Increasing evidence shows that the early lesions of Parkinson's disease (PD) originate from gut, and correction of microbiota dysbiosis is a promising therapy for PD. FLZ is a neuroprotective agent on PD, which has been validated capable of alleviating microbiota dysbiosis in PD mice. However, the detailed mechanisms still need elucidated. Through metabolomics and 16S rRNA analysis, we identified glycoursodeoxycholic acid (GUDCA) was the most affected differential microbial metabolite by FLZ treatment, which was specially and negatively regulated by Clostridium innocuum, a differential microbiota with the strongest correlation to GUDCA production, through inhibiting bile salt hydrolase (BSH) enzyme. The protection of GUDCA on colon and brain were also clarified in PD models, showing that it could activate Nrf2 pathway, further validating that FLZ protected dopaminergic neurons through promoting GUDCA production. Our study uncovered that FLZ improved PD through microbiota-gut-brain axis, and also gave insights into modulation of microbial metabolites may serve as an important strategy for treating PD.

Although enteric glial cell (EGC) abnormal activation is reported to be involved in the pathogenesis of Parkinson's disease (PD), and inhibition of EGC gliosis alleviated gut and dopaminergic neuronal dysfunction was verified in our previous study, the potential role of gut microbiota on EGC function in PD still need to be addressed. In the present study, fecal microbiota transplantation revealed that EGC function was regulated by gut microbiota. By employing 16S rRNA and metabolomic analysis, we identified that 3-indolepropionic acid (IPA) was the most affected differential microbial metabolite that regulated EGC gliosis. The protective effects of IPA on PD were validated in rotenone-stimulated EGCs and rotenone (30 mg/kg i.g. for 4 weeks)-induced PD mice, as indicated by decreased inflammation, improved intestinal and brain barrier as well as dopaminergic neuronal function. Mechanistic study showed that IPA targeted pregnane X receptor (PXR) in EGCs, and inhibition of IL-13Rα1 involved cytokine-cytokine receptor interaction pathway, leading to inactivation of downstream JAK1-STAT6 pathway. Our data not only provided evidence that EGC gliosis was critical in spreading intestinal damage to brain, but also highlighted the potential role of microbial metabolite IPA in alleviating PD pathological damages through gut-brain axis.

[This corrects the article DOI: 10.1016/j.apsb.2025.02.029.].

Perimenopause raises the risk and incidence of depression, whereas the underlying molecular mechanism remains unclear. Disturbed glucose regulation has been widely documented in depressive disorders, which renders the brain susceptible to various stresses such as estrogen depletion. However, whether and how glucose dysfunction regulates depression-like behaviors and neuronal damage in perimenopausal transition remains unexplored. Here, a prominent depressive phenotype was found in perimenopausal mice induced by the ovarian toxin 4-vinylcyclohexene diepoxide (VCD). The VCD depression susceptible group (VCD^SS) and the VCD depression resilient group (VCD^RES) were determined using a ROC-based behavioral screening approach. We found that the hippocampus, a crucial region linked to depression, had hyperglycemia and mitochondrial abnormalities. Interestingly, oral administration of the SGLT2 inhibitor empagliflozin (EMPA) and intrahippocampal glucose infusion suggest a close relationship between hyperglycemia in the hippocampus and the susceptibility to depression. We verified that cytochrome c oxidase 7c (COX7C) downregulation is a potential cause of the high glucose-induced neuronal injury using proteomic screening and biochemical validations. High glucose causes COX7C to be ubiquitinated in a S-phase kinase associated protein 1 (SKP1)-dependent manner. According to these results, SKP1/COX7C represents a unique therapeutic target and a novel molecular route for treating perimenopausal depression.

OBJECTIVE: Microcirculatory disturbance is pathologically critical to acute pancreatitis (AP), which can be effectively alleviated by traditional Chinese medicine (TCM) formulas that activate blood flow. However, there has been no evidence-based research to date. Therefore, a well-designed systematic review and meta-analysis is necessary to elucidate the therapeutic transformative benefit of improving microcirculation during AP. This study aims to confirm the therapeutic efficacy of TCM formulas and explore the potential mechanisms underlying their effects on AP treatment. METHODS: Studies from eight databases including Pubmed, Embase, Web of Science, Cochrane Library, CNKI, CBM, Wanfang, and Chinese VIP, were screened for the eligible randomized controlled trials (RCTs). The APACHE II score and effectiveness rate were set as primary outcomes, while mortality rate, complications, total hospital stays, serum amylase recovery time, the time until the disappearance of abdominal pain, microcirculation indicators, and inflammation indicators were chosen as secondary outcomes. A systematic review and meta-analysis were subsequently conducted. Network pharmacology analysis was performed to analyze potential bioactive components with relevant targets of the core herbs included in the TCM formulas for activating blood flow. RESULTS: A total of 51 RCTs (n = 3 721) were included. Compared with conventional western medical treatments alone, TCM groups were associated with lower APACHE II score (SMD =  - 1.36, 95% CI: -2.01 to - 0.71, P = 0.000) and higher effectiveness rate (RR: 1.22, 95% CI: 1.18 to 1.26, P = 0.000). Furthermore, the formulas for activating blood flow demonstrated significant efficacy in improving both microcirculation and inflammation indicators. Additionally, six core Chinese herbal medicines including Rhei Radix et Rhizoma with the highest frequency, Aurantii Fructus Immaturus, Paeoniae Radix Rubra, Bupleuri Radix, Salviae Miltiorrhizae Radix et Rhizoma, and Corydalis Rhizoma were filtered out from the adopted TCM formulas. Finally, 166 shared targets between the six herbs and AP were identified. KEGG analysis indicated that lipid and atherosclerosis pathway is highly related to microcirculation. CONCLUSION TCM formulas for activating blood flow significantly improve microcirculation and alleviate AP. Further high-quality, well-designed RCTs and deep mechanism exploration are required.

Objective:To assess the core competencies of internal medicine residents undergoing standardized residency training and to explore the effectiveness of core competency evaluation on mobile devices.Methods:The mobile formative evaluation module was developed based on the "Xueyiku" teaching management platform. From January to December 2023, clinical teachers were asked to evaluate 150 internal medicine residents based on the "Resident Core Competency Milestone Evaluation System in China Consortium of Elite Teaching Hospitals", and the results were analyzed using non-parametric tests.Results:Among the six core competencies of internal medicine residents, professionalism received the highest score, whereas teaching skill received a lower score (97.50 vs. 90.00; H=167.31, P<0.001). Second-year residents had significantly higher scores than first-year residents (93.00 vs. 90.00; P<0.001), but similar scores to third-year residents (93.00 vs. 93.00; P>0.05). In addition, there was no significant difference in score among residents with different medical education backgrounds ( P>0.05). Conclusions:More emphasis should be placed on improving the teaching skills of internal medicine residents, along with the implementation of tiered progressive training. The mobile core competency evaluation is an effective means for assessing the comprehensive skills of residents in a timely manner.

To study the ameliorative effect of Eucommiae Cortex extract on spatial learning disabilities in APP/PS1 double-transgenic mice and explore its relationship with estrogen receptor β(ERβ)/c-Jun N-terminal kinase(JNK) signaling pathway, sixty 3-month-old male APP/PS1 mice were randomly divided into a model group, an anti-brain failure capsule group(0.585 g·kg~(-1)), a donepezil hydrochloride group(0.65 mg·kg~(-1)), and a Eucommiae Cortex extract group(1.3 g·kg~(-1)), and 15 C57BL/6 mice of the same genetic background were set as WT control group. The learning and memory ability of mice was assessed by the Morris water maze test(MWM), the passive avoidance test(PAT), and the novel object recognition test(NOR). The histomorphological and cellular ultrastructural features of the hippocampal region of the mice were observed by hematoxylin-eosin(HE) staining and transmission electron microscopy(TEM); the molecular docking validation of the key active ingredients and the key targets was performed by using AutoDock Vina software, and the immunohistochemical method(IHC) was used to detect the ERβ expression in the dentate gyrus(DG) area of mouse hippocampus. Western blot(WB) was utilized to detect the expression of ERβ, p-JNK, and JNK in mouse hippocampal area. Compared with those in the WT control group, the results of behavioral experiments showed that the latency of the mice in the model group was significantly increased, the number of platform traversals, and the target quadrant residence time were significantly decreased in the MWM. The evasion latency was significantly reduced, and the number of errors was significantly increased in the PAT. The index of recognition of novel objects was significantly reduced in the NOR. The results of HE staining indicated that the hippocampal area of mice in the model group showed a decrease in the number of neurons, disorganization of pyramidal cell arrangement, nucleus consolidation, and other changes. TEM results showed that some neuronal nuclei in the hippocampal area had a consolidated state, slightly thickened and aberrant nuclear membranes, and fewer intracytoplasmic nidus bodies; the IHC results showed that the expression of ERβ in the hippocampal DG area of the mice was reduced. The WB results showed that the ERβ expression in the hippocampal tissue was decreased, and the p-JNK/JNK level was elevated. Compared with the model group, the Eucommiae Cortex extract group showed a significant decrease in latency, and increase in number of platform traversals and target quadrant residence time in the MWM, a significant increase in evasion latency and decrease in number of errors in the PAT, and a significant increase in the index of recognition of novel objects in the NOR. In addition, there was an increase in the number of neurons in the hippocampal area of mice. The pyramidal cells tended to be arranged in an orderly manner; the nuclei of neurons in the hippocampal area were in a better state; the expression of ERβ in the hippocampal DG area of the mice was elevated; the expression of ERβ in the hippocampal tissue was elevated, and the level of p-JNK/JNK was reduced. The effects of donepezil hydrochloride group and anti-brain failure capsule on APP/PS1 mice in terms of behavioral, HE, and TEM indexes were similar to those of Eucommiae Cortex extract, and there was no significant difference between donepezil hydrochloride group and the model group in IHC and WB experiments, and the results of molecular docking indicated that the estrogen-like components in Eucommiae Cortex extract were tightly bound to ERβ. In conclusion, the binding of Eucommiae Cortex extract to estrogen receptors, regulation of ERβ expression, and activation of ERβ/JNK signaling pathway may be one of the key mechanisms by which it improves the learning and memory ability of APP/PS1 mice.
Animals ; Male ; Mice ; Mice, Transgenic ; Memory/drug effects* ; Mice, Inbred C57BL ; Estrogen Receptor beta/genetics* ; Eucommiaceae/chemistry* ; Alzheimer Disease/psychology* ; Amyloid beta-Protein Precursor/metabolism* ; Presenilin-1/metabolism* ; Humans ; MAP Kinase Signaling System/drug effects* ; Drugs, Chinese Herbal/administration & dosage* ; Hippocampus/metabolism* ; Maze Learning/drug effects* ; Learning/drug effects*

Network pharmacology and molecular docking were employed to predict the mechanism of Zhizhu Decoction in regulating macrophage polarization to reduce adipose tissue inflammation in obese children, and animal experiments were then carried out to validate the prediction results. The active ingredients and targets of Zhizhu Decoction were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP). The inflammation related targets in the adipose tissue of obese children were searched against GeneCards, OMIM, and DisGeNET, and a drug-disease-target network was established. STRING was used to construct a protein-protein interaction(PPI) network and screen for core targets. R language was used to carry out Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analyses. AutoDock was used for the molecular docking between core targets and active ingredients. 24 SPF grade 6-week C57B/6J male mice were adaptively fed for 1 week, and 8 mice were randomly selected as the blank group. The remaining 16 mice were fed with high-fat diet for 8 weeks to onstruct a high-fat diet induced mouse obesity model. After successful modeling, the 16 mice were randomly divided into model group and Zhizhu Decoction group, with 8 mice in each group. Zhizhu Decoction group was intervened by gavage for 14 days, once a day. Blank group and model group were given an equal amount of sterile double distilled water(ddH_2O) by gavage daily. After the last gavage, serum and inguinal adipose tissue were collected from mice for testing. The morphology of inguinal adipose tissue was observed by hematoxylin-eosin(HE) staining, the levels of inflammatory factors interleukin-6(IL-6) and tumor necrosis factor-α(TNF-α)were detected by enzyme-linked immunosorbent assay(ELISA), and the protein expression of macrophage marker molecule nitric oxide synthase(iNOS) and epidermal growth factor like hormone receptor 1(F4/80) was detected by immunofluorescence staining. Network pharmacology predicted luteolin, naringenin, and nobiletin as the main active ingredients in Zhizhu Decoction and 15 core targets. KEGG pathway enrichment analysis revealed involvement in the key signaling pathway of nuclear factor κB(NF-κB). Molecular docking showed that the active ingredients of Zhizhu Decoction bound well to the core targets. Animal experiment showed that compared with the model group, Zhizhu Decoction reduced the distribution of inflammatory cytokines in the inguinal adipose tissue of mice, lowered the levels of TNF-α and IL-6 in the serum(P<0.05, P<0.01), and down-regulated the expression of iNOS and F4/80(P<0.05). The results showed that the active ingredients in Zhizhu Decoction, such as luteolin, naringenin, and nobiletin, inhibit the aggregation of macrophages in adipose tissue, downregulate their classic activated macrophage(M1) polarization, reduce the expression of inflammatory factors IL-6 and TNF-α, and thus improve adipose tissue inflammation in obese mice.
Animals ; Drugs, Chinese Herbal/pharmacology* ; Molecular Docking Simulation ; Adipose Tissue/immunology* ; Mice ; Male ; Humans ; Network Pharmacology ; Macrophages/immunology* ; Mice, Inbred C57BL ; Child ; Protein Interaction Maps/drug effects* ; Obesity/genetics* ; Inflammation/drug therapy*

Guided by the theory of "the kidney storing essence, governing the bones, and producing marrow", this study explored the mechanism of icariin(ICA) in regulating the osteogenic differentiation of rat bone mesenchymal stem cells(BMSCs) through caveolin-1(Cav1) via in vitro and in vivo experiments, aiming to provide a theoretical basis for the prevention and treatment of postmenopausal osteoporosis with traditional Chinese medicine(TCM). Primary cells were obtained from 4-week-old female SD rats using the whole bone marrow adherent method. Flow cytometry was used to detect the expression of surface markers CD29, CD90, CD11b, and CD45. The potential for osteogenic and adipogenic differentiation was assessed. The effect of ICA on cell viability was determined using the CCK-8 assay, and the impact of ICA on the formation of mineralized nodules was verified by alizarin red staining. A stable Cav1-silenced cell line was constructed using lentivirus. The effect of Cav1 silencing on osteogenic differentiation was observed via alizarin red staining. Western blot analysis was conducted to detect the expression of Cav1, Hippo/TAZ, and osteogenic markers such as Runt-related transcription factor 2(RUNX2) and alkaline phosphatase(ALP). The results showed that primary cells were successfully obtained using the whole bone marrow adherent method, positively expressing surface markers of rat BMSCs and possessing the potential for both osteogenic and adipogenic differentiation. The CCK-8 assay and alizarin red staining results indicated that 1×10~(-7) mol·L~(-1) was the optimal concentration of ICA for intervention in this experiment(P<0.05). During osteogenic induction, ICA inhibited Cav1 expression(P<0.05) while promoting TAZ expression(P<0.05). Alizarin red staining demonstrated that Cav1 silencing significantly promoted the osteogenic differentiation of BMSCs. After ICA intervention, TAZ expression was activated, and the expression of osteogenic markers ALP and RUNX2 was increased. In conclusion, Cav1 silencing significantly promotes the osteogenic differentiation of BMSCs, and ICA promotes this differentiation by inhibiting Cav1 and regulating the Hippo/TAZ signaling pathway.
Animals ; Mesenchymal Stem Cells/metabolism* ; Caveolin 1/genetics* ; Osteogenesis/drug effects* ; Rats, Sprague-Dawley ; Rats ; Cell Differentiation/drug effects* ; Female ; Signal Transduction/drug effects* ; Flavonoids/administration & dosage* ; Protein Serine-Threonine Kinases/genetics* ; Drugs, Chinese Herbal/pharmacology* ; Cells, Cultured ; Humans

Based on the ultra performance liquid chromatography-quadrupole Exactive Orbitrap mass spectrometry(UPLC-Q-Exactive Orbitrap-MS) technology, combined with related literature, databases, and reference material information, this study qualitatively analyzed the components of Dayuanyin in the tissue of rats after gavage and employed molecular docking technology to predict the rationality of the mechanism behind the antipyretic effect of the in vivo components in Dayuanyin. A total of 21, 26, 20, 21, 14, and 31 prototype components and 3, 16, 3, 7, 5, and 24 metabolites were identified from the heart, liver, spleen, lung, kidney, and hypothalamus of the rats, respectively, and the binding ability of key components and targets was further verified by molecular docking. The results showed that all components had good binding ability with targets. The established UPLC-Q-Exactive Orbitrap-MS could effectively and quickly identify the Dayuanyin components distributed in tissue and preliminarily identify their metabolites. Many components were identified in the hypothalamus, which suggested that the components delivered to the brain should be focused on in the study on Dayuanyin in the treatment of febrile diseases. The molecular docking technology was used to predict the rationality of the mechanism behind its antipyretic effect, which lays the foundation for the clarification of the material basis and action mechanism of Dayuanyin, the development of new preparations, and the prediction of quality markers.
Animals ; Drugs, Chinese Herbal/administration & dosage* ; Rats ; Molecular Docking Simulation ; Male ; Antipyretics/metabolism* ; Rats, Sprague-Dawley ; Tissue Distribution ; Mass Spectrometry ; Chromatography, High Pressure Liquid ; Hypothalamus/metabolism*