ObjectiveTaking the cuproptosis/oxidative stress pathway as the entry point， this study investigated the effect and mechanism of Liangyi Paste on hepatic lipid deposition in naturally aged mice fed with a high-fat diet. MethodsAfter adaptive feeding， 80 ten-week-old male C57BL/6 mice were used. Thirty of them were randomly divided into three groups （10 mice per group）： The 12-month-old control group （12MCON）， the 15-month-old control group （15MCON）， and the 15-month-old group with a high-fat diet （15MHFD）. The 12MCON and 15MCON groups were continuously fed a standard diet， while the 15MHFD group started receiving a high-fat diet at 12 months of age. Tissue samples were collected at the corresponding time points for each group. The remaining 50 mice were randomly divided into five groups （10 mice per group）： the 20-month-old control group （20MCON）， the model group， and the low-， medium-， and high-dose Liangyi Paste groups （2.91 ， 5.82 ， 11.64 g·kg^-1·d^-1， respectively）. The 20MCON group was continuously fed a standard diet， while the other groups started receiving a high-fat diet at 15 months of age. At 18 months of age， the Liangyi Paste groups were administered the corresponding doses of Liangyi Paste by gavage， while the 20MCON and model groups were given an equal volume of saline by gavage. After 8 weeks of continuous gavage （when the mice reached 20 months of age）， tissue samples were collected. Hepatic TG levels were measured using assay kits； liver histology and lipid deposition were observed via hematoxylin-eosin （HE） and oil red O staining； reactive oxygen species （ROS） were detected by enzyme-linked immunosorbent assay （ELISA）； Cu²⁺， superoxide dismutase （SOD）， and malondialdehyde （MDA） levels were measured by colorimetry； mRNA and protein expression of genes related to cuproptosis and oxidative stress pathways were analyzed by Real-time polymerase chain reaction（Real-time PCR） and Wes automated protein expression system. ResultsCompared with 12MCON， the 15MCON group showed significantly increased hepatic TG， Cu²⁺， ROS， and MDA levels （P<0.01）， decreased SOD （P<0.01）， hepatocyte swelling， and disordered arrangement. The mRNA and protein levels of ferredoxin 1 （FDX1）， dihydrolipoamide S-acetyltransferase （DLAT）， heat shock protein 70 （HSP70）， dihydrolipoamide dehydrogenase （DLD）， pyruvate dehydrogenase E1 subunit-β （PDHB）， nuclear factor erythroid 2-related factor 2 （Nrf2）， and peroxisome proliferator-activated receptor γ （PPARγ） were significantly elevated （P<0.05， P<0.01）. Compared with 15MCON group， the 15MHFD and 20MCON groups exhibited further increases in TG， Cu²⁺， ROS， and MDA （P<0.01）， reduced SOD （P<0.01）， and aggravated hepatocyte swelling and disorder. There were increased lipid droplets with mild vacuolization in the 15MHFD group， and no significant lipid deposition was observed in the 20MCON group. FDX1， DLAT， HSP70， DLD， PDHB， Nrf2， and PPARγ mRNA and protein levels were significantly increased （P<0.05， P<0.01）. Compared with 20MCON group， the model group demonstrated markedly elevated TG， Cu²⁺， ROS， and MDA （P<0.01）， reduced SOD （P<0.01）， severe hepatic steatosis， and upregulated expression of FDX1， DLAT， HSP70， DLD， PDHB， Nrf2， and PPARγ mRNA and proteins （P<0.05， P<0.01）. All abnormalities were significantly reversed after Liangyi Paste treatment. ConclusionLiangyi paste can ameliorate hepatic lipid deposition in naturally aged mice with a high-fat diet by modulating the cuproptosis/oxidative stress pathway.

Cholestatic liver disease （CLD） is closely associated with bile acid homeostasis imbalance， oxidative stress， inflammatory responses， mitochondrial damage， and hepatic fibrosis. Nuclear factor-erythroid 2-related factor 2 （Nrf2） can regulate molecules related to antioxidation， detoxification， and bile acid transport， and together with signaling pathways such as farnesoid X receptor （FXR）， silent information regulator 1/AMP-activated protein kinase， and nuclear factor-κB， participates in the development and progression of CLD. This review summarizes the role of Nrf2 in the development and progression of CLD， as well as the research progress on traditional Chinese medicine （TCM） active constituents and formulas/Chinese patent medicine in regulating Nrf2 for the intervention of CLD. The results indicate that TCM active constituents such as terpenoids， saponins， flavonoids， and polysaccharides， as well as formulas/Chinese patent medicine with the effects of heat-clearing and dampness-draining， liver-soothing and choleretic-promoting， and body-strengthening and liver-protecting， can improve bile acid metabolism and transport and alleviate oxidative stress， inflammatory responses， and hepatic fibrosis by regulating Nrf2-related signaling pathways. However， existing studies still primarily judge based on Nrf2 expression， nuclear translocation， and downstream molecular expression changes， and the understanding of the regulatory relationship between Nrf2 and signaling pathways such as FXR， as well as the synergistic mechanisms of multiple constituents in formulas， remains insufficient. Future studies can strengthen gene intervention and functional validation， utilize liver or bile duct organoids， co-culture systems， and other approaches， and combine bile acid profiling and multi-omics analysis to further elucidate the mechanism by which TCM regulates Nrf2 to ameliorate CLD.

Objective To analyze the clinical characteristics and risk factors of extreme thrombocytosis caused by piperacillin sodium and tazobactam sodium injection, and provide reference for medical treatment and pharmaceutical care of such patients. Methods Extreme thrombocytosis of a patient treated with piperacillin sodium and tazobactam sodium injection was found by clinical pharmacists, who participated in clinical diagnosis and treatment by analyzing of the adverse drug reaction, optimization of the medical treatment and pharmaceutical care. Results After correlation analysis, the patient's extreme thrombocytosis was likely to be an adverse reaction caused by the piperacillin sodium and tazobactam sodium injection. The medication was immediately discontinued, and antiplatelet therapy with aspirin was administered. Two weeks later, the patient's platelet count had significantly decreased compared to before. Conclusion Clinical pharmacists participated in patients’ clinical diagnosis and treatment, carried out pharmaceutical care and assisted physicians in adjusting treatment plans, which ensured the safety and effectiveness of patients' clinical drug therapy.

ObjectiveTo investigate the effects of Ditantang on metabolic dysfunction-associated fatty liver disease （MAFLD） in rats by focusing on the regulation of glycogen synthesis mediated by the uridine diphosphate glucose （UDPG）-site-1-protease （S1P）-sterol regulatory element-binding protein （SREBP） axis. MethodsMAFLD was modeled in SD rats by feeding a high-fat diet for 12 weeks. Rats were randomized into a control group， a model group， low-， medium-， and high-dose （2.68， 5.36， and 10.72 g·kg^-1·d^-1， respectively） Ditantang groups， and a positive control （Yishanfu， 0.18 g·kg^-1·d^-1） group. Starting from week 9 of modeling， each treatment group received corresponding drug interventions via gavage. After the experiment， the serum levels of total cholesterol （TC）， triglyceride （TG）， low-density lipoprotein cholesterol （LDL-C）， and high-density lipoprotein cholesterol （HDL-C） were measured. The levels of TG， non-esterified fatty acids （NEFA）， glycogen， glucose-6-phosphate （G6P）， glucose-1-phosphate （G1P）， and UDPG in the liver tissue samples were measured by biochemical assay kits. Liver pathological morphology and lipid/glycogen deposition were observed via hematoxylin-eosin （HE） staining， oil red O staining， and Periodic acid-Schiff （PAS） staining. Immunofluorescence assay was conducted to detect the expression and localization of phosphoglucomutase-1 （Pgm1） and UDP-glucose pyrophosphorylase 2 （Ugp2） in the rat liver. Real-time PCR and Western blot were employed to quantify mRNA and protein levels， respectively， of key glycogen synthesis enzymes （Pgm1 and Ugp2）， key lipogenesis-related transcription factor SREBP and its target genes ［acetyl-CoA carboxylase （ACC）， fatty acid synthetase （FASN）， and stearoyl-CoA desaturase （SCD1）］， as well as S1P. ResultsCompared with the control group， the model group exhibited elevated levels of TC， TG， LDL-C in the serum and TG and NEFA in the liver， decreased serum HDL-C level （P<0.01）， reduced hepatic levels of G1P， G6P， UDPG， and glycogen （P<0.01）， appearance of fat vacuoles of varying sizes and abundant red lipid droplets， with prominent lipid deposition and reduced areas of deep glycogen staining in the liver tissue， upregulated mRNA and protein levels of SREBP1， S1P， ACC， FASN， and SCD1 （P<0.01）， and downregulated mRNA and protein levels of Pgm1 and Ugp2 （P<0.01）. Compared with the model group， all doses of Ditantang reduced the levels of TC and TG in the serum and TG and NEFA in the liver， while elevating the serum HDL-C level. Additionally， medium- and high-dose Ditantang reducted the LDL-C level （P<0.05）. Ditantang at all doses increased the hepatic levels of G1P， G6P， UDPG， and glycogen， alleviated hepatic steatosis and lipid deposition， enhanced glycogen storage， downregulated the mRNA and protein levels of SREBP1， S1P， ACC， FASN， and SCD1 （P<0.05）， while upregulating the expression of Pgm1 and Ugp2 （P<0.01）. Immunofluorescence analysis revealed decreased fluorescence intensity of S1P and enhanced fluorescence intensity of Ugp2 （P<0.01）. ConclusionDitantang can regulate glycogen synthesis through the UDPG-S1P-SREBP axis to prevent and treat MAFLD.

Objectives:To describe the use of antihypertensive, antidiabetic and lipid-lowering drugs, and evaluate the effects on blood pressure, blood glucose and blood lipids controls required by Chinese Guideline on the Primary Prevention of Cardiovascular Diseases (the guideline) in a community-based cohort of individuals at high risk for cardiovascular disease. To analyze the association of the uses of antihypertensive, antidiabetic and lipid-lowering drugs, and the comprehensive control of blood pressure, blood glucose and blood lipids with cardiovascular disease. Methods:From the CHinese Electronic health Records Research in Yinzhou (CHERRY), those who were at high risk for cardiovascular disease and aged 40-75 years as of January 1, 2013 in in Yinzhou District of Ningbo, Zhejiang Province were selected as study subjects. The information about their antihypertensive, antidiabetic, and lipid-lowering drug uses between 2013 and 2015 was collected, and blood pressure, blood glucose, and blood lipid measurements were conducted during the follow-up. The study constructed two kinds of comprehensive scores: the comprehensive medication score based on the guideline requirement for the treatment of hypertension, diabetes and hyperlipidemia, dividing the study participants into the compliancy group and non-compliancy group; and the comprehensive control score based on the guideline requirement for blood pressure, blood glucose, and blood lipids control, dividing the study participants into better control group, moderate control group, and poor control group. Cox proportional hazards regression model was used to analyze the association of the comprehensive medication score and comprehensive control score with cardiovascular disease. The incidence data of cardiovascular disease were collected from January 1, 2015 (baseline time) to August 31, 2020 (follow up end time).Results:A total of 79 734 participants at high risk for cardiovascular disease were included in the study, in whom 68.4%, 27.4%, and 4.2% had 1, 2, or 3 cardiometabolic conditions (hypertension, diabetes, or hyperlipidemia), respectively. In the participants with hypertension, diabetes, and hyperlipidemia from 2013 to 2015, the proportions of those who had two years of medication compliancy records were 66.0%, 67.4%, and 13.9%, respectively. In the hypertension patients, 59.2% had better blood pressure control, in the diabetes patients, 28.7% had better blood glucose control, and in the patients with hyperlipidemia, 27.4% had better blood lipid control. After a median follow-up of 5.66 years, 4 088 cardiovascular disease cases or deaths occurred. After multivariate adjustment, compared with the non-compliancy group, the compliancy group had lower risk for cardiovascular disease ( HR=0.91, 95% CI: 0.85-0.96). Compared with the better control group, the poor control group had an increased risk for cardiovascular disease ( HR=1.67, 95% CI: 1.53-1.81). In the moderate control group, the risk increased significantly in the diabetes patients ( HR=1.29, 95% CI: 1.07-1.56), while no additional risk for cardiovascular disease was observed in non-diabetes patients ( HR=1.06, 95% CI: 0.97-1.16). Conclusions:Compliancy to the medication required by the guideline is associated with lower risk for cardiovascular disease. However, it is still necessary to improve the medication compliancy in people at high risk in primary prevention, especially in the patients with hyperlipidemia, due to their low taking rate of lipid-lowering drugs. Additionally, as the requirement of the guideline becomes more stringent, the management of disease has met more challenges. Notably, diabetes patients who have not met the guideline requirement are at high risk for cardiovascular disease, to whom the disease management should be strengthened.

Objective:To explore the mechanism of resveratrol in treatment of sleep disorders in mice based on network pharmacology and experimental verification.Methods:Resveratrol targets were obtained through traditional Chinese medicine systems pharmacology database and analysis platform, Swiss Target Prediction and SuperPred databases. Targets related to sleep disorders were collected from the gene expression omnibus, GeneCards, DrugBank, OMIM, CTD and MalaCards databases. Cytoscape 3.8.0 software was used to identify the core targets of resveratrol in treatment of sleep disorders via protein-protein interaction analysis. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analyses were performed, and AutoDockvina software was used to conduct molecular docking between the top five core targets and resveratrol. Thirty ICR female mice were selected and divided into a control group, a model group, and low-, medium- and high-dose (10, 20, and 30 mg/kg) resveratrol groups according to the random number table method, with 6 mice in each group. Resveratrol was dissolved in 0.9% sodium chloride aqueous solution and 3% dimethyl sulfoxide. For mice in the low-, medium-, and high-dose resveratrol groups, 10, 20, and 30 mg/kg of resveratrol solution were intraperitoneally injected, respectively. The mice in the control group and the model group were intraperitoneally injected with 10 ml/kg of 0.9 % sodium chloride aqueous solution and 3 % dimethyl sulfoxide. Each group was injected once a day for 7 consecutive days. After 7 days of administration, a mouse sleep deprivation model was constructed using an improved multi platform water environment method. The spatial recognition and memory abilities of mice were tested using the Y-maze experiment, and the mRNA and protein relative expression levels of estrogen receptor 1 (ESR1) and B-cell lymphoma-2 (Bcl-2) were detected using real-time reverse transcription-PCR and Western blotting, respectively. Comparisons were made using t-test. Results:There were 47 common targets between resveratrol and sleep disorders, and the top five core targets were ESR1, Bcl-2, cytochrome P450, family 1, subfamily A, polypeptide 1 (CYP1A1), cytochrome P450, family 2, subfamily A, polypeptide 4 (CYP3A4) and cytochrome P450, family 1, subfamily B, polypeptide 1 (CYP1B1). GO enrichment analysis revealed that resveratrol in treatment of sleep disorders was mainly related to the regulation of unsaturated fatty acid metabolic processes, secondary metabolic processes, and responses to exogenous stimuli. KEGG pathway analysis showed that resveratrol acted mainly through pathways involving chemical carcinogenic-DNA adducts, cytochrome P450 metabolism of exogenous substances and estrogen signaling pathways. Molecular docking results indicated that resveratrol had strong binding affinity with ESR1, Bcl-2, CYP1A1, CYP3A4 and CYP1B1, with binding energies of ?31.92, ?27.72, ?34.44, ?34.02 and ?31.92 kJ/mol, respectively. In vivo experiments results demonstrated that the novel arm residence time in the low-, medium- and high-dose resveratrol groups [(52±5, 55±7, and 61±9) s] was higher than that in the model group [(45±4) s] ( P<0.05 or 0.01), and the percentage of spontaneous alternation [(53±4)%, (57±5)%, and (65±7)%] was higher than that in the model group [(47±3)%] ( P<0.05 or 0.01). The relative expression levels of ESR1 mRNA (0.42±0.10, 0.49±0.11, and 0.58±0.10) were higher than those in the model group (0.29±0.06) ( P<0.05 or 0.01). The relative expression levels of Bcl-2 mRNA (0.56±0.07, 0.65±0.10, and 0.77±0.11) were higher than those in the model group (0.44±0.08) ( P<0.05 or 0.01). Similarly, the relative expression levels of ESR1 protein (0.32±0.02, 0.50±0.02, and 0.62±0.02) were higher than those in the model group (0.24±0.01) ( P<0.05 or 0.01). The relative expression levels of Bcl-2 protein (0.45±0.08, 0.69±0.06, and 0.72±0.06) were higher than those in the model group (0.17±0.04) ( P<0.05 or 0.01). Conclusions:Resveratrol exerts therapeutic effects on sleep disorders by acting on ESR1 and Bcl-2.

Mycophenolic acid (MPA), the active moiety of both mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS), serves as a primary immunosuppressant for maintaining solid organ transplants. Therapeutic drug monitoring (TDM) enhances treatment outcomes through tailored approaches. This study aimed to develop an evidence-based guideline for MPA TDM, facilitating its rational application in clinical settings. The guideline plan was drawn from the Institute of Medicine and World Health Organization (WHO) guidelines. Using the Delphi method, clinical questions and outcome indicators were generated. Systematic reviews, Grading of Recommendations Assessment, Development, and Evaluation (GRADE) evidence quality evaluations, expert opinions, and patient values guided evidence-based suggestions for the guideline. External reviews further refined the recommendations. The guideline for the TDM of MPA (IPGRP-2020CN099) consists of four sections and 16 recommendations encompassing target populations, monitoring strategies, dosage regimens, and influencing factors. High-risk populations, timing of TDM, area under the curve (AUC) versus trough concentration (C₀), target concentration ranges, monitoring frequency, and analytical methods are addressed. Formulation-specific recommendations, initial dosage regimens, populations with unique considerations, pharmacokinetic-informed dosing, body weight factors, pharmacogenetics, and drug‍-‍drug interactions are covered. The evidence-based guideline offers a comprehensive recommendation for solid organ transplant recipients undergoing MPA therapy, promoting standardization of MPA TDM, and enhancing treatment efficacy and safety.
Mycophenolic Acid/administration & dosage* ; Drug Monitoring/methods* ; Humans ; Organ Transplantation ; Immunosuppressive Agents/administration & dosage* ; Delphi Technique

Cardiac fibrosis is characterized by an elevated amount of extracellular matrix (ECM) within the heart. However, the persistence of cardiac fibrosis ultimately diminishes contractility and precipitates cardiac dysfunction. Circular RNAs (circRNAs) are emerging as important regulators of cardiac fibrosis. Here, we elucidate the functional role of a specific circular RNA CELF1 in cardiac fibrosis and delineate a novel feedback loop mechanism. Functionally, circ-CELF1 was involved in enhancing fibrosis-related markers' expression and promoting the proliferation of cardiac fibroblasts (CFs), thereby exacerbating cardiac fibrosis. Mechanistically, circ-CELF1 reduced the ubiquitination-degradation rate of BRPF3, leading to an elevation of BRPF3 protein levels. Additionally, BRPF3 acted as a modular scaffold for the recruitment of histone acetyltransferase KAT7 to facilitate the induction of H3K14 acetylation within the promoters of the Celf1 gene. Thus, the transcription of Celf1 was dramatically activated, thereby inhibiting the subsequent response of their downstream target gene Smad7 expression to promote cardiac fibrosis. Moreover, Celf1 further promoted Celf1 pre-mRNA transcription and back-splicing, thereby establishing a feedback loop for circ-CELF1 production. Consequently, a novel feedback loop involving CELF1/circ-CELF1/BRPF3/KAT7 was established, suggesting that circ-CELF1 may serve as a potential novel therapeutic target for cardiac fibrosis.

Depression is increasingly prevalent among adolescents and can profoundly impact their lives. However, the early detection of depression is often hindered by the time-consuming diagnostic process and the absence of objective biomarkers. In this study, we propose a novel approach for depression detection based on an affective brain-computer interface (aBCI) and the resting-state electroencephalogram (EEG). By fusing EEG features associated with both emotional and resting states, our method captures comprehensive depression-related information. The final depression detection model, derived through decision fusion with multiple independent models, further enhances detection efficacy. Our experiments involved 40 adolescents with depression and 40 matched controls. The proposed model achieved an accuracy of 86.54% on cross-validation and 88.20% on the independent test set, demonstrating the efficiency of multimodal fusion. In addition, further analysis revealed distinct brain activity patterns between the two groups across different modalities. These findings hold promise for new directions in depression detection and intervention.
Humans ; Male ; Female ; Adolescent ; Case-Control Studies ; Depression/diagnosis* ; Early Diagnosis ; Rest ; Electroencephalography/methods* ; Brain-Computer Interfaces ; Models, Psychological ; Reproducibility of Results ; Affect/physiology* ; Photic Stimulation/methods* ; Video Recording ; Brain/physiopathology*

Objective:To investigate the clinical efficacy and safety of different combination therapies with aminolevulinic acid photodynamic therapy (ALA-PDT) in the treatment of facial basal cell carcinoma in the elderly.Methods:A retrospective analysis was conducted on 131 elderly patients with facial basal cell carcinoma who visited Shanghai Skin Disease Hospital from August 2020 to October 2023. According to the depth of the lesions, the patients were divided into 3 groups to receive intensive pretreatment with curettage (41 cases), CO 2 laser therapy (35 cases), and narrow-margin excision surgery without sutures (55 cases) respectively, all followed by ALA-PDT. During the follow-up period of 17.7 ± 9.0 months, the efficacy was evaluated and adverse reactions were recorded in each group. Results:The total remission rates were 100%, 100%, and 96.4% in the curettage + ALA-PDT group, CO 2 laser + ALA-PDT group, and narrow-margin excision surgery without sutures + ALA-PDT group, respectively. The patients experienced mild pain and local erythematous swelling during ALA-PDT treatment, which were temporary and fully tolerable, and no wound infections or difficulties in healing were observed. After treatment, scar formation was observed in 3 cases of basal cell carcinoma on the nose and nasolabial folds in the narrow-margin excision surgery without sutures + ALA-PDT group, but the rest of the patients retained a good facial appearance. Conclusions:In this preliminary exploration study on PDT for basal cell carcinoma of different depths, ALA-PDT combined with curettage, CO 2 laser or narrow-margin excision surgery without sutures all exhibited definite efficacy and minimal damage, providing effective treatment options for facial basal cell carcinoma in the elderly.