This study aims to explore the synergistic effects of the main components in salvianolic acids for Injection(SAFI) on key pathological events in cerebral ischemia, elucidating the pharmacological characteristics of SAFI in neuroprotection. Two major pathological gene modules related to endothelial injury and neuroinflammation in cerebral ischemia were mined from single-cell data. According to the topological distance calculated in network medicine, potential synergistic component combinations of SAFI were screened out. The results showed that the combination of caffeic acid and salvianolic acid B scored the highest in addressing both endothelial injury and neuroinflammation, demonstrating potential synergistic effects. The cell experiments confirmed that the combination of these two components at a ratio of 1∶1 significantly protected brain microvascular endothelial cells(bEnd.3) from oxygen-glucose deprivation/reoxygenation(OGD/R)-induced reperfusion injury and effectively suppressed lipopolysaccharide(LPS)-induced neuroinflammatory responses in microglial cells(BV-2). This study provides a new method for uncovering synergistic effects among active components in traditional Chinese medicine(TCM) and offers novel insights into the multi-component, multi-target acting mechanisms of TCM.
Brain Ischemia/metabolism* ; Neuroprotective Agents/pharmacology* ; Animals ; Drugs, Chinese Herbal/administration & dosage* ; Benzofurans/pharmacology* ; Mice ; Drug Synergism ; Caffeic Acids/pharmacology* ; Polyphenols/pharmacology* ; Humans ; Alkenes/pharmacology* ; Endothelial Cells/drug effects* ; Depsides

Tumor lineage plasticity (LP) is an emerging hallmark of cancer progression. Through pharmacologically probing the function of epigenetic regulators in prostate cancer cells and organoids, we identified bromodomain protein BRD4 as a crucial player. Integrated ChIP-seq and RNA-seq analysis of tumors revealed, for the first time, that BRD4 directly activates hundreds of genes in the LP programs which include neurogenesis, axonogenesis, EMT and stem cells and key drivers such as POU3F2 (BRN2), ASCL1/2, NeuroD1, SOX2/9, RUNX1/2 and DLL3. Interestingly, BRD4 genome occupancy is reprogrammed by anti-AR drugs from facilitating AR function in CRPC cells to activating the LP programs and is facilitated by pioneer factor FOXA1. Significantly, we demonstrated that BRD4 inhibitor AZD5153, currently at clinical development, possesses potent activities in complete blockade of tumor growth of both de novo neuroendocrine prostate cancer (NEPC) and treatment-induced NEPC PDXs and that suppression of tumor expression of LP programs through reduction of local chromatin accessibility is the primary mechanism of action (MOA) by AZD5153. Together, our study revealed that BRD4 plays a fundamental role in direct activation of tumor LP programs and that its inhibitor AZD5153 is highly promising in effective treatment of the lethal forms of the diseases.

OBJECTIVE: Burning solid cooking fuel contributes to household air pollution and is associated with frailty. However, how solid cooking fuel use contributes to the development of frailty has not been well illustrated. METHODS: This study recruited 8,947 participants aged ≥ 45 years from the China Health and Retirement Longitudinal Study, 2011-2018. Group-based trajectory modeling was employed to identify frailty trajectories. Multinomial logistic regression was used to assess the association between solid cooking fuel use and frailty trajectories. Population-attributable fractions were used to estimate the frailty burden from solid fuel use. RESULTS: We identified three frailty trajectories: low-stable ( n = 5,789), moderate-increasing ( n = 2,603), and fast-increasing ( n = 555). Solid fuel use was associated with higher odds of being in the moderate-increasing ( OR: 1.24, 95% CI: 1.08-1.42) and fast-increasing ( OR: 1.48, 95% CI: 1.14-1.92) trajectories. These associations were strengthened by longer solid fuel use ( P for trend < 0.001). Switching to clean fuel significantly reduced the risk of being in these trajectories compared with persistent solid fuel users. Without solid fuel, 8% of moderate- and 19% of fast-increasing trajectories demonstrated frailty development like the low-stable group. CONCLUSION Solid cooking fuel use is associated with frailty trajectories in middle-aged and older Chinese populations.
Humans ; China/epidemiology* ; Cooking ; Male ; Female ; Middle Aged ; Aged ; Air Pollution, Indoor/adverse effects* ; Frailty/etiology* ; Longitudinal Studies ; Cohort Studies

OBJECTIVE: To investigate the spatiotemporal patterns and socioeconomic factors influencing the incidence of tuberculosis (TB) in the Guangdong Province between 2010 and 2019. METHOD: Spatial and temporal variations in TB incidence were mapped using heat maps and hierarchical clustering. Socioenvironmental influencing factors were evaluated using a Bayesian spatiotemporal conditional autoregressive (ST-CAR) model. RESULTS: Annual incidence of TB in Guangdong decreased from 91.85/100,000 in 2010 to 53.06/100,000 in 2019. Spatial hotspots were found in northeastern Guangdong, particularly in Heyuan, Shanwei, and Shantou, while Shenzhen, Dongguan, and Foshan had the lowest rates in the Pearl River Delta. The ST-CAR model showed that the TB risk was lower with higher per capita Gross Domestic Product (GDP) [Relative Risk ( RR), 0.91; 95% Confidence Interval ( CI): 0.86-0.98], more the ratio of licensed physicians and physician ( RR, 0.94; 95% CI: 0.90-0.98), and higher per capita public expenditure ( RR, 0.94; 95% CI: 0.90-0.97), with a marginal effect of population density ( RR, 0.86; 95% CI: 0.86-1.00). CONCLUSION The incidence of TB in Guangdong varies spatially and temporally. Areas with poor economic conditions and insufficient healthcare resources are at an increased risk of TB infection. Strategies focusing on equitable health resource distribution and economic development are the key to TB control.
Humans ; China/epidemiology* ; Incidence ; Bayes Theorem ; Spatio-Temporal Analysis ; Tuberculosis/epidemiology* ; Socioeconomic Factors

″Boundarics in biomedicine″(or″Biomedical boundarics″)is an emerging frontier interdisciplinary subject that focuses on addressing key scientific issues related to the formation,identification,and evolution of biological boundaries within living organisms.In this field,the study of tumor boundaries is of particular importance.Imaging tumor boundaries not only helps to reveal the molecular mechanisms of tumor boundary evolution and interaction with the microenvironment,tumor invasion and metastasis,but is also crucial for clinical tumor diagnosis,treatment decision-making,efficacy monitoring and prognosis evaluation.Molecular probes,as functional substances that enhance imaging signals,play a crucial role in tumor boundary recognition.In this article,the basic concepts and research significance of boundarics in biomedicine and tumor boundarics in biomedicine were summarized firstly.Then a comprehensive review of the research progress in tumor boundary imaging molecular probes was provided,covering areas such as magnetic imaging,optical imaging,acoustic imaging,nuclear imaging,and multimodal imaging.The strategies to regulate the sensitivity,specificity,and safety of molecular probes through chemical structure modifications,conjugation with targeting ligands,and tumor microenvironment-responsive designs were emphasized.Finally,the research trends of molecular probes for tumor boundary imaging were analyzed,and the challenges faced in this field and the future research directions were discussed.

Objective To analysis the efficacy and safety of antiviral therapy in patients with chronic hepatitis B virus in indeterminate phase based on the new guidelines(2022 Edition of the Guidelines for the Prevention and Treatment of Chronic Hepatitis B).Methods A total of 170 patients with newly diagnosed HBV infection who visited the Third People's Hospital of Kunming from August 1,2020,to July 31,2024,were selected as study subjects.The clinical indicators of patients with normal ALT in the indeterminate phase were analyzed after 12 weeks,24 weeks,and 48 weeks of antiviral treatment,as well as those who did not receive antiviral treatment for 48 weeks.Results(1)Among the 170 patients with normal ALT during the indeterminate phase of HBV infection,the treatment group consisted of 125 patients(36 HBeAg positive and 89 HBeAg negative),while the untreated group had 45 patients.In the treatment group,the HBV-DNA load and HBsAg titer decreased significantly after 48 weeks compared to before treatment,with statistically significant differences(both P<0.05).In the untreated group,the HBV-DNA load showed an upward trend,and the HBsAg titer slightly decreased,with statistically significant differences(both P<0.05).(2)The CVR rate in the treatment group after 48 weeks was 66.67%(24/36)for HBeAg positive patients and 95.51%(85/89)for HBeAg negative patients,with a statistically significant difference(P<0.05).(3)The treatment group showed a significant decrease in GGT and AFP after 48 weeks compared to before treatment,while the untreated group saw an increase in ALT,GGT,and AFP,with statistically significant differences(all P<0.05).(4)The fibrosis indicators APRI,FIB-4,and LSM in the treatment group significantly decreased after 48 weeks compared to before treatment,with statistically significant differences(all P<0.05).(5)The safety indicators CREA,blood calcium,and blood phosphorus in the treatment group significantly decreased after 48 weeks compared to before treatment,with statistically significant differences(all P<0.05).Conclusion Expanding the antiviral treatment indications according to the new guidelines for patients with normal ALT in the indeterminate phase of HBV infection demonstrates good efficacy in controlling HBV-DNA,improving CVR rates,and enhancing fibrosis indicators,while also showing favorable renal safety.However,there may be a risk of osteoporosis due to calcium and phosphorus metabolism disorders,necessitating enhanced monitoring and prevention.

The aim of this study was to investigate the virulence determinants and genetic diversity of foodborne Yersinia enterocolitica from Wenzhou.A total of 71 strains of Yersinia enterocolitica were isolated from food and foodborne diarrhea ca-ses in Wenzhou,and their biotypes,serotypes,and drug resistance were analyzed.On the basis of whole genome sequencing,we assessed virulence gene profiles,and performed multilocus sequence typing(MLST)and core gene multilocus sequence typ-ing(cgMLST).A total of 94.4％(67/71)of isolates belonged to biotype 1A,and the highest proportion had serotype lA/O∶5(29.6％,21/71).The sensitivity rates of the isolates to 14 antibiotics exceeded 95.8％.A total of 16 categories and 126 viru-lence genes were identified,with two strains carrying the pYV plasmid and chromosome-related virulence genes.ST3(31.6％,12/38)was the most widespread MLST type,and cgMLST analysis revealed no dense clusters of genotypes except for strains sharing the same ST.In conclusion,pathogenic strains were identified from foodborne Yersinia enterocolitica in Wenzhou and were found to exhibit high genetic polymorphism.Enhanced regulatory supervision is essential to prevent the outbreak of food-borne diseases caused by Yersinia enterocolitica.

Objective To investigate the effect of antinuclear antibodies(ANAs)on hormone response in patients with autoimmune hepatitis(AIH)-primary biliary cholangitis(PBC)overlap syndrome(AIH-PBC OS)and AIH-only within half a year.Methods A retrospective analysis of 77 patients with autoimmune liver disease(AILD)admitted to First Clinical Medical College of Lanzhou University from January 2018 to December 2021,all of whom were confirmed by liver biopsy and receiving glucocorticoid treatment.Among them,46 patients were in AIH-PBC OS group and 31 were in AIH-only group.The general clinical characteristics,liver puncture-related indexes,autoantibodies and immunoglobulin indexes of patients in each group at the time of diagnosis were collected and compared,and the biochemical and immunoglobulin indexes of patients at the time of hormone use and at the time of review within 6 months were also collected,and the hormone response within 6 months was evaluated according to the levels of glutamic transaminase(AST),glutamic alanine transaminase(ALT)and immunoglobulin G(IgG),and the effect of ANAs on hormone response outcomes in both groups over a six-month period was analyzed.Multifactorial ordered logistic analysis was performed to evaluate the effect of ANAs on hormone response between two groups.Results There was no statistically significant difference in the percentage of AIH-PBC OS and AIH-only patients among both ANAs-positive and-negative AILD patients(55.6%vs.44.4%and 65.6%vs.34.4%,P>0.05).Among 46 patients with AIH-PBC OS,there were 25 in ANAs-positive group and 21 in ANAs-negative group.The rate of complete hormone response within 6 months was lower than that of ANAs-negative group(44.0%vs.76.2%),while the rate of hormone non-response was higher than that of ANAs-negative group(20.0%vs.0),and the difference was statistically significant(P<0.05).There were 20 cases of ANAs-positive and 11 cases of ANAs-negative in the 31 AIH-only patients.There was no statistically significant difference in the results of hormone response within 6 months between the two groups(P>0.05).Multifactorial ordered logistic analysis showed that AIH-PBC OS patients were more likely to have a higher likelihood of 6-month hormone non-response rate in ANAs-positive patients,and the difference was statistically different(P<0.05).And there was no significant effect of ANAs type on hormone response outcome in AIH-only patients(P>0.05).Conclusion AIH-PBC OS ANAs-positive patients have a poor hormone response within half a year.In AIH-only patients,ANAs have no significant effect on hormone response results.

BACKGROUND:Pressing massage applied to myofascial trigger points(MTrPs)has shown clear effect in relieving pain.However,further research is needed to investigate the effects of different levels of pressure applied during the massage. OBJECTIVE:To investigate the different strength of pressing on MTrPs in rats with chronic pain. METHODS:Sixty SPF-rated male Sprague-Dawley rats were randomly divided into a blank group of 10 rats not involved in MTrPs modeling and 50 rats involved in modeling.The MTrPs model was established in the left medial thigh muscle of rats by blunt strikes combined with centrifugal exercise and 40 rats that met the evaluation criteria after modeling were randomly divided into model group,light press group,medium press group and heavy press group,with 10 rats in each group.The rats in the blank group and the model group were not intervened,while the rats in the light press group,the medium press group and the heavy press group were intervened with a homemade press stimulator with light force(0.3 kg),medium force(0.5 kg)and heavy force(0.7 kg)to MTrPs.The intervention time was 7.5 minutes per session,with one session every other day,totaling seven sessions.Electromyogram,soft tissue tension and mechanical pain threshold were detected by electrophysiological instruments,soft tissue tension tester,and pressure painmeter,respectively.After the intervention,in the blank group,muscle tissue was taken from the inside of the left thigh,while in the other groups,MTrPs tissue was taken.The pathological morphology was observed by hematoxylin-eosin staining,while enzyme-linked immunosorbent assay(ELISA)was used to detect the levels of cyclooxygenase-2,prostaglandin E2 and bradykinin. RESULTS AND CONCLUSION:Compared with the blank group,the model group had lower mechanical pain thresholds,higher soft tissue tone,higher amplitude frequency of spontaneous electrical activity,significant pathomorphological changes,and increased levels of cyclooxygenase-2,prostaglandin E2 and bradykinin(P<0.05).Compared with the model group,the medium press group and the heavy press group showed increased mechanical pain thresholds,decreased soft tissue tension,decreased spontaneous potential frequency amplitude,and decreased levels of cyclooxygenase-2,prostaglandin E2 and bradykinin(P<0.05),and significant recovery on pathomorphological changes.No significant changes in the above indicators were observed in the light press group(P>0.05).Compared with the medium press group,the heavy press group showed better improvement in the above indicators(P<0.05).To conclude,moderate to heavy pressing is often required to alleviate MTrPs pain.

Objective To evaluate the effect of para-esophageal and para-gastric vessels(PEPGV)on endoscopic secondary prophylaxis for varices.Methods The clinical data of patients with cirrhosis-related esophagogastric varices(EGV)who underwent endoscopic variceal ligation and/or obliteration,and had hepatic venous pressure gradient(HVPG)result between January 2020 and December 2020 in Zhongshan Hospital,Fudan University were retrospectively analyzed.Patients were divided into a group without PEPGV and a group with PEPGV based on CT imaging of the portal vein.The main outcome was 2-year re-bleeding.Results A total of 69 patients were included,and 27 of them had PEPGV.There was no statistical difference in baseline characteristics,blood indexes(included hemoglobin level,prothrombin time and albumin level),HVPG,and the secondary prophylactic endoscopic treatment ways between the two groups.A total of 25 patients experienced re-bleeding within 2 years after endoscopic treatment,including 15 in the group with PEPGV and 10 in the group without PEPGV.Kaplan-Meier analysis showed that the cumulative 2-year re-bleeding rate was significantly higher in the group with PEPGV than in the group without PEPGV(60.07％vs 32.79％,P=0.022).Further multivariate Cox analysis showed that PEPGV was an independent predictor of re-bleeding after endoscopic treatment in EGV patients(HR=2.33,95％CI 1.01-5.39,P=0.047).Conclusions The PEPGV is an independent predictor of re-bleeding after endoscopic treatment in EGV patients.It is suggested that when patients with EGV receive endoscopic treatment to prevent re-bleeding,portal vascular CT is suggested to evaluate PEPGV.For patients with giant extraluminal vascular masses,fully evaluating other treatment options such as transjugular intrahepatic portosystemic shunt,or adjusting endoscopic treatment ways is recommended.