This study investigated the effects and underlying mechanisms of vanillic acid(VA) against cardiac fibrosis(CF) induced by isoproterenol(ISO) in mice. Male C57BL/6J mice were randomly divided into control group, VA group(100 mg·kg~(-1), ig), ISO group(10 mg·kg~(-1), sc), ISO + VA group(10 mg·kg~(-1), sc + 100 mg·kg~(-1), ig), ISO + dynamin-related protein 1(Drp1) inhibitor(Mdivi-1) group(10 mg·kg~(-1), sc + 50 mg·kg~(-1), ip), and ISO + VA + Mdivi-1 group(10 mg·kg~(-1), sc + 100 mg·kg~(-1), ig + 50 mg·kg~(-1), ip). The treatment groups received the corresponding medications once daily for 14 consecutive days. On the day after the last administration, cardiac functions were evaluated, and serum and cardiac tissue samples were collected. These samples were analyzed for serum aspartate aminotransferase(AST), lactate dehydrogenase(LDH), creatine kinase-MB(CK-MB), cardiac troponin I(cTnI), reactive oxygen species(ROS), interleukin(IL)-1β, IL-4, IL-6, IL-10, IL-18, and tumor necrosis factor-α(TNF-α) levels, as well as cardiac tissue catalase(CAT), glutathione(GSH), malondialdehyde(MDA), myeloperoxidase(MPO), superoxide dismutase(SOD), total antioxidant capacity(T-AOC) activities, and cytochrome C levels in mitochondria and cytoplasm. Hematoxylin-eosin, Masson, uranium acetate and lead citrate staining were used to observe morphological and mitochondrial ultrastructural changes in the cardiac tissues, and myocardial injury area and collagen volume fraction were calculated. Flow cytometry was applied to detect the relative content and M1/M2 polarization of cardiac macrophages. The mRNA expression levels of macrophage polarization markers [CD86, CD206, arginase 1(Arg-1), inducible nitric oxide synthase(iNOS)], CF markers [type Ⅰ collagen(Coll Ⅰ), Coll Ⅲ, α-smooth muscle actin(α-SMA)], and cytokines(IL-1β, IL-4, IL-6, IL-10, IL-18, TNF-α) in cardiac tissues were determined by quantitative real-time PCR. Western blot was used to detect the protein expression levels of Coll Ⅰ, Coll Ⅲ, α-SMA, Drp1, p-Drp1, voltage-dependent anion channel(VDAC), hexokinase 1(HK1), NOD-like receptor protein 3(NLRP3), apoptosis-associated speck-like protein(ASC), caspase-1, cleaved-caspase-1, gasdermin D(GSDMD), cleaved N-terminal gasdermin D(GSDMD-N), IL-1β, IL-18, B-cell lymphoma-2(Bcl-2), B-cell lymphoma-xl(Bcl-xl), Bcl-2-associated death promoter(Bad), Bcl-2-associated X protein(Bax), apoptotic protease activating factor-1(Apaf-1), pro-caspase-3, cleaved-caspase-3, pro-caspase-9, cleaved-caspase-9, poly(ADP-ribose) polymerase-1(PARP-1), and cleaved-PARP-1 in cardiac tissues. The results showed that VA significantly improved cardiac function in mice with CF, reduced myocardial injury area and cardiac index, and decreased serum levels of AST, CK-MB, cTnI, LDH, ROS, IL-1β, IL-6, IL-18, and TNF-α. VA also lowered MDA and MPO levels, mRNA expressions of IL-1β, IL-6, IL-18, and TNF-α, and mRNA and protein expressions of Coll Ⅰ, Coll Ⅲ, and α-SMA in cardiac tissues, and increased serum levels of IL-4 and IL-10, cardiac tissue levels of CAT, GSH, SOD, and T-AOC, and mRNA expressions of IL-4 and IL-10. Additionally, VA ameliorated cardiac pathological damage, inhibited myocardial cell apoptosis, inflammatory infiltration, and collagen fiber deposition, reduced collagen volume fraction, and alleviated mitochondrial damage. VA decreased the ratio of F4/80~+CD86~+ M1 cells and the mRNA expressions of CD86 and iNOS in cardiac tissue, and increased the ratio of F4/80~+CD206~+ M2 cells and the mRNA expressions of CD206 and Arg-1. VA also reduced protein expressions of p-Drp1, VDAC, NLRP3, ASC, caspase-1, cleaved-caspase-1, GSDMD, GSDMD-N, IL-1β, IL-18, Bad, Bax, Apaf-1, cleaved-caspase-3, cleaved-caspase-9, cleaved-PARP-1, and cytoplasmic cytochrome C, and increased the expressions of HK1, Bcl-2, Bcl-xl, pro-caspase-3, pro-caspase-9 proteins, as well as the Bcl-2/Bax and Bcl-xl/Bad ratios and mitochondrial cytochrome C content. These results indicate that VA has a significant ameliorative effect on ISO-induced CF in mice, alleviates ISO-induced oxidative damage and inflammatory response, and its mechanism may be closely related to the inhibition of Drp1/HK1/NLRP3 and mitochondrial apoptosis signaling pathways, suppression of myocardial cell inflammatory infiltration and collagen fiber deposition, reduction of collagen volume fraction and CollⅠ, Coll Ⅲ, and α-SMA expressions, thus mitigating CF.
Animals ; Isoproterenol/adverse effects* ; Male ; Mice ; Signal Transduction/drug effects* ; Vanillic Acid/administration & dosage* ; Dynamins/genetics* ; Mice, Inbred C57BL ; Fibrosis/genetics* ; Apoptosis/drug effects* ; Mitochondria/metabolism* ; NLR Family, Pyrin Domain-Containing 3 Protein/genetics* ; Myocardium/metabolism* ; Humans

By employing the analytic hierarchy process(AHP), the CRITIC method(a weight determination method based on indicator correlations), and the AHP-CRITIC hybrid weighting method, the weight coefficients of evaluation indicators were determined, followed by a comprehensive score comparison. The grey correlation analysis was then performed to analyze the results calculated using the hybrid weighting method. Subsequently, a backpropagation-artificial neural network(BP-ANN) model was constructed to predict the extraction process parameters and optimize the extraction process for Shenxiong Huanglian Jiedu Granules(SHJG). In the extraction process, an L_9(3~4) orthogonal experiment was designed to optimize three factors at three levels, including extraction frequency, water addition amount, and extraction time. The evaluation indicators included geniposide, berberine, ginsenoside Rg_1 + Re, ginsenoside Rb_1, ferulic acid, and extract yield. Finally, the optimal extraction results obtained by the orthogonal experiment, grey correlation analysis, and BP-ANN method were compared, and validation experiments were conducted. The results showed that the optimal extraction process involved two rounds of aqueous extraction, each lasting one hour; the first extraction used ten times the amount of added water, while the second extraction used eight times the amount. In the validation experiments, the average content of each indicator component was higher than the average content obtained in the orthogonal experiment, with a higher comprehensive score. The optimized extraction process parameters were reliable and stable, making them suitable for subsequent preparation process research.
Drugs, Chinese Herbal/analysis* ; Neural Networks, Computer

Non-small cell lung cancer(NSCLC) is the most common type of lung cancer worldwide, accounting for approximately 80%-85% of all lung cancer cases. Despite the clinical benefits of traditional treatments such as surgery, chemotherapy, and radiotherapy, challenges such as the high rate of postoperative recurrence and resistance of some patients to chemotherapy and targeted therapies limit their effectiveness, necessitating the exploration of more effective treatment options. In recent years, immunotherapy, especially immune checkpoint inhibitors(ICIs), has revolutionized NSCLC treatment and significantly improved the survival prognosis of some patients. However, the efficacy of immunotherapy is limited by tumor immune escape, drug resistance, and immune-related adverse events(irAEs), which have not been effectively addressed. Traditional Chinese medicine(TCM), as a traditional therapeutic approach, has shown unique advantages in NSCLC treatment, with studies indicating its ability to enhance immune responses, regulate immune checkpoints, and improve the tumor microenvironment(TME), thus boosting the efficacy of immunotherapy. Additionally, the multi-target and multi-pathway effects of TCM help mitigate the side effects of immunotherapy, further improving efficacy and safety. This review summarizes the latest research progress of TCM in NSCLC immunotherapy, focusing on the research results of TCM in enhancing the effect of immunotherapy by regulating immune cells, optimizing the immune microenvironment, and being applied with ICIs, etc. The latest research progress of TCM in alleviating irAEs is also elucidated. The aim is to provide theoretical support for the clinical application of TCM in the prevention and treatment of NSCLC and the research and development of new drugs and promote the optimization and development of combined immunotherapy and TCM treatment models.
Humans ; Carcinoma, Non-Small-Cell Lung/therapy* ; Lung Neoplasms/therapy* ; Immunotherapy/methods* ; Drugs, Chinese Herbal/therapeutic use* ; Medicine, Chinese Traditional ; Animals ; Tumor Microenvironment/drug effects*

To investigate the associations of serum gamma-glutamyl transferase (GGT) levels with the risk of cardiovascular disease (CVD) and its subtypes in patients with type 2 diabetes mellitus (T2DM) in Jiangsu Province.Methods:The participants were enrolled in the Comprehensive Research project regarding 'Prevention and Control of Diabetes' in Jiangsu Province. The baseline survey was conducted from 2013 to 2014, and follow-up until December 31, 2021. After excluding the participants who self-reported with chronic liver disease/stroke/coronary heart disease at baseline survey and those with incomplete information on GGT, a total of 16 147 T2DM patients were included in the final analysis. Cox proportional hazard regression models were used to calculate the hazard ratio ( HR) and their 95% CI of GGT for CVD, myocardial infarction, and stroke. Restricted cubic spline models were applied to analyze the dose-response relationship between GGT and the risk of CVD and its subtypes. Results:During the median follow-up time of 8.02 years, 2 860 CVD cases were registered, including 196 cases of myocardial infarction and 2 730 cases of stroke. Multivariate Cox proportional risk regression model indicated that compared to the lowest serum GGT level group, the highest GGT level group had a 24% increased risk of CVD ( HR=1.24, 95% CI: 1.09-1.41) and a 23% increased risk of stroke ( HR=1.23, 95% CI: 1.08-1.40). The restricted cubic spline model showed a nonlinear dose-response relationship between GGT and the risk of CVD, myocardial infarction, and stroke in T2DM patients. Conclusions:High levels of GGT may be associated with an increased risk of cardiovascular disease in T2DM patients, which needs further exploration and validation in future clinical practice.

ObjectiveTo explore the protective effect and mechanism of Yangxin Dingji capsules on isoproterenol （ISO）-induced ventricular arrhythmia in SD rat cardiomyocytes based on the transforming growth factor-β activated kinase 1 （TAK1）-mitogen-activated protein kinase kinase 3 （MKK3）-p38 mitogen-activated protein kinase （p38 MAPK） signaling pathway. MethodFifty male SPF-grade SD rats were randomly divided into a normal group， a model group， a propranolol group， a low-dose Chinese medicine group， and a high-dose Chinese medicine group. The ventricular arrhythmia model was constructed using the ISO "6+1" method. The propranolol group received propranolol at 0.015 g·kg^-1·d^-1. The Chinese medicine groups received Yangxin Dingji capsules at doses of 0.5、 2 g·kg^-1·d^-1， respectively. The normal and model groups were given an equal volume of 0.9% NaCl solution. Electrocardiogram （ECG） changes in SD rats were recorded using the BL-420F biological function experimental system. Hematoxylin-eosin （HE） staining was used to observe the pathological changes in the heart. Serum levels of cardiac troponin I （cTnI）， creatine kinase-MB （CK-MB）， interleukin-1β （IL-1β）， tumor necrosis factor-α （TNF-α）， and transforming growth factor-β₁ （TGF-β₁） were measured using enzyme-linked immunosorbent assay （ELISA）. The mRNA expression of IL-1β and TNF-α was assessed using real-time fluorescence quantitative polymerase chain reaction （Real-time PCR）. Reactive oxygen species （ROS） expression was detected using immunofluorescence. Protein expression levels of TAK1， phosphorylated TAK1 （p-TAK1）， MKK3， phosphorylated MKK3 （p-MKK3）， p38 MAPK， phosphorylated p38 MAPK （p-p38 MAPK）， nuclear factor-κB （NF-κB）， phosphorylated NF-κB （p-NF-κB）， IL-1β， and TNF-α were measured using Western blot or immunohistochemistry. ResultCompared with normal group， the model group showed significant ventricular arrhythmia in ECG， with an increased arrhythmia score （P<0.01）. Pathological damage to myocardial tissue was evident， and serum levels of cTnI， CK-MB， IL-1β， TNF-α， and TGF-β₁ were elevated （P<0.01）. The mRNA and protein expression of IL-1β and TNF-α in myocardial tissue was also increased （P<0.01）. ROS level and protein expression of p-TAK1， p-MKK3， p-p38 MAPK， and p-NF-κB were elevated in myocardial tissue （P<0.01）. In the propranolol and Chinese medicine groups， the incidence of sustained ventricular tachycardia （SVT） and arrhythmia scores were significantly reduced compared to model group （P<0.05， P<0.01）. Pathological damage to cardiomyocytes was alleviated， and levels of myocardial injury markers and inflammatory factors in serum and myocardial tissue were decreased. The ROS level in myocardial tissue was also reduced （P<0.01）， with a noticeable reduction in related molecules in the p38 MAPK pathway （P<0.05， P<0.01）. ConclusionThe expression of p38 MAPK pathway molecules was up-regulated in myocardial tissue of ISO-induced ventricular arrhythmia rats. Yangxin Dingji capsules may inhibit cardiac inflammation damage by regulating the expression of related molecules in the p38 MAPK pathway， thereby exerting a protective effect on myocardial cells， with TAK1 being a potential target.

Objective To evaluate the effect of modified vertical tooth preparation with full zirconium crown resto-ration in molar area.Methods A randomized study was conducted in 84 patients with all-ceramic crown restoration of posterior teeth.90 full crown restorations were collected and randomly divided into two groups:45 teeth in exper-imental group were treated with modified vertical tooth preparation,while 45 teeth in control group were treated with conventional horizontal tooth preparation with full zirconium crown restoration.When patients wore teeth,the resto-ration effects of the two groups were evaluated respectively,and then the marginal and internal fitness of the two groups were measured by silicone rubber replication method;gingival index(GI)and sulcus bleeding index(SBI)scores were recorded 6 months after wearing teeth.Results The results of chair-side evaluation of the two groups showed that the marginal fitness of the experimental group was better than that of the control group,and the differ-ence was statistically significant(P=0.036);the measured value of marginal fitness of prostheses in experimental group was better than that in control group,and the difference was statistically significant(P＜0.001);after 6 months,there was no mechanical complication between the two groups,and there was no significant difference in GI and SBI scores of periodontal soft tissue indexes.Conclusion Modified vertical tooth preparation abutment can significantly improve the marginal fitness of all-ceramic crown,which will not change the health status of peri-crown gingiva.

Objective To explore the differences in brain activation related to anhedonia in patients with schizophrenia(SCZ)and major depressive disorder(MDD)during a verbal fluency task(VFT)based on functional near-infrared spectroscopy(fNIRS).Methods A total of 31 patients with first-episode SCZ,45 patients with first-episode MDD and 45 healthy controls(HC)were included.The clinical symptoms were assessed using the 17-item Hamilton depression scale(HAMD-17),the positive and negative symptom scale(PANSS)and the Snaiss-Hamilton pleasure scale(SHAPS).All subjects completed the 48-channel fNIRS-VFT and the Chinese characters"Bai","Bei",and"Da"were recorded in the VFT.The Homer2 software in Matlab was used to extract information of oxy-hemoglobin(Oxy-Hb)concentration during the task.Results In the fNIRS-VFT task,compared with HC,patients with SCZ had decreased Oxy-Hb concentration in the bilateral middle frontal gyrus,superior frontal gyrus,inferior frontal gyrus,right superior temporal gyrus,and left posterior cingulate gyrus(including 25 channels,P<0.05),compared with MDD patients,patients with SCZ exhibited significantly reduced Oxy-Hb concentration in the bilateral superior frontal gyrus,left middle frontal gyrus,and right superior temporal gyrus(including 6 channels,P<0.05).The results of the general linear model showed that SHAPS scores in the MDD group were negatively correlated with Oxy-Hb concentration in the right superior frontal gyrus(channels 26,42)(β=-5.46,P=0.02;β=-5.01,P=0.01).Conclusion Patients with first-episode SCZ and those with first-episode MDD had functional abnormalities in bilateral middle frontal gyrus,and the left superior frontal,inferior frontal gyrus and postcentral gyrus.Additionally,abnormal activation of the right superior temporal gyrus and superior frontal gyrus was neurobiological markers of SCZ,abnormal activation of the right superior frontal gyrus was associated with anhedonia in MDD.

The establishment of an intelligent audit system for hospital medical insurance is crucial for standardizing irrational practices and curbing the unwarranted escalation of medical insurance costs. A tertiary hospital has developed comprehensive prescription review rules in terms of indications, nutritional risk assessments, pain score evaluations, drug sensitivity test results, and target patient populations. When using medical insurance funds for settlement, both systematic and manual reviews are conducted, and three-level intervention measures such as " prompt, review, and interception" are implemented based on prescription issues. After the system was put into use, the hospital′s in-process information system supervision mode shifted from the previous focus on prompts to focus on audits. The medical insurance intelligent audit system provided timely prompts and interventions, and the number of unreasonable medical insurance prescriptions and deductions from medical insurance sampling prescriptions significantly decreased ( P<0.001), while the number of medical insurance medication prescription audits increased ( P<0.001). The application of the intelligent medical insurance medication audit system has improved the efficiency of prescription auditing and ensured the rationality of the use of medical insurance funds.

Objective To investigate the effects of arginine-glycine-aspartic acid(RGD)peptide hydrogels at differ-ent concentrations on the activation of Tenon capsule fibroblasts(HTF)and the expression of Yes-associated protein(YAP).Methods Three concentrations(0.5％,1.0％,2.0％)of RGD peptide hydrogels were prepared.Their internal microstructures were observed under a transmission electron microscope,and their elastic moduli(E)were measured using the rheological test.SD male rat models with conjunctival injury were established and divided into a blank group(no treatment),a low-concentration RGD group(subconjunctival injection of 0.5％RGD peptide hydrogel),a medium-con-centration RGD group(subconjunctival injection of 1.0％RGD peptide hydrogel),and a high-concentration RGD group(subconjunctival injection of 2.0％RGD peptide hydrogel).After one week,tissues were collected,and collagen fiber pro-liferation in the rat conjunctiva was observed after Masson staining.Immunohistochemistry was performed to detect the ex-pression of YAP and α-smooth muscle actin(α-SMA)in the rat conjunctiva.Scar formation cell models were constructed by stimulating HTF activation with transforming growth factor-β2(TGF-β2).According to experimental requirements,the cells were divided into a control group,a 0.5％RGD hydrogel group,a 1.0％RGD hydrogel group,a 2.0％RGD hydrogel group,and a normal group,and co-cultured for 24 hours.The relative expression levels of YAP,connective tissue growth factor(CTGF),α-SMA,fibronectin(FN),and type Ⅰ collagen(Col Ⅰ)proteins in HTF were detected by Western blot.The localization of cytoskeletal protein(F-actin)and YAP protein expression was observed under a confocal laser scanning mi-croscope.Results Electron microscopy showed that the crosslinking density of the nanofibers inside the RGD peptide hydrogel increased with the rise of the peptide concentration.Rheological measurements indicated that the E values of the 0.5％,1.0％,and 2.0％RGD peptide hydrogels were approximately 0.067 kPa,0.150 kPa,and 2.170 kPa,respectively.Masson staining results revealed that the area of collagen fiber proliferation in the conjunctiva of rats in the medium-concen-tration RGD group was significantly lower than that in the blank group(P＜0.05),while it showed no significant difference in the low-concentration and high-concentration RGD groups compared with the blank group(both P＞0.05).Immunohis-tochemistry results showed that the relative expression levels of YAP and α-SMA proteins in the conjunctiva of rats in the low-,medium-,and high-concentration RGD groups decreased compared to the blank group,and the decrease was the most significant in the medium-concentration RGD group(all P＜0.05).Cell immunofluorescence staining results indicated that the green fluorescence of F-actin was attenuated,and the red fluorescence of YAP was translocated from the nucleus to the cytoplasm in the 0.5％,1.0％,and 2.0％RGD hydrogel groups compared to the control group.Western blot results showed that the relative expression levels of YAP,CTGF,α-SMA,FN,and Col Ⅰ proteins in HTF were lower in the 0.5％,1.0％,and 2.0％RGD hydrogel groups compared to the control group,with the 1.0％RGD hydrogel group showing the most significant reduction(all P＜0.05).Conclusion With the optimal concentration of 1.0％,the RGD peptide hydro-gel can inhibit YAP protein expression and nuclear translocation and reduce HTF activation and the expression of fibrotic proteins,thus alleviating scar formation.

Background/Aims: Low educational attainment is a well-established risk factor for nonalcoholic fatty liver disease (NAFLD) in developed areas. However, the association between educational attainment and the risk of NAFLD is less clear in China. Methods: A cross-sectional study including over 200,000 Chinese adults across mainland China was conducted. Information on education level and lifestyle factors were obtained through standard questionnaires, while NAFLD and advanced fibrosis were diagnosed using validated formulas. Outcomes included the risk of NAFLD in the general population and high probability of fibrosis among patients with NAFLD. Logistic regression analysis was employed to estimate the risk of NAFLD and fibrosis across education levels. A causal mediation model was used to explore the potential mediators. Results: Comparing with those receiving primary school education, the multi-adjusted odds ratios (95% confidence intervals) for NAFLD were 1.28 (1.16 to 1.41) for men and 0.94 (0.89 to 0.99) for women with college education after accounting for body mass index. When considering waist circumference, the odds ratios (95% CIs) were 0.94 (0.86 to 1.04) for men and 0.88 (0.80 to 0.97) for women, respectively. The proportions mediated by general and central obesity were 51.00% and 68.04% for men, while for women the proportions were 48.58% and 32.58%, respectively. Furthermore, NAFLD patients with lower educational attainment showed an incremental increased risk of advanced fibrosis in both genders. Conclusions In China, a low education level was associated with a higher risk of prevalent NAFLD in women, as well as high probability of fibrosis in both genders.