Background Per- and polyfluoroalkyl substances (PFAS) are persistent organic pollutants widely distributed in the environment. Epidemiological studies have shown that PFAS exposure is closely associated with liver dysfunction and an increased risk of liver cancer. Some animal and cell experiments have also revealed its hepatotoxicity and potential carcinogenicity; however, the related carcinogenic mechanism has not yet been fully elucidated. Objective To explore the potential molecular mechanism of PFAS-induced liver cancer, identify the key causal genes, and specifically evaluate the causal association and expression changes of KMT2C in this process, as well as the binding stability between KMT2C and PFAS, and to provid a theoretical basis for mechanistic studies and molecular target discovery in PFAS-related liver cancer. Methods Toxicity prediction was performed on six representative PFAS. Potential target genes of PFAS were identified by integrating results from SwissTargetPrediction, STITCH, and TargetNet databases. Liver cancer-related genes were retrieved from GeneCards, Online Mendelian Inheritance in Man (OMIM), and Therapeutic Target Database (TTD). The intersection of PFAS targets and liver cancer-related genes was used to obtain core genes. A compound-gene-disease regulatory network was constructed, and a protein–protein interaction network was established using STRING database. A core gene network was visualized based on node degree values. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to explore biological functions and enriched signaling pathways. Subsequently, two-sample Mendelian randomization was employed to assess potential causal relationships between candidate genes and hepatocellular carcinoma, enabling the identification of key genes. Molecular docking analysis using AutoDock was conducted to evaluate the binding stability between KMT2C and PFAS, and TCGA data were used to validate the differential expression of KMT2C between hepatocellular carcinoma and adjacent normal tissues. Results PFAS exhibited multisystem toxicity and posed significant risks of liver injury and carcinogenesis. A total of 266 PFAS target genes and 2923 liver cancer-related genes were identified, with 61 intersecting genes obtained. The enrichment analysis revealed that these intersecting genes were primarily involved in epigenetic regulation, nuclear receptor signaling pathways, and apoptosis-related pathways including TGF-β FoxO and Notch, suggesting their roles in diverse tumor-related biological processes. The two-sample Mendelian randomization results showed a significant negative causal association between KMT2C and hepatocellular carcinoma (OR=0.68, P <0.05). The molecular docking results demonstrated that all tested PFAS exhibited favorable binding to the KMT2C protein, with binding energies below –5.0 kcal·mol⁻¹. KMT2C was significantly upregulated in hepatocellular carcinoma tissues (unpaired P=0.025; paired P=8.38 × 10⁻⁴). Conclusion The KMT2C protein is found to stably bind with all six PFAS, exhibiting strong structural affinity. A causal relationship is identified between KMT2C and the development of hepatocellular carcinoma. TCGA data indicate that KMT2C is significantly upregulated in hepatocellular carcinoma tissues, and it may serve as a key regulatory target in PFAS-related liver cancer.

Gastric cancer remains one of the most prevalent and lethal malignancies of the digestive tract worldwide,underscoring the urgent need for more effective targeted therapeutic strategies.Poly(ADP-ri-bose)polymerase(PARP)inhibitors have demonstrated remarkable efficacy in tumors with homologous recombination repair(HRR)deficiency;however,their clinical application in gastric cancer remains limited.Clinical evidence suggests that patients harboring Helicobacter pylori infection in combination with HRR gene mutations exhibit a significantly elevated risk of developing gastric cancer,thereby supporting the potential benefit of PARP inhibition in this setting.In this study,a kinase inhibitor library was screened in combination with the PARP inhibitor olaparib in gastric cancer cells.And we identify the cy-clin-dependent kinase 8/19(CDK8/19)inhibitor Senexin A as a compound that synergistically enhances the cytotoxic effect of PARP inhibition(P<0.05).Phenotypic validation using CCK-8 and colony for-mation assays demonstrated that the combination treatment significantly suppressed cellular proliferation and clonogenic potential compared to either monotherapy(P<0.0001).Mechanistically,alkaline comet assays revealed a significant increase in DNA damage in the combination treatment group relative to either single-agent group(P<0.0001),suggesting that the synergistic effect results from the exacerbation of DNA damage via impaired DNA repair mechanisms.In addition,treatment with CDK8/19 inhibitors a-lone markedly increased the formation of γH2AX and 53BP1 foci in irradiated gastric cancer cells(P<0.0001),indicating inhibition of DNA damage repair pathways.Transcriptome sequencing further re-vealed that CDK8/19 inhibition impacts critical cellular pathways,including DNA repair,cell cycle reg-ulation,and RNA splicing.Co-immunoprecipitation assays confirmed that inhibition of CDK8/19 kinase activity significantly reduces the phosphorylation level of PARP1,suggesting a potential regulatory inter-action.Immunohistochemical analysis of tumor and adjacent non-tumor tissues from gastric cancer pa-tients demonstrated that CDK8 is significantly overexpressed in tumor tissues,supporting its potential as both a prognostic biomarker and a therapeutic target.Collectively,this study elucidates a mechanistic ba-sis by which CDK8/19 inhibition enhances the sensitivity of gastric cancer cells to PARP inhibitors.These findings provide a strong rationale for the combined use of CDK8/19 and PARP inhibitors as a tar-geted therapeutic strategy and offer promising translational implications for advancing personalized medi-cine in gastric cancer treatment.

Gastric cancer remains one of the most prevalent and lethal malignancies of the digestive tract worldwide,underscoring the urgent need for more effective targeted therapeutic strategies.Poly(ADP-ri-bose)polymerase(PARP)inhibitors have demonstrated remarkable efficacy in tumors with homologous recombination repair(HRR)deficiency;however,their clinical application in gastric cancer remains limited.Clinical evidence suggests that patients harboring Helicobacter pylori infection in combination with HRR gene mutations exhibit a significantly elevated risk of developing gastric cancer,thereby supporting the potential benefit of PARP inhibition in this setting.In this study,a kinase inhibitor library was screened in combination with the PARP inhibitor olaparib in gastric cancer cells.And we identify the cy-clin-dependent kinase 8/19(CDK8/19)inhibitor Senexin A as a compound that synergistically enhances the cytotoxic effect of PARP inhibition(P<0.05).Phenotypic validation using CCK-8 and colony for-mation assays demonstrated that the combination treatment significantly suppressed cellular proliferation and clonogenic potential compared to either monotherapy(P<0.0001).Mechanistically,alkaline comet assays revealed a significant increase in DNA damage in the combination treatment group relative to either single-agent group(P<0.0001),suggesting that the synergistic effect results from the exacerbation of DNA damage via impaired DNA repair mechanisms.In addition,treatment with CDK8/19 inhibitors a-lone markedly increased the formation of γH2AX and 53BP1 foci in irradiated gastric cancer cells(P<0.0001),indicating inhibition of DNA damage repair pathways.Transcriptome sequencing further re-vealed that CDK8/19 inhibition impacts critical cellular pathways,including DNA repair,cell cycle reg-ulation,and RNA splicing.Co-immunoprecipitation assays confirmed that inhibition of CDK8/19 kinase activity significantly reduces the phosphorylation level of PARP1,suggesting a potential regulatory inter-action.Immunohistochemical analysis of tumor and adjacent non-tumor tissues from gastric cancer pa-tients demonstrated that CDK8 is significantly overexpressed in tumor tissues,supporting its potential as both a prognostic biomarker and a therapeutic target.Collectively,this study elucidates a mechanistic ba-sis by which CDK8/19 inhibition enhances the sensitivity of gastric cancer cells to PARP inhibitors.These findings provide a strong rationale for the combined use of CDK8/19 and PARP inhibitors as a tar-geted therapeutic strategy and offer promising translational implications for advancing personalized medi-cine in gastric cancer treatment.

AIM To study the chemical constituents from n-butanol fraction of Corydalis impatiens(Pall.)Fisch.and their antioxidant activities.METHODS The n-butanol fraction was isolated and purified by silica gel,MCI,ODS,Sephadex LH-20 and semi-preparative HPLC,then the structures of obtained compounds were identified by physicochemical properties and spectral data.The antioxidant activities were determined by DPPH method and tyrosinase method.RESULTS Fourteen compounds were isolated and identified as nicotinamide(1),methyl L-pyroglutamate(2),bungeanoline F(3),monomethyl fumarate(4),5-hydroxymethylfurfural(5),4-hydroxybenzoic acid(6),hydroxybenzoate(7),methyl 3,4-dihydroxybenzoate(8),methyl ferulate(9),dimethylcaffeic acid(10),dimethyl feruloyl malate(11),(-)-4-O-feruloylquinic acid(12),syringaresinol(13)and(-)-loliolide(14).Compounds 1,8,11 and 13 showed strong antioxidant activites on DPPH free radicals,with IC50 values ranging from 54.47 to 97.4 μmol/L.Compound 13 had potential inhibitory effect on tyrosinase.CONCLUSION Compounds 4-14 are first isolated from Corydalis genus,and 3 is isolated from this plant for the first time.Compounds 1,8,11 and 13 have strong antioxidant activities.

Objective Human papillomavirus(HPV)is a detriment virus to human health,because it can cause malignant tumors.HPV vaccine has been developed and plays an important role in preventing a range of diseases caused by HPV.HPV vaccine as a primary prevention measure,has demonstrated excellent protective efficacy and safety in preventing HPV-related infection and cervical cancer.This article summarizes the application of preventive HPV vaccine and its safety,and provides reference for the widespread vaccination of HPV vaccine in China.

BACKGROUND: This study aimed to develop a comprehensive instrument for evaluating and ranking clinical practice guidelines, named Scientific, Transparent and Applicable Rankings tool (STAR), and test its reliability, validity, and usability. METHODS: This study set up a multidisciplinary working group including guideline methodologists, statisticians, journal editors, clinicians, and other experts. Scoping review, Delphi methods, and hierarchical analysis were used to develop the STAR tool. We evaluated the instrument's intrinsic and interrater reliability, content and criterion validity, and usability. RESULTS: STAR contained 39 items grouped into 11 domains. The mean intrinsic reliability of the domains, indicated by Cronbach's α coefficient, was 0.588 (95% confidence interval [CI]: 0.414, 0.762). Interrater reliability as assessed with Cohen's kappa coefficient was 0.774 (95% CI: 0.740, 0.807) for methodological evaluators and 0.618 (95% CI: 0.587, 0.648) for clinical evaluators. The overall content validity index was 0.905. Pearson's r correlation for criterion validity was 0.885 (95% CI: 0.804, 0.932). The mean usability score of the items was 4.6 and the median time spent to evaluate each guideline was 20 min. CONCLUSION The instrument performed well in terms of reliability, validity, and efficiency, and can be used for comprehensively evaluating and ranking guidelines.
Reproducibility of Results ; Surveys and Questionnaires ; Practice Guidelines as Topic ; Humans

This paper aimed to study the chemical constituents from the root bark of Schisandra sphenanthera. Silica, Sephadex LH-20 and RP-HPLC were used to separate and purify the 80% ethanol extract of S. sphenanthera. Eleven compounds were identified by ~1H-NMR, ~(13)C-NMR, ESI-MS, etc., which were 2-[2-hydroxy-5-(3-hydroxypropyl)-3-methoxyphenyl]-propane-1,3-diol(1), threo-7-methoxyguaiacylglycerol(2),4-O-(2-hydroxy-1-hydroxymethylethyl)-dihydroconiferylalcohol(3), morusin(4), sanggenol A(5), sanggenon I(6), sanggenon N(7), leachianone G(8),(+)-catechin(9), epicatechin(10), and 7,4'-dimethoxyisoflavone(11). Among them, compound 1 was a new compound, and compounds 2-9 were isolated from S. sphenanthera for the first time. Compounds 2-11 were subjected to cell viability assay, and the results revealed that compounds 4 and 5 had potential cytotoxicity, and compound 4 also had potential antiviral activity.
Schisandra ; Plant Bark ; Antiviral Agents ; Biological Assay ; Catechin ; Phenols

Complicated chemical reactions occur in the decoction of traditional Chinese medicines(TCMs) which features complex components, influencing the safety, efficacy, and quality controllability of TCMs. Therefore, it is particularly important to clarify the chemical reaction mechanism of TCMs in the decoction. This study summarized eight typical chemical reactions in the decoction of TCMs, such as substitution reaction, redox reaction, isomerization/stereoselective reaction, complexation, and supramolecular reaction. With the "toxicity attenuation and efficiency enhancement" of aconitines and other examples, this study reviewed the reactions in decoction of TCMs, which was expected to clarify the variation mechanisms of key chemical components in this process and to help guide medicine preparation and safe and rational use of medicine in clinical settings. The current main research methods for chemical reaction mechanisms of decoction of TCMs were also summed up and compared. The novel real-time analysis device of decoction system for TCMs was found to be efficient and simple without the pre-treatment of samples. This device provides a promising solution, which has great potential in quantity evaluation and control of TCMs. Moreover, it is expected to become a foundational and exemplary research tool, which can advance the research in this field.
Medicine ; Medicine, Chinese Traditional ; Research Design

ObjectiveTo study the virulence and biofilm inhibition effect of Fufang Huangbai Fluid Paint （FFHBFP） on methicillin-resistant Staphylococcus aureus （MRSA）， and to explore the antibacterial effect of FFHBFP on MRSA， which provides a theoretical basis and reference for clinical medication. MethodFirstly， the microdilution method and time–growth curve were used to determine the minimum inhibitory concentration （MIC） of FFHBFP and vancomycin （VAN） against MRSA and the effect on bacterial growth. The effects of FFHBFP and VAN on the inhibition of MRSA virulence factor lipase and restoration of hydrogen peroxide （H₂O₂） sensitivity were detected under sub-minimum inhibitory concentration （sub-MIC）. The inhibitory effect of FFHBFP and VAN on MRSA biofilm formation and maturation was detected by the microplate method. The morphological changes of mature biofilms before and after administration were observed under a scanning electron microscope （SEM）. Real-time polymerase chain reaction （Real-time PCR） was utilized to detect the effect of 50.600 g·L^-1 concentration of FFHBFP on the expression of MRSA virulence gene crtM and biofilm-forming genes fnbA and icaA. Finally， molecular docking technology was used to predict the mechanism of potential antibacterial active ingredients of FFHBFP in inhibiting the virulence and biofilm of MRSA. ResultThe MIC of VAN was 2 mg·L^-1， and VAN below 1 mg·L^-1 exerted no effect on MRSA growth. The MIC of FFHBFP was not determined， while the 101.200-202.400 g·L^-1 original solution inhibited MRSA growth. Compared with the blank group and the VAN group， sub-MIC （25.300-50.600 g·L^-1 original solution） inhibited lipase and recovered MRSA sensitivity to H₂O₂ （P<0.01）. The results of the microplate method showed that FFHBFP （25.300-202.400 g·L^-1 original solution） inhibited biofilm formation and maturation （P<0.05， P<0.01）. The SEM exhibited that FFHBFP made the structure of biofilm loose and the size of the bacteria varied. FFHBFP at 50.600 g·L^-1 concentration can inhibit the expression of related virulence genes and biofilm-forming genes （P<0.05， P<0.01）， and molecular docking results also showed that the main antibacterial active ingredients in FFHBFP have good binding ability to the target. ConclusionFFHBFP that cannot directly kill MRSA exerts clinical efficacy by impairing virulence expression， biofilm formation， and other pathogenic properties.

Objective: To investigate the clinical characteristics and diagnosis and treatment strategies of patients with severe traumatic aortic injury (TAI). Methods: A total of 25 patients with TAI, who hospitalized in our hospital between August 2005 to March 2021 and underwent thoracic aortic endovascular repair (TEVAR), were included in this retrospective study. According to the time from admission to TEVAR, the patients were divided into emergency TEVAR group (14 cases, TEVAR within 24 h of admission) and elective TEVAR group (11 cases, patients underwent surgery or fracture reduction and fixation first for serious injuries and then underwent TEVAR more than 24 h after admission). The general clinical data of patients, injury severity score (ISS), time from admission to intervention, total hospital stay, the proportion of closed chest drainage and the proportion of abdominal organ repair were obtained and compared. Clinical follow-up and 1-year postoperative aortic computed tomography angiography (CTA) were performed on the patients. Death, the occurrence of aortic adverse events and injury recovery were followed up and recorded. Results: The mean age of these 25 TAI patients was (41.4±14.4) years, 20 patients were males (80.0%). 21 patients (84.0%) had persistent chest and back pain, 17 (68.0%) had pleural effusion and 5 (20.0%) had mediastinal hematoma. The injury severity score (ISS) was significantly higher in the elective TEVAR group than in the emergency TEVAR group (24.9±14.4 vs. 35.5±9.3, P=0.044). The time from admission to intervention ((1.0±0.0) d vs. (3.4±0.9) d, P<0.001], the time from admission to TEVAR ((1.0±0.0) d vs. (11.5±13.8) d, P=0.030) and total hospital stay ((6.1±2.3) d vs. (26.8±7.7) d, P<0.001) were significantly longer in elective TEVAR group than in emergency TEVAR group. The proportion of thoracic closed drainage was significantly lower in the elective TEVAR group than in the emergency TEVAR group (9 (64.3%) vs. 2 (18.2%), P=0.042). The proportion of abdominal organ repair was significantly higher than in the emergency TEVAR group (0 vs. 4 (36.4%), P=0.026). All of 25 patients were discharged alive and followed up for (84.0±30.5) months. All patients survived and completed 1-year postoperation CTA. There were no aortic adverse events occurred, and no complications after surgery, and the fractures and organ injuries healed well. Conclusions: The clinical characteristics of severe TAI are acute multi-injuries combined with persistent chest and/or back pain, pleural effusion, and mediastinal hematoma. Timely diagnosis and treatment are important factors for the outcome. The treatment strategy for multi-injuries should give priority to dealing with life-threatening injuries. TEVAR is the primary treatment strategy for severe TAI and is related to satisfactory outcomes.
Adult ; Aorta, Thoracic/surgery* ; Aortic Diseases ; Blood Vessel Prosthesis Implantation/adverse effects* ; Endovascular Procedures/methods* ; Female ; Hematoma/surgery* ; Humans ; Male ; Middle Aged ; Pleural Effusion/surgery* ; Retrospective Studies ; Risk Factors ; Treatment Outcome