With the rapid development of social economy and the continuous improvement of human living standard, the incidence, fatality and recurrence rates of cardiovascular disease (CVD) are increasing year by year, which seriously affects people's life and health. Conventional therapeutic drugs have limited improvement on the disability rate, so the search for new therapeutic drugs and action targets has become one of the hotspots of current research. In recent years, the therapeutic role of the natural compound rosmarinic acid (RA) in CVD has attracted much attention, which is capable of preventing CVD by modulating multiple signalling pathways and exerting physiological activities such as antioxidant, anti-apoptotic, anti-inflammatory, anti-platelet aggregation, as well as anti-coagulation and endothelial function protection. In this paper, the role of RA in the prevention of CVD is systematically sorted out, and its mechanism of action is summarised and analysed, with a view to providing a scientific basis and important support for the in-depth exploration of the prevention value of RA in CVD and its further development as a prevention drug.

BACKGROUND: The atherogenic index of plasma (AIP) has been shown to be positively correlated with cardiovascular disease in previous studies. However, it is unclear whether elderly people with long-term high AIP levels are more likely to develop coronary heart disease (CHD). Therefore, the aim of this study was to investigate the relationship between AIP trajectory and CHD incidence in elderly people. METHODS: 19,194 participants aged ≥ 60 years who had three AIP measurements between 2018 and 2020 were included in this study. AIP was defined as log₁₀ (triglyceride/high-density lipoprotein cholesterol). The group-based trajectory model was used to identify different trajectory patterns of AIP from 2018 to 2020. Cox proportional hazards models were used to estimate the hazard ratio (HR) with 95% CI of CHD events between different trajectory groups from 2020 to 2023. RESULTS: Three different trajectory patterns were identified through group-based trajectory model: the low-level group (n = 7410, mean AIP: -0.25 to -0.17), the medium-level group (n = 9981, mean AIP: 0.02-0.08), and the high-level group (n = 1803, mean AIP: 0.38-0.42). During a mean follow-up of 2.65 years, a total of 1391 participants developed CHD. After adjusting for potential confounders, compared with the participants in the low-level group, the HR with 95% CI of the medium-level group and the high-level group were estimated to be 1.24 (1.10-1.40) and 1.43 (1.19-1.73), respectively. These findings remained consistent in subgroup analyses and sensitivity analyses. CONCLUSIONS There was a significant correlation between persistent high AIP level and increased CHD risk in the elderly. This suggests that monitoring the long-term changes in AIP is helpful to identify individuals at high CHD risk in elderly people.

OBJECTIVE: To explore the therapeutic effects and underlying mechanisms of Dendrobium officinale (Tiepi Shihu) extract (DOE) on insomnia. METHODS: Forty-two male Sprague-Dawley rats were randomly divided into 6 groups (n=7 per group): normal control, model control, melatonin (MT, 40 mg/kg), and 3-dose DOE (0.25, 0.50, and 1.00 g/kg) groups. Rats were raised in a strong-light (10,000 LUX) and -noise (>80 db) environment (12 h/d) for 16 weeks to induce insomnia, and from week 10 to week 16, MT and DOE were correspondingly administered to rats. The behavior tests including sodium pentobarbital-induced sleep experiment, sucrose preference test, and autonomous activity test were used to evaluate changes in sleep and emotions of rats. The metabolic-related indicators such as blood pressure, blood viscosity, blood glucose, and uric acid in rats were measured. The pathological changes in the cornu ammonis 1 (CA1) region of rat brain were evaluated using hematoxylin and eosin staining and Nissl staining. Additionally, the sleep-related factors gamma-aminobutyric acid (GABA), glutamate (GA), 5-hydroxytryptamine (5-HT), and interleukin-6 (IL-6) were measured using enzyme linked immunosorbent assay. Finally, we screened potential sleep-improving receptors of DOE using polymerase chain reaction (PCR) array and validated the results with quantitative PCR and immunohistochemistry. RESULTS: DOE significantly improved rats' sleep and mood, increased the sodium pentobarbital-induced sleep time and sucrose preference index, and reduced autonomic activity times (P<0.05 or P<0.01). DOE also had a good effect on metabolic abnormalities, significantly reducing triglyceride, blood glucose, blood pressure, and blood viscosity indicators (P<0.05 or P<0.01). DOE significantly increased the GABA content in hippocampus and reduced the GA/GABA ratio and IL-6 level (P<0.05 or P<0.01). In addition, DOE improved the pathological changes such as the disorder of cell arrangement in the hippocampus and the decrease of Nissel bodies. Seven differential genes were screened by PCR array, and the GABA_A receptors (Gabra5, Gabra6, Gabrq) were selected for verification. The results showed that DOE could up-regulate their expressions (P<0.05 or P<0.01). CONCLUSION DOE demonstrated remarkable potential for improving insomnia, which may be through regulating GABA_A receptors expressions and GA/GABA ratio.
Animals ; Dendrobium/chemistry* ; Rats, Sprague-Dawley ; Male ; Sleep Initiation and Maintenance Disorders/blood* ; Plant Extracts/therapeutic use* ; Receptors, GABA-A/metabolism* ; Noise/adverse effects* ; Light/adverse effects* ; gamma-Aminobutyric Acid/metabolism* ; Sleep/drug effects* ; Rats ; Receptors, GABA/metabolism*

Mechanical pain is one of the most common causes of clinical pain, but there remains a lack of effective treatment for debilitating mechanical and chronic forms of neuropathic pain. Recently, neurotoxin GsMTx4, a selective mechanosensitive (MS) channel inhibitor, has been found to be effective, while the underlying mechanism remains elusive. Here, with multiple rodent pain models, we demonstrated that a GsMTx4-based 17-residue peptide, which we call P10581, was able to reduce mechanical hyperalgesia and neuropathic pain. The analgesic effects of P10581 can be as strong as morphine but is not toxic in animal models. The anti-hyperalgesic effect of the peptide was resistant to naloxone (an μ-opioid receptor antagonist) and showed no side effects of morphine, including tolerance, motor impairment, and conditioned place preference. Pharmacological inhibition of TRPV4 by P10581 in a heterogeneous expression system, combined with the use of Trpv4 knockout mice indicates that TRPV4 channels may act as the potential target for the analgesic effect of P10581. Our study identified a potential drug for curing mechanical pain and exposed its mechanism.

Most cancers are currently incurable, partly due to abnormal post-translational modifications (PTMs). In this study, we initially used multiple myeloma (MM) as a working model and found that SUMOylation activating enzyme subunit 1 (SAE1) promotes the malignancy of MM. Through proteome microarray analysis, SAE1 was identified as a potential target for bioactive colcemid or its derivative colchicine. Elevated levels of SAE1 were associated with poor clinical survival and increased MM proliferation in vitro and in vivo. Additionally, SAE1 directly SUMOylated and upregulated the total protein expression of p27, leading to LLPS-mediated nuclear export of p27. Our study also demonstrated the involvement of SAE1 in other types of cancer cells, and provided the first monomer crystal structure of SAE1 and its key binding model with colchicine. Colchicine also showed promising results in the Patient-Derived Tumor Xenograft (PDX) model. Furthermore, a controlled clinical trial with 56 MM patients demonstrated the clinical efficacy of colchicine. Our findings reveal a novel mechanism by which tumor cells evade p27-induced cellular growth arrest through p27 SUMOylation-mediated nuclear export. SAE1 may serve as a promising therapeutic target, and colchicine may be a potential treatment option for multiple types of cancer in clinical settings.

ObjectiveTo analyze the impact of maternal postpartum depression (PPD) at 2 months postpartum on caregiving for infants aged2 to 24 months, and to provide a scientific basis for future maternal and infant healthcare services. MethodsBased on the Shanghai Maternal-Child Pairs Cohort, 1 060 mother-child pairs were selected from those fully participating in follow-up visits at 2, 6, 12, and 24 months postpartum. Pregnancy and childbirth-related information was collected using standardized questionnaire surveys and hospital obstetric and maternity records. The Edinburgh postpartum depression scale was used to assess the maternal postpartum depressive symptoms at 2 months postpartum. At 2, 6, 12, and 24 months postpartum, questionnaire survey was used to evaluate the maternal responsiveness in caregiving and the provision of early learning opportunities for infants. Scores for responsive caregiving and early learning opportunities at 2, 6, 12, and 24 months were grouped based on the 25th percentile (P₂₅) of total scores. The mixed-effects model was used to analyze the longitudinal impact of maternal postpartum depression at 2 months on the caregiving of 2 to 24-month-old infants. ResultsThe longitudinal results from the mixed-effects model did not show an impact of maternal PPD on infant responsive caregiving within 12 months and early learning opportunities within24 months. However, cross-sectional analysis revealed that, compared to the non-PPD group, the risk of low responsive caregiving at 2 months in the PPD group was 93% higher (OR=1.931, 95%CI: 1.113‒3.364, P=0.019). The risks for low provision of early learning opportunities at2 months and 24 months increased by 59% (OR=1.589, 95%CI: 1.082‒2.324, P=0.017) and 60% (OR=1.598, 95%CI:1.120‒2.279, P=0.010), respectively. ConclusionMaternal postpartum depression increases the risk of low responsive caregiving at 2 months, but its long-term effects warrant further research.

Background and aims:Primary sclerosing cholangitis(PSC)is an autoimmune liver disease characterized by complex pathogenesis and limited available therapeutic options.The mechanisms underlying the development and progression of PSCs remain unclear.Liver X receptor beta(LXR-β)is recognized to modulate lipid metabolism and immune response,but its specific involvement in the PSC has not been elucidated.Here,we explored the role and mechanism of LXR-β in PSC induced by 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-collidine(DDC).Methods:CRISPR-Cas9 technology was applied to generate Abcb4(coding MDR2,next named as Mdr2),Nr1h2(coding LXR-β,next named as Lxrβ),and Rag2(coding RAG2)knockout mice.DDC was used to induce PSC.Hematoxylin and eosin and Sirius red staining were used to assess the extent of hepatic injury and fibrosis.Flow cytometry was used to observe immune cell subsets.Results:We observed a declining trend in hepatic Lxrβ in the PSC model.Unexpectedly,Lxrβ knockout failed to modulate DDC-induced PSC pathogenesis.Concomitantly,assessment of the influence of Rag2 deficiency on PSC progression revealed the absence of aggravated or alleviated hepatic injury or fibrosis in the Rag2-/-DDC mice.However,Lxrβ depletion intensified DDC-induced PSC in the Rag2-/-mice,with more abundant infiltrative inflammatory cells and more severe liver fibrosis.Compared with Rag2-/-DDC mice,Lxrβ-/-Rag2-/-DDC mice had higher serum ALT and AST levels and mRNA expression of proinflammatory and profibrotic genes.Flow cytometry showed that LXR-β deficiency resulted in a diminished population of hepatic innate immune cells.Conclusion:This study indicated innate immune cell LXR-β deficiency can exacerbate hepatic injury and fibrosis in murine models of PSC suggesting that LXR-β may regulate the function of innate immunity in the fibrotic advancement of PSC.

Objective To investigate the clinical efficacy of Xinxuetong Oral Liquid in the treatment of patients with acute coronary syndrome(ACS).Methods A total of 80 patients with ACS of blood stasis syndrome who were hospitalized in Shunde Hospital of Guangzhou University of Chinese Medicine from January 2023 to September 2023 were randomly divided into the treatment group and control group according to random number table method,40 patients in each group.The patients in the two groups were given conventional western medicine treatment including lifestyle guidance,percutaneous coronary intervention(PCI),and conventional western medicine therapy.Additionally,the treatment group was treated with Xinxuetong Oral Liquid.The course of treatment for the two groups covered eight weeks.Before and after treatment the two groups were observed in the changes of traditional Chinese medicine(TCM)syndrome score,blood stasis syndrome score,angina pectoris score,blood lipid indicators,carotid ultrasonography indicators,echocardiography indicators,and serum levels of trimethylamine-N-oxide(TMAO),nitric oxide(NO),endothelin 1(ET-1),interleukin 8(IL-8),serine/threonine-protein kinase 1(AKT-1),and vascular endothelial growth factor A(VEGF-A).After treatment,the efficacy on TCM syndrome efficacy and the safety of the regimen in the two groups were evaluated.Results(1)During the trial,there were two cases of loss to follow-up and one case of withdrawal due to pneumonia,and eventually a total of 77 patients completed the full course of treatment,among which 39 patients were in the treatment group and 38 patients were in the control group.(2)After eight weeks of treatment,the total effective rate of the treatment group was 89.74％(35/39),and that of the control group was 63.16％(24/38).The intergroup comparison(tested by chi-square test)showed that the effective rate of TCM syndrome efficacy in the treatment group was significantly superior to that in the control group(P＜0.01).(3)After treatment,the scores of TCM symptoms such as chest pain,chest distress,symptom aggravation at night,and palpitation in the two groups,as well as the score of gloomy complexion in the treatment group,were significantly decreased compared with those before treatment(P＜0.05 or P＜0.01),and the decrease of scores of chest distress,symptom aggravation at night,and palpitation in the treatment group was significantly superior to that in the control group(P＜0.05 or P＜0.01).(4)After treatment,the blood stasis syndrome score and angina pectoris symptom score of the two groups of patients were significantly decreased compared with those before treatment(P＜0.01),and the decrease in the treatment group was significantly superior to that in the control group(P＜0.01).(5)After treatment,the serum TMAO,ET-1,IL-8,AKT-1,and VEGF-A levels in the two groups were significantly decreased compared with those before treatment(P＜0.01),and the serum NO level was significantly increased compared with that before treatment(P＜0.01).The decrease of serum TMAO,ET-1,IL-8,and AKT-1,VEGF-A levels and the increase of serum NO level in the treatment group were significantly superior to those of the control group(P＜0.05 or P＜0.01).(6)After treatment,the total cholesterol(TCHO)and low-density lipoprotein cholesterol(LDL-C)levels of the two groups(P＜0.01)and the triglyceride(TG)level of the treatment group(P＜0.05)were decreased significantly compared with those before treatment,while the high-density lipoprotein cholesterol(HDL-C)level of the treatment group was increased significantly compared with that before treatment(P＜0.01).No obvious changes of TG and HDL-C levels before and after treatment were shown in the control group(P＞0.05).The comparison of blood lipid indicators after treatment between groups showed that there were no statistically significant differences(P＞0.05).(7)After treatment,the carotid ultrasonography indicators of carotid intima-media thickness(IMT)and Crouse score of the carotid plaque in the two groups were significantly improved compared with those before treatment(P＜0.01).However,there was no statistical significance in the comparison of the two indicators between the two groups after treatment(P＞0.05).(8)The observation of echocardiography indicators showed that only the post-treatment left ventricular diameter(LVd)of the treatment group was significantly larger than that before treatment(P＜0.05),while no obvious changes of the other echocardiography indicators before and after treatment were shown in the two groups(P＞0.05).The comparison between the groups after treatment also showed no statistically significant differences(P＞0.05).(9)During the treatment,no serious drug-induced adverse reactions or drug-related severe cardiovascular events and complications occurred in the two groups.Conclusion The combination of Xinxuetong Oral Liquid with conventional western medicine treatment exerts certain efficacy and safety on improving the clinical symptoms of patients with ACS of blood stasis syndrome,and its therapeutic mechanism may be related to the improvement of blood lipid levels,inflammatory response,and TMAO level.

Objective Heart failure(HF)complicated by acute kidney injury(AKI)significantly impacts patient outcomes,and it is crucial to make early predictions of short-term mortality.This study is focused on developing an interpretable machine learning model to enhance early prediction accuracy in such clinical scenarios.Methods This retrospective cohort study utilized data from the Medical Information Mart for Intensive Care Ⅳ(MIMIC-Ⅳ,version 2.0)database.Data from the first 24 hours after admission to the ICU were extracted and divided into a training set(70％)and a validation set(30％).We utilized the SHapley Additive exPlanation(SHAP)method to interpret the workings of an extreme gradient boosting(XGBoost)model and identify key prognostic factors.The XGBoost model's predictive ability was evaluated against three other machine learning models using the area under the curve(AUC)metric,and its interpretation was enhanced using the SHAP method.Results The study included 8 028 patients with HF complicated by AKI.The XGBoost model outperformed the other models,achieving an AUC of 0.93(95％confidence interval[CI]:0.78-0.94;accuracy=0.89),while neural network model showed the worst performance(AUC=0.79,95％CI:0.77-0.82;accuracy=0.82).Decision curve analysis showed the superior net benefit of the XGBoost model within the 9％to 60％threshold probabilities.SHAP analysis was performed to identify the top 20 predictors,with age(mean SHAP value 1.29)and Glasgow Coma Scale score(mean SHAP value 1.24)emerging as significant factors.Conclusions Our interpretable model offers an enhanced ability to predict mortality risk in HF patients with AKI in ICUs.This model can be used to assist in formulating effective treatment plans and optimizing resource allocation.