting the PPAR-γ/nuclear transcription factor （NF）-κB pathway， and reducing AGEs/RAGE-mediated inflammation， Buyang Huanwu Tongfeng decoction exerts anti-inflammatory and analgesic effects and activates blood circulation and diuresis in the treatment of hyperuricemia and gouty arthritis.

Plant-derived extracellular vesicles (PDEVs), describe a group of nanoparticles released by plants. These particles are characterized by a lipid bilayer structure containing various proteins, lipids, nucleic acids, and unique metabolites. Although the study on PDEVs is relatively new, having only been around for ten years, they have shown promising development prospects in both basic research and clinical transformation areas. Evidence suggests that PDEVs have excellent application prospects in regulating inflammation and treating tumors. Their distinctive, vesicle-mimicking architecture and stellar biocompatibility render them prime candidates for ferrying various anti-cancer agents, including RNA, proteins, and conventional chemotherapy drugs. Increasingly, studies have shown that PDEVs can be engineered as an innovative platform for combination cancer immunotherapy. Consequently, this paper provides an extensive summary of current developments in engineering methods and strategies for PDEVs in cancer treatment and combined cancer immune therapeutics. The essential characteristics of PDEVs, including the biogenesis process and components, as well as their anti-tumor activity and mechanism, are summarized. Finally, the in vivo safety of PDEVs as delivery vectors and the challenges of scale-up production and clinical transformation are discussed.

Crigler-Najjar syndrome (CNS) and Gilbert syndrome (GS; OMIM: 143500) are rare autosomal recessive diseases that cause unconjugated hyperbilirubinemia due to decreased UGT1A1 enzyme activity. Crigler-Najjar syndrome type 2 (CNS2; OMIM: 606785) increases the risk of gallbladder stone formation and cholecystitis, while GS seldom causes health issues. We found a 28-year-old male patient with recurring right upper abdomen pain who experienced persistent jaundice from birth. CNS2 with gallbladder stones and cholecystitis was diagnosed after genetic testing revealed rare double homozygous mutations A(TA)₇TAA (rs3064744) and P229Q (rs35350960) in the UGT1A1 gene. After pedigree investigation, we found that the patient's parents with modestly increased bilirubin had compound heterozygous mutations A(TA)₇TAA and P229Q, which were GS. Bioinformatics analysis showed that A(TA)₇TAA is in the TATA-box region of the gene UGT1A1 promoter, affecting gene transcriptional initiation, whereas P229Q modifies protein three-dimensional structure and may be harmful. In this pedigree, double homozygous mutations have a more severe phenotype than compound heterozygous mutations. Inherited causes of hyperbilirubinemia should be suspected after ruling out biliary obstruction, and early bilirubin reduction (< 103 µmol/L (6 mg/dL)) may reduce the risk of complications like cholecystitis in CNS2 patients, though further studies with longer follow-up are needed to confirm this observation.
Humans ; Male ; Glucuronosyltransferase/genetics* ; Adult ; Crigler-Najjar Syndrome/complications* ; Cholecystitis/etiology* ; Homozygote ; Mutation ; Pedigree

Non-alcoholic fatty liver disease (NAFLD) is a metabolic disease characterized by abnormal deposition of lipid in hepatocytes. If not intervened in time, NAFLD may develop into liver fibrosis or liver cancer, and ultimately threatening life. NAFLD has complicated etiology and pathogenesis, and there are no effective therapeutic means and specific drugs. Currently, insulin sensitizers, lipid-lowering agents and hepatoprotective agents are often used for clinical intervention, but these drugs have obvious side effects, and their effectiveness and safety need to be further confirmed. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) plays a central role in maintaining energy homeostasis. Activated AMPK can enhance lipid degradation, alleviate insulin resistance (IR), suppress oxidative stress and inflammatory response, and regulate autophagy, thereby alleviating NAFLD. Natural herbal medicines have received extensive attention recently because of their regulatory effects on AMPK and low side effects. In this article, we reviewed the biologically active natural herbal medicines (such as natural herbal medicine formulas, extracts, polysaccharides, and monomers) that reported in recent years to treat NAFLD via regulating AMPK, which can serve as a foundation for subsequent development of candidate drugs for NAFLD.

Objective To explore the value of peripheral blood sCD146 as a long-term survival ben-efit marker in elderly patients with acute ST segment elevation myocardial infarction(ASTEMI)after PCI.Methods A total of 210 patients who were diagnosed with ASTEMI and underwent PCI in our hospital from January 2021 to July 2022 were enrolled,and according to the postopera-tive sCD146 level,they were divided into low-,medium-and high-level groups(69,65 and 76 cases respectively).All of them were followed up,with endpoint events including all cause death,cardiac death,and major adverse cardiovascular events(MACE).Kaplan-Meier survival curve was plotted to compare the cumulative survival rate of each group,and COX regression analysis was used to analyze the relationship between peripheral blood sCD146 level and prognosis.Results The mor-tality rate and MACE incidence were significantly higher in the high-level group than the low-and medium-level groups(P＜0.05).Kaplan-Meier curve analysis showed that the high-level group had obviously lower cumulative survival rate than the other two groups(P＜0.05).COX regres-sion analysis revealed that the sCD146 level in peripheral blood after PCI was independently cor-related with the occurrence of death in ASTEMI patients after PCI(OR=1.530,95％CI:1.144-2.044,P=0.004).Conclusion The peripheral blood level of sCD146 is closely related to long-term survival benefits in ASTEMI patients after PCI,and sCD146 can be used as a biomarker to evaluate their long-term survival benefits.

OBJECTIVE To explore the mechanism Baitouweng Decoction on mice with vulvovaginal candidiasis(VVC)based on phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)-hypoxia-inducible factor-1α(HIF-1α)pathway.METHODS Female SPF-grade Kunming mice were injected subcutaneously with estradiol benzoate and vaginally inoculated with Candida albicans suspension to establish a VVC mouse model.The mice with successful modeling were randomly divided into model group,high-,me-dium-,and low-dose Baitouweng Decoction groups(23.4,11.7,and 5.85 g·kg-1),and fluconazole group(0.02 g·kg-1),with 20 mice in each group.Another 20 mice were injected with estradiol benzoate as control group.Treatment started the day after success-ful model establishment and continued for 14 days.Two hours after the last administration,the number of neutrophils in vaginal lavage fluid was examined with Papanicolaou stain.The HE staining method was used to observe the morphology of vaginal tissue.ELISA was used to measure the levels of nicotinamide adenine dinucleo-tide phosphate oxidase 2(NOX2),reactive oxygen species(ROS),su-peroxide dismutase(SOD),malondialdehyde(MDA)in the vaginal tissues.The mRNA expression levels of PI3K,AKT and HIF-1α were detected using qPCR.Western blot was employed to evaluate the protein expression of p-PI3K,PI3K,p-AKT,AKT,and HIF-1α in vaginal tissue.RESULTS Compared to the control group,the model group exhibited a significant increase in neutrophils in va-ginal lavage fluid(P<0.001);the vaginal mucosal layer was severely desquamated and a large number of inflammatory cells infiltrated.Additionally,there was an elevation in NOX2,ROS,and MDA levels in vaginal tissue(P<0.001),while SOD content decreased(P<0.001).Furthermore,the mRNA expression of PI3K,AKT and HIF-1α was reduced along with decreased protein ex-pression of p-PI3K/PI3K,p-AKT/AKT,and HIF-1α(P<0.001).In comparison to the model group,both high-dose and medi-um-dose groups treated with Baitouweng Decoction demonstrated a significant decrease in neutrophil count in lavage fluid(P<0.01,P<0.001);the condition of the vaginal mucosa improved to varying degrees.Moreover,the levels of ROS and MDA in vaginal tissue were reduced(P<0.05,P<0.01,P<0.001),the activity of NOX2 was decreased(P<0.01,P<0.001),and the activity of SOD was increased(P<0.01,P<0.001).The high-dose group showed that,the mRNA expression of PI3K,AKT,and HIF-1α in vaginal tissue was increased(P<0.001),the ratios of p-PI3K/PI3K and p-AKT/AKT,and the protein expression of HIF-1α were increased(P<0.001).CONCLUSION Baitouweng Decoction has a therapeutic effect on VVC,and its mechanism of action may be related to the PI3K/AKT-HIF-1α signal pathway.

Objective The present study conducted a comprehensive literature review and visualization analysis of both domestic and international research on the utilization of hemodialysis water over the past two decades,aiming to gain insights into the current research status,identify prominent areas of interest,and highlight future development trends in this field,thereby of-fering valuable references for subsequent studies.Methods By employing bibliometric analysis,the relevant literature on hemo-dialysis water usage was retrieved from the Web of Science Core Collection(WoSCC)database and China National Knowledge Network(CNKI)for the period between 2004 and 2024.Subsequently,an in-depth examination of countries,research institu-tions,authors,and keywords associated with these publications was conducted.The visualization map was generated using CiteSpace 6.2.R4 software.Results A total of 3 304 papers were included,with 147 in Chinese and 3 157 in English.Over the past two decades,there has been a consistent upward trend in the number of publications both domestically and international-ly,although the growth rate of domestic literature lags behind that of foreign countries.The United States,China,and Japan rank as the top three countries in terms of publication volume,with the United States exhibiting the highest centrality.Foreign coun-tries tend to form small research groups with close institutional collaborations,while domestic research teams and institutions are relatively dispersed.Currently,foreign research primarily focuses on Fabrication,Ultrafiltration Membranes and Performance;meanwhile,domestic research emphasizes infection control,quality control,and daily maintenance.Conclusion From 2004 to 2024,both domestic and international researchers have consistently focused on water research for hemodialysis.However,China lags behind foreign countries in this field,necessitating enhanced collaboration among nations,institutions,and regions to broad-en the scope and depth of domestic research.

Objective:To compare the prognostic values of different classification by using transpulmonary pressure gradient (TPG), diastolic pressure gradient (DPG) and pulmonary vascular resistance (PVR) in patients with pulmonary hypertension due to left heart disease (PH-LHD), and investigated hemodynamic and clinical factors associated with mortality in patients with PH-LHD.Methods:This was a single-center prospective cohort study. In-hospital patients diagnosed with PH-LHD via right heart catheterization at the Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, from September 2013 to December 2019 were enrolled. Patients were divided according to TPG (cutoff value 12 mmHg; 1 mmHg=0.133 kPa), DPG (cutoff value 7 mmHg), PVR (cutoff value 3 Wood Units), and the combination of TPG and PVR. Baseline characteristic was recorded. All patients were followed up until the occurrence of endpoint event, defined as all-cause death that occurred during the follow-up period, or until April 18, 2022. Receiver operating characteristic curves were used to compare the predictive value of 3 classification methods for all-cause death in PH-LHD patients. The optimal cutoff values were calculated using Jorden index. Survival analysis was performed using Kaplan-Meier analysis, and log-rank test was used to compare the predictive efficacy of classification methods based on optimal cutoff values or guidance-recommended thresholds for the survival of PH-LHD patients. Variables showing statistical significance in the univariate analysis were incorporated into multivariate Cox regression model to analyze the independent risk factors for all-cause mortality.Results:A total of 243 patients were enrolled, aged (54.9±12.7) years old, including 169 (69.5%) males. During a median follow-up of 57 months, there were 101 (41.6%) deaths occurred. Grouping results were as follows: (1) TPG: TPG≤12 mmHg group 115 patients, TPG>12 mmHg group 128 patients; (2) DPG: DPG<7 mmHg group 193 patients, DPG≥7 mmHg group 50 patients; (3) PVR: PVR≤3 Wood Units group 108 patients, PVR>3 Wood Units group 135 patients; (4) TPG and PVR: TPG≤12 mmHg and PVR≤3 Wood Units group 89 patients, TPG>12 mmHg and PVR>3 Wood Units group 109 patients. PVR ( AUC=0. 698,95% CI:0.631-0.766) had better predictive value for all-cause mortality than TPG ( AUC=0.596, 95% CI: 0.523-0.669) and DPG ( AUC=0.526, 95% CI: 0.452-0.601) (all P<0.05). The optimal cutoff values for TPG, DPG, and PVR were13.9 mmHg, 2.8 mmHg, and 3.8 Wood Units, respectively. Kaplan-Meier analysis based on the optimal cutoff values or guidance-recommended thresholds showed that PVR and TPG were the predictors of survival ( P<0.05), while DPG did not showed significance ( P>0.05). Multivariate Cox regression analysis showed that age, PVR and log 2N-terminal pro-B-type natriuretic peptide were independent risk factors for all-cause mortality in PH-LHD patients (all P<0.05). Conclusion:Classification according to PVR was most valuable in predicting all-cause death in PH-LHD patients, while TPG showed moderate predictive ability and DPG had no predictive value.

Objective:To investigate the effect of early protein supplementation on the clinical outcomes of elderly ICU patients with critically ill.Methods:The study was a post-hoc analysis of a multicenter, cluster randomized controlled trial (NEED trial), which aimed to evaluate the impact of feeding protocol on nutritional implementation and outcomes in ICU patients. It was planned to include elderly patients aged ≥70 years from the NEED trial, and patients who had not started nutritional therapy by the Day 3 after enrolment, stayed in the ICU less than 7 days, missing the primary outcome were excluded. The primary outcome of this study was 28-day mortality of enrolment. Patients were categorized into Q1 (<0.6 g/kg/d), Q2 (0.6-0.83 g/kg/d), and Q3 (≥0.83 g/kg/d) groups according to the tertiles of protein supply. The log-rank test was used to compare the Kaplan-Meier survival curves for 28-day mortality. The associations between different protein groups and 28-day mortality were tested by Cox proportional hazards regression models. Subgroup analysis was conducted in patients with high (mNUTRIC score≥5) nutritional risk or patients with baseline acute kidney injury.Results:A total of 789 elderly (≥70 years) patients was included in the study, with a mean protein amount of 0.69 (0.53, 0.91) g/(kg·d) during days 3-7 after ICU admission, and mean protein amounts in the Q1 low-protein group, the Q2 medium-protein group, and the Q3 high-protein group were 0.46 (0.36, 0.53), 0.69 (0.63, 0.76), and 1.03 (0.91, 1.23) g/(kg·d), respectively. The results showed that the medium protein group associated with lower 28-day mortality compared to the high protein group, and the association between the medium protein group and lower 28-day mortality still held after controlling for possible confounders by Cox multivariate regression analysis. In the high-nutritional risk subgroup (mNUTRIC≥5), a significant association was also found between the medium protein group and lower 28-day mortality.Conclusions:Early high protein supply are not beneficial for elderly ICU patients by this large sample size post-hoc analysis, and medium protein supply associate with lower 28-day mortality compared with the high protein group. This study may provide a theoretical basis for the optimal dose of early protein supply in elderly ICU patients, as well as a reference for clinical implementation.

ObjectiveTo study the mechanism of Danggui Sinitang in mitigating gouty arthritis （GA） in rats by regulating autophagy via the phosphatidylinositol 3-kinase （PI3K）/protein kinase B （Akt）/mammalian target of rapamycin （mTOR） signaling pathway. MethodSixty male SD rats were randomly assigned into normal， model， colchicine （0.3 mg·kg^-1）， and low-， medium-， and high-dose Danggui Sinitang （6.54， 13.08， and 26.16 g·kg^-1） groups （n=10） and administrated with corresponding drugs by gavage. The rats in the normal group and model group were administrated with equal volume of normal saline by gavage for 7 days. One hour after administration on day 5， the GA model was established by injecting sodium urate suspension （50 g·L^-1） into the right ankle joint of rats in other groups except the normal group， and the rats in the normal group were injected with sterile normal saline of the same volume. The swelling and pathological changes of the ankle joint were observed. The serum levels of tumor necrosis factor-α （TNF-α）， interleukin-6 （IL-6）， and IL-1β were determined. Western blot was employed to determine the protein levels of PI3K， phosphorylated PI3K （p-PI3K）， protein kinase B （Akt）， phosphorylated Akt （p-Akt）， mTOR， phosphorylated mTOR （p-mTOR）， microtubule-associated protein 1 light chain 3 Ⅱ/Ⅰ （LC3Ⅱ/Ⅰ）， autophagy effector Beclin-1， and ubiquitin-binding protein p62 in the synovial tissue. Real-time fluorescent quantitative PCR （Real-time PCR） was employed to determine the mRNA levels of PI3K， Akt， mTOR， LC3， Beclin-1 and p62. ResultCompared with the normal control， the model group showed increased joint swelling index （P<0.01）， elevated serum levels of TNF-α， IL-6， and IL-1β， inflammatory cell infiltration， and fibrous tissue hyperplasia. In addition， the model group showed up-regulated protein levels of PI3K， p-PI3K， Akt， p-Akt， mTOR， p-mTOR， and p62 and mRNA levels of PI3K， Akt， mTOR， and p62 in the synovial tissue， while it showed down-regulated protein levels of LC3Ⅱ/Ⅰ and Beclin-1 and mRNA levels of LC3 and Beclin-1 （P<0.01）. Compared with the model group， medium- and high-dose Danggui Sinitang alleviated the joint swelling （P<0.01）， lowered the serum levels of TNF-α， IL-6， and IL-1β （P<0.05）， and relieved the inflammatory cell infiltration in the synovial tissue of the ankle joint and the fibrous tissue hyperplasia. Moreover， they down-regulated the protein levels of PI3K， p-PI3K， Akt， p-Akt， mTOR， p-mTOR， and p62 and the mRNA levels of PI3K， Akt， mTOR， and p62 in the synovial tissue （P<0.05）， while they up-regulated the protein levels of LC3Ⅱ/Ⅰ and Beclin-1 and the mRNA levels of LC3 and Beclin-1 （P<0.05）. ConclusionDanggui Sinitang， especially at a high dose， can inhibit PI3K/Akt/mTOR signaling pathway to improve autophagy in the synovial tissue， thereby mitigating GA.