OBJECTIVE: To construct a prediction model for the clinical effect of eye acupuncture combined with rehabilitation therapy on ischemic stroke based on interpretable machine learning. METHODS: From January 1st, 2020 to October 1st, 2024, the clinical data of 470 patients with ischemic stroke were collected in the the Second Department of Encephalopathy Rehabilitation of the Affiliated Hospital of Liaoning University of TCM. The modified Barthel index (MBI) score before and after treatment was used to divide the patients into an effect group (291 cases) and a non-effect group (179 cases). Random forest and recursive feature elimination with cross-validation were combined to screen the predictors of the therapeutic effect of patients. Seven representative machine learning models with different principles were established according to the screening results. The predictive effect of the best model was evaluated by receiver operating characteristics (ROC), calibration, and clinical decision-making (DCA) curves. Finally, the Shapley additive explanation (SHAP) framework was used to interpret the prediction results of the best model. RESULT: ①All the machine learning models presented the area under curve (AUC) to be above 85%. Of these models, the random forest model showed the best prediction ability, with AUC of 0.96 and the precision of 0.87. ②The prediction probability of calibration curve and the actual probability showed a good prediction consistency. ③The net benefit rate of DCA curve in the range of 0.1 to 1.0 was higher than the risk threshold, indicating a good effect of model. ④SHAP explained the characteristic values of variables that affected the prediction effect of the model, meaning, more days of treatment, lower MBI score before treatment, lower level of fibrinogen, shorter days of onset and younger age. These values demonstrated the better effect of eye acupuncture rehabilitation therapy. CONCLUSION The rehabilitation effect prediction model constructed in this study presents a good performance, which is conductive to assisting doctors in formulating targeted personalized rehabilitation programs, and identifying the benefit groups of eye acupuncture combined with rehabilitation therapy and finding the advantageous groups with clinical effect. It provides more ideas for the treatment of ischemic stroke with eye acupuncture combined with rehabilitation therapy.
Humans ; Acupuncture Therapy ; Machine Learning ; Male ; Female ; Middle Aged ; Ischemic Stroke/rehabilitation* ; Aged ; Stroke Rehabilitation ; Adult ; Eye

Homo- or heterodimeric compounds that affect dimeric protein function through interaction between monomeric moieties and protein subunits can serve as valuable sources of potent and selective drug candidates. Here, we screened an in-house dimeric natural product collection, and panepocyclinol A (PecA) emerged as a selective and potent STAT3 inhibitor with profound anti-tumor efficacy. Through cross-linking C712/C718 residues in separate STAT3 monomers with two distinct Michael receptors, PecA inhibits STAT3 DNA binding affinity and transcription activity. Molecular dynamics simulation reveals the key conformation changes of STAT3 dimers upon the di-covalent binding with PecA that abolishes its DNA interactions. Furthermore, PecA exhibits high efficacy against anaplastic large T cell lymphoma in vitro and in vivo, especially those with constitutively activated STAT3 or STAT3^Y640F. In summary, our study describes a distinct and effective di-covalent modification for the dimeric compound PecA to disrupt STAT3 function.

Iron is an essential trace element in the human body, crucial in maintaining normal physiological functions. Recent studies have identified iron ions as a significant factor in initiating the ferroptosis process, a novel mode of programmed cell death characterized by iron overload and lipid peroxide accumulation. The iron metabolism pathway is one of the primary mechanisms regulating ferroptosis, as it maintains iron homeostasis within the cell. Numerous studies have demonstrated that abnormalities in iron metabolism can trigger the Fenton reaction, exacerbating oxidative stress, and leading to cell membrane rupture, cellular dysfunction, and damage to tissue structures. Therefore, regulation of iron metabolism represents a key strategy for ameliorating ferroptosis and offers new insights for treating diseases associated with iron metabolism imbalances. This review first summarizes the mechanisms that regulate iron metabolic pathways in ferroptosis and discusses the connections between the pathogenesis of various diseases and iron metabolism. Next, we introduce natural and synthetic small molecule compounds, hormones, proteins, and new nanomaterials that can affect iron metabolism. Finally, we provide an overview of the challenges faced by iron regulators in clinical translation and a summary and outlook on iron metabolism in ferroptosis, aiming to pave the way for future exploration and optimization of iron metabolism regulation strategies.

Objective To investigate the effect and mechanism of macrophage colony stimulating factor(M-CSF)on myocardial function after acute myocardial infarction(AMI)in mice by regulating cardiac macrophages.Methods Fifty C57mice were randomly di-vided into Sham Group(n=10,sham operation group),MI Group(n=20,AMI model was prepared,and normal saline was injected in-traderitoneally)and MM Group { n=20,AMI model was prepared,and M-CSF reagent[500μg/(kg·d)]was injected intraderitoneal-ly}.At the end of the experiment,after completing a cardiac ultrasound,the myocardial tissue was collected,interleukin-4(IL-4),interleukin-6(IL-6),monocyte ehemoattractant protein-1(MCP-1),tumor necrosis factor-α(TNF-α),interleukin-10(IL-10),interferon-α(IFN-α),atrial natriuretic peptide(ANP),brain natriuretic peptide(BNP),Collagen Ⅰ and Collagen Ⅲ were detected by enzyme-linked immunosorbent assay(ELISA),the apoptosis-related proteins Bax,C-caspase-3,caspase-3,nuclear transcription facter(NF)-κB p65,transduction and activator of transcription 3(STAT3),transduction and activator of transcription 6(STAT6)were detected by Western blot assay,and the neovascularization markers in MI peripheral area were determined by immunohis-tochemistry,the expression levels of M1-type macrophages and M2-type macrophages were detected by flow cytometry.Results The left ventricular size and left ventricular ejection fraction(LVEF)were significantly improved in MM Group when compared with the MI Group,and the indexex of myocardial inflammation,hypertrophy,apoptosis,and fibrosis decreased significantly(P＜0.05).The expres-sion of neovascularization mardker CD31 was significantly up-regulated in MM Group.The expression of M2macrophage in MM group was significantly higher than when compared with the MI group,while the level of M1 macrophage was lower(P＜0.05).The expression of NF-κB p65 in MI group was statistically higher than that in the Sham group and MM group,while the levels of STAT3 and STAT6 were higher in the MM group than in the MI group(P＜0.05).Conclusion M-CSF can inhibit inflammatory response,reduce myo-cardial fibrosis,hypertrophy and apoptosis,promote angiogenesis,inhibit M1-type macrophages and up-regulate the expression of M2-type macrophages to promote myocardial tissue repair and improve ventricular structural remodeling,in which NF-κB/STAT signa-ling pathway plays an important role.

Objective:To explore the mechanism of peritoneal dialysis solution (PDS)-induced peritoneal microinflammation through activation of ceramide (CER) in peritoneal dialysis model mice.Methods:Thirty 5-week-old male C57BL/6 mice weighing about 22 g were used to set up peritoneal dialysis models, and then were randomly divided into 4 groups: sham operation group (1.5 ml sterilized water, n=7), high glucose-PDS group (1.5 ml 4.25% PDS, n=8), high glucose-PDS+ acid sphingomyelinase (ASMase) inhibitor desipramine (DES) group (1.5 ml sterilized water+10 mg/kg DES, n=8), high glucose-PDS+Src kinase inhibitor PP2 group (1.5 ml sterilized water +1 mg/kg PP2, n=7), with intraperitoneal injection once a day. After 28 days, the mice were sacrificed to retain peritoneal tissues. HE staining and Masson staining were used to observe the histological changes of peritoneum. Immunohistochemistry was used to detect the Toll-like receptor 4 (TLR4) and macrophages. High performance liquid chromatography, liquid chromatography/mass spectrometry and immunofluorescence were used to detect the expression of ASMase and CER. Real-time quantitative PCR was used to detect the mRNA levels of c-Src, p-Src, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). Western blotting was used to detect the protein levels of c-Src, and p-Src. Enzyme-linked immunosorbent assay was used to detect the serum C reactive protein (CRP), IL-6 and TNF-α. Results:(1) High glucose-PDS led to peritoneal hyperplasia, collagen deposition and fibrosis in the peritoneal dialysis mice, indicating successful modeling. Compared with high glucose-PDS group, peritoneal hyperplasia, collagen deposition and fibrosis of mice treated with DES and PP2 were significantly improved (all P<0.05). (2) Compared with sham operation group, ASMase activation and CER level of peritoneal tissues were significantly higher in high glucose-PDS group, and DES could significantly inhibit activated ASMase and increased CER expression caused by high glucose-PDS (both P<0.05). PP2 had no significant effect on ASMase activation and CER level (both P>0.05). (3) Compared with sham operation group, there were more TLR4 and macrophage positive staining cells in peritoneal tissues in high glucose-PDS group, and the mRNA expression levels of IL-6 and TNF-α in peritoneal tissues and serum CRP, IL-6 and TNF-α were higher (all P<0.05). DES and PP2 could significantly inhibit the increased TLR4, macrophages and related inflammatory factors induced by high glucose-PDS (all P<0.05). (4) Compared with sham operation group, c-Src and p-Src mRNA and protein expression levels of peritoneal tissues in high glucose-PDS group were significantly higher (all P<0.05). PP2 significantly inhibited the increased p-Src mRNA and protein levels caused by high glucose-PDS (both P<0.05), but had no significant effect on the mRNA and protein expression levels of c-Src (both P>0.05). DES had no significant effect on the mRNA and protein expression levels of c-Src and p-Src (all P>0.05). Conclusions:High glucose-PDS may enhance the expression of CER through stimulating the activity of ASMase, phosphorylate Src, activate TLR4 and induce inflammatory damage of peritoneum in peritoneal dialysis model mice.

Abstract: Objective　To explore the effect of Yiaikang on the expression of sterile alpha motif and histidine-aspartic acid domain-containing protein 1(SAMHD1), a host restriction factor, and interferon levels in peripheral blood of HIV-infected patients with lung-spleen Qi deficiency syndrome. This aims to provide insights into the mechanism of YiaiKang in the treatment of AIDS. Methods According to the diagnostic criteria of Western medicine for AIDS and traditional Chinese medicine for lung-spleen Qi deficiency syndrome, 22 cases of HIV patients with lung and spleen Qi deficiency syndrome were enrolled in the study from the First Affiliated Hospital of Henan University of TCM between September 2020 and May 2021, and 20 healthy people in the area were taken as control. The patients with lung and spleen Qi deficiency syndrome were treated with Yiaikang for 6 months. T lymphocyte subpopulation changes and expression level of SAMHD1 protein in T cells were detected by flow cytometry. SAMHD1 mRNA expression in peripheral blood mononuclear cells (PBMCs) was detected by fluorescence quantitative PCR. The levels of IFN-α, IFN-β, IFN-γ, and IL-2 in plasma were detected by enzyme-linked immunosorbent assay (ELISA). The changes of SAMHD1 and interferon in peripheral blood of HIV patients with lung and spleen Qi deficiency syndrome were analyzed to explore the intervention effect of Yiaikang. Results Compared with healthy people, HIV patients with lung and spleen Qi deficiency syndrome exhibited a reduction in the CD4 + T lymphocyte count and CD4/CD8 ratio (Z=-3.526, P<0.001; Z=-0.881, P<0.001). There was an increase in the expression of SAMHD1 protein in T lymphocytes (SAMHD1 MFI/CD4: Z=-3.425, P=0.001; SAMHD1 MFI/CD8: Z=-2.153, P=0.031) and an increase in the expression of SAMHD1 gene in PBMCs (Z=-3.828, P<0.001). Yiaikang treatment significantly increased the CD4 + T cell count and CD4/CD8 ratio (Z=-2.711, P=0.007; Z=-2.062, P=0.039), decreased the expression of SAMHD1 mRNA (Z=-2.581, P=0.010), and decreased the levels of IFN-α and IFN-γ (Z=-1.985, P=0.047; Z=-2.744, P=0.006). Conclusions Patients with lung-spleen Qi deficiency syndrome have reduced numbers of CD4 + T cells and CD4/CD8 ration, with increased expression of SAMHD1 and interferon factors. Yiaikang treatment can increase the number of CD4 + T cells and CD4/CD8 ratio and reduce the expression of SAMHD1 and interferon factor, thereby improving the immune imbalance caused by HIV infection.

Acquired immune deficiency syndrome is an infectious disease with high mortality caused by human immunodefi-ciency virus(HIV).Even after antiretroviral therapy,the virus reservoir formed by the provirus integrated in the host genome can evade host immune surveillance and clearance.The existing methods of HIV reservoir detection mainly include cell culture induced virus growth assay in vitro and direct detection of the provirus genome based on PCR technology.Understanding and measuring accurately of HIV reservoir can provide reliable technical basis for HIV treatment research.This article summarizes and analyzes various detection methods of HIV reservoirs in recent years and their advantages and disadvantages,in order to select the suitable method for different detection objects of HIV reservior,and give appropriate suggestions,to provide technical support and theoretical guidance for further research on acquired immune deficiency syndrome.

Ras homolog gene family member A(RhoA)is a small GTPase protein.Rho-associated coiled-coil forming protein kinase(ROCK)can be activated during the occurrence and development of ischemic stroke.RhoA/ROCK signaling pathway is an important regulatory factor in the pathological process of ischemic stroke,and regulation of this signaling pathway has become a research focus in promoting neuronal recovery and improving cerebral ischemia/reperfusion injury after ischemic stroke.However,only Fasudil is currently available as a RhoA/ROCK inhibitor.The rest is still in the stage of research and development or clinical trials,and has broad research prospects.In this paper,the regulatory role and mechanism of RhoA/ROCK signaling pathway in ischemic stroke were analyzed,and the application of inhibitors and regulatory drugs were described,aiming to provide new ideas for the prevention and treatment of ischemic stroke.

Background/Aims: Four-week treatment of linvencorvir (RO7049389) was generally safe and well tolerated, and showed anti-viral activity in chronic hepatitis B (CHB) patients. This study evaluated the efficacy, safety, and pharmacokinetics of 48-week treatment with linvencorvir plus standard of care (SoC) in CHB patients. Methods: This was a multicentre, non-randomized, non-controlled, open-label phase 2 study enrolling three cohorts: nucleos(t)ide analogue (NUC)-suppressed patients received linvencorvir plus NUC (Cohort A, n=32); treatment-naïve patients received linvencorvir plus NUC without (Cohort B, n=10) or with (Cohort C, n=30) pegylated interferon-α (Peg-IFN-α). Treatment duration was 48 weeks, followed by NUC alone for 24 weeks. Results: 68 patients completed the study. No patient achieved functional cure (sustained HBsAg loss and unquantifiable HBV DNA). By Week 48, 89% of treatment-naïve patients (10/10 Cohort B; 24/28 Cohort C) reached unquantifiable HBV DNA. Unquantifiable HBV RNA was achieved in 92% of patients with quantifiable baseline HBV RNA (14/15 Cohort A, 8/8 Cohort B, 22/25 Cohort C) at Week 48 along with partially sustained HBV RNA responses in treatment-naïve patients during follow-up period. Pronounced reductions in HBeAg and HBcrAg were observed in treatment-naïve patients, while HBsAg decline was only observed in Cohort C. Most adverse events were grade 1–2, and no linvencorvir-related serious adverse events were reported. Conclusions 48-week linvencorvir plus SoC was generally safe and well tolerated, and resulted in potent HBV DNA and RNA suppression. However, 48-week linvencorvir plus NUC with or without Peg-IFN did not result in the achievement of functional cure in any patient.

Objective:To investigate the effects of early sleep deprivation(SD) on depressive-like behavior and hippocampus synaptic plasticity in adult mice with chronic unpredictable mild stress(CUMS) model.Methods:Thirty 2-week-old clean grade male mice were randomly divided into control group (CON group), CUMS group and SD + CUMS group according to the random number table, with 10 mice in each group. The mice in SD + CUMS group were subjected with sleep deprivation for 4 hours once a day during puberty (3 ~ 6 weeks old), and then were stimulated by CUMS after adulthood (9 weeks old). The mice in CUMS group were subjected with CUMS at the age of 9 weeks. And the mice in CON group were not given any intervention.The depressive-like behavior was evaluated by body weight, sugar water preference, tail suspension test and forced swimming test.The density of dendritic spines of basal and apical neurons in hippocampal CA1 was measured by Golgi staining, the frequency and amplitude of miniature excitatory postsynaptic current(mEPSC) of pyramidal neurons in the hippocampal CA1 region of mice were measured by electro-physiological patch clamp technique.Graphpad prism 7.0 software was used for statistical analysis and mapping. One-way ANOVA was used for comparison among multiple groups, and Tukey test was used for further pairwise comparison.Results:(1) After stress modeling, there were significant differences in body weight, sugar water preference percentage, forced swimming immobility time and tail suspension time among the three groups ( F=71.63, 39.82, 44.13, 43.07, all P<0.01). Compared with CON group, the mice in CUMS group and SD+ CUMS group had lower body weight ((25.51±0.37) g, (22.92±0.31) g, (20.12±0.27) g, both P<0.01), lower sugar water percentage preference ((87.40±1.65) %, (63.42±3.33) %, (49.68±3.70)%, both P<0.01), longer immobile time of forced swimming ((34.30±5.32) s, (119.20±12.03) s, (153.80±9.17) s, both P<0.01) and longer immobile time of tail suspension test((115.20±8.19)s, (156.80±4.35) s, (192.00±4.12) s, both P<0.01). Compared with CUMS group, SD+ CUMS group had lower body weight ( P<0.01), lower sugar water preference percentage ( P<0.05), longer immobile time in forced swimming test( P<0.05) and longer immobile time in tail suspension test( P<0.01). (2) Golgi staining results showed that the densities of dendritic spines of apical neurons and basal neurons in hippocampal CA1 area of the three groups were significantly different ( F=38.41, 41.34, both P<0.01). The densities of dendritic spines of basal and apical hippocampal neurons in CUMS group and SD+ CUMS group were lower than those in CON group ((7.74±0.22)/10 μm, (6.58±0.27)/10 μm, (5.00±0.13)/10 μm, both P<0.01), ((8.90±0.23)/10 μm, (7.63±0.30)/10 μm, (6.01±0.14)/10 μm, both P<0.01). Compared with CUMS group, the mice in SD+ CUMS group had lower densities of dendritic spines of basal and apical hippocampal neurons(both P<0.01). (3) Electrophysiological results showed that there were significant differences in the frequency and amplitude of mEPSC in hippocampal pyramidal neurons of the three groups ( F=38.90, 63.37, both P<0.01). Compared with CON group, the frequency and amplitude of mEPSC in pyramidal neurons of CA1 in CUMS group and SD+ CUMS group were significantly lower ((0.39±0.03)Hz, (0.20±0.02)Hz, (0.07±0.02)Hz, both P<0.01; (9.98±0.31)pA, (7.74±0.21)pA, 6.36±0.13)pA, both P<0.01). Compared with CUMS group, the frequency and amplitude of mEPSC in SD+ CUMS group were lower (both P<0.01). Conclusion:Adolescent sleep deprivation aggravates depressive behavior and hippocampus synaptic plasticity impairment in adult CUMS model mice.