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.].

Objective To investigate the effects of low-to-moderate intensity treadmill exercise on pain and anxiety-like behaviors in rats with chronic constriction injury of the sciatic nerve(CCI),and to explore the neural mechanism of the exercise-related brain-derived neurotrophic factor(BDNF)/tropomyosin receptor kinase B(TrkB)-cAMP-response element binding protein(CREB)pathway in relieving pain and anxiety behaviors in CCI rats.Methods Thirty-two D rats were divided randomly into four groups:sham group,CCI group,sham+exercise(Sham+Exe)group,and CCI+exercise(CCI+Exe)group.Rats in the exercise groups underwent treadmill training for 4 weeks.The paw withdrawal threshold(PWT)and paw withdrawal latency(PWL)were measured before and at different time points after the operation.The elevated plus maze(EPM)and open field test(OFT)were used to evaluate anxiety-like behaviors in the rats.mRNA and protein expression levels of BDNF,TrkB,and CREB in the hippocampus were detected by real-time quantitative reverse transcription PCR and Western Blot,respectively.Results(1)The PWT and PWL on the operative side of the rats were significantly lower in the CCI compared with the sham group at 7,14,21,28,and 35 days after the operation(P＜0.001).The PWT on the ipsilateral side was significantly increased in the CCI+Exe group after 21 days compared with the CCI group(P＜0.05),and the PWL on the ipsilateral side increased significantly after 14 days(P＜0.05).(2)The EPM result showed that rats in the CCI group spent a significantly lower proportion of time in the open arms(P＜0.001)and significantly more time in the closed arms compared with the sham group(P＜0.01).Rats in the CCI+Exe group spent significantly more time in the open arms than the CCI group(P＜0.05).(3)The OFT result showed that rats in the CCI group spent a significantly lower proportion of time in the central area of the open field compared with the sham group(P＜0.001),while the percentage of time was significantly increased in the CCI+Exe group compared with the CCI group(P＜0.05).(4)BDNF,TrkB,and CREB mRNA and protein levels in the hippocampus were significantly lower in the CCI group compared with the sham group(P＜0.05,P＜0.01).Four-week treadmill exercise increased the mRNA and protein expression levels of BDNF,TrkB,and CREB in the hippocampus of CCI rats(P＜0.05).Conclusions Four weeks of treadmill exercise alleviates mechanical and thermal hyperalgesia and anxiety induced by chronic pain in CCI rats.Up-regulation of the BDNF/TrkB-CREB pathway may be one of the mechanisms by which exercise relieves chronic pain and improves anxiety.

Recent studies revealed the relationship among homologous recombination repair (HRR), androgen receptor (AR), and poly(adenosine diphosphate-ribose) polymerase (PARP); however, the synergy between anti-androgen enzalutamide (ENZ) and PARP inhibitor olaparib (OLA) remains unclear. Here, we showed that the synergistic effect of ENZ and OLA significantly reduced proliferation and induced apoptosis in AR-positive prostate cancer cell lines. Next-generation sequencing followed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses revealed the significant effects of ENZ plus OLA on nonhomologous end joining (NHEJ) and apoptosis pathways. ENZ combined with OLA synergistically inhibited the NHEJ pathway by repressing DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and X-ray repair cross complementing 4 (XRCC4). Moreover, our data showed that ENZ could enhance the response of prostate cancer cells to the combination therapy by reversing the anti-apoptotic effect of OLA through the downregulation of anti-apoptotic gene insulin-like growth factor 1 receptor ( IGF1R ) and the upregulation of pro-apoptotic gene death-associated protein kinase 1 ( DAPK1 ). Collectively, our results suggested that ENZ combined with OLA can promote prostate cancer cell apoptosis by multiple pathways other than inducing HRR defects, providing evidence for the combined use of ENZ and OLA in prostate cancer regardless of HRR gene mutation status.
Male ; Humans ; Prostatic Neoplasms, Castration-Resistant/genetics* ; Drug Resistance, Neoplasm/genetics* ; Cell Line, Tumor ; Receptors, Androgen/genetics* ; Nitriles ; Apoptosis

GJ-4 is crocin enrichments extracted from Gardenia jasminoides J. Ellis, and our previous studies have shown that GJ-4 significantly improved learning and memory impairment induced by Aβ in mice. Herein, a memory deficit model was developed by injecting okadaic acid (OA) into the lateral ventricle of mice, and the neuroprotection and underlying mechanism of GJ-4 on neuronal injury caused by Tau hyperphosphorylation were investigated. The Animal Care & Welfare Committee, Institute of Materia Medica, CAMS & PUMC has approved all procedures (No.00000318). GJ-4 at different doses was intragastric administration to mice for 16 days. Step-down test and Morris water maze test showed that GJ-4 could significantly improve OA-induced memory impairment in mice, and reduced the loss of Nissl bodies in the hippocampus of mice. GJ-4 could also decrease the phosphorylation level of Tau protein at Ser396, Thr231 and Ser404 via increasing protein phosphatase 2A (PP2A) activity and inhibiting glycogen synthase kinase-3β (GSK-3β) activity. Besides, further researches indicated that GJ-4 could inhibit the level of oxidative stress in the brain of OA mice, reduce neuronal apoptosis and inhibit the neuroinflammation mediated by activation of astrocytes in the hippocampus of mice, and eventually achieve its effects in improving learning and memory impairment in mice. According to these findings, we anticipated that GJ-4 might be a potential therapeutic drug for Alzheimer's disease.

Humans ; Child ; Primary Myelofibrosis/genetics* ; Prognosis ; Mutation

ObjectiveTo compare and evaluate the improvement degree of spermatogenic dysfunction mice at different recovery periods after cyclophosphamide modeling. MethodsForty-eight male ICR mice aged 4-5 weeks with the body weight of approximately 18-20 g were randomly divided into three control groups and three model groups, with 8 mice in each group. Each mouse of three model groups was intraperitoneally injected with 60 mg/kg cyclophosphamide continuously from the 1^st to 7^th day of the experiment, while each mouse of three control groups was intraperitoneally injected with the corresponding volume of normal saline. Then these mice were continued to be fed for another 7, 14 and 21 days after cyclophosphamide injection, respectively. A corresponding control group was set for each model group. The mice in each group were sacrificed after blood collection through orbital veins at corresponding time points. Testis, epididymis and seminal vesicle were taken and weighed, and their reproductive organ indexes were calculated. Histopathological changes of testis and epididymis were compared after HE staining.Sperm quality analysis was used to determine sperm-related indexes. Serum reproductive hormone content, testicular oxidative stress level and testicular signature enzyme activity were detected by ELISA and related kits.Results Compared with the control group, on the 7^th, 14^th and 21^st day after cyclophosphamide treatment, the testicular index of mice in the model group decreased significantly (P<0.01). The epididymis index decreased significantly on the 7^th and 14^th day, and the seminal vesicle index decreased obviously on the 7^th and 21^st day (P<0.05). And the histopathological damage of testis and epididymis of the model group gradually alleviated over time. On the 7^th and 14^th day after cyclophosphamide treatment, the sperm count of the model group declined remarkably (P<0.01), the serum testosterone (T) level reduced (P<0.05), the malonaldehyde (MDA) content of testis increased significantly (P<0.01), the content of reduced glutathione (GSH) and superoxide dismutase (SOD) decreased obviously (P<0.05),the lactic dehydrogenase (LDH) activity of testis reduced obviously (P<0.05), the gamma-glutamyl transpeptidase (γ-GT) activity increased significantly (P<0.05), the latter two of which are important testicular signature enzymes. Therein on the 7^th day after cyclophosphamide treatment, the sperm motility decreased significantly (P<0.001), the rate of sperm malformation increased obviously (P<0.05), the serum levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) increased notably (P<0.01). Nevertheless on the 21^st day after cyclophosphamide treatment, the sperm-related indexes, the content of serum reproductive hormone, the level of testicular oxidative stress and the activity of testicular signature enzyme did not change significantly (P＞0.05). ConclusionThe reproductive toxicity in mice was more apparent on the 7^th day after intraperitoneal injection with 60 mg/kg cyclophosphamide for seven days, at which time the more desirable spermatogenic dysfunction model of mice could be established. However, with the prolongation of the recovery period, the indexes of spermatogenic dysfunction in mice gradually recovered and approached the normal level on the 21^st day after cyclophosphamide treatment.

OBJECTIVE：To investigate the clini cal features of thrombocytopenia induced by antidepressants ，and to provide reference for the rational use of clinical drugs. METHODS ：Retrieved from CNKI ，Wanfang database ，VIP，PubMed and Web of Science，during Jan. 1st in 1985 to Aug. 31st in 2020，case reports about antidepressants-induced thrombocytopenia was collected and analyzed descriptively in terms of demographic characteristics ，medication，clinical manifestations ，treatment and outcome. RESULTS：A total of 17 literatures were retrieved ，and 19 patients were included ，involving 10 male and 9 female，aged from 5 to 95 years old ，with an average of （48±24）years old. Nine kinds of drugs were involved ，including 4 cases of escitalopram ，3 cases of citalopram ，3 cases of fluoxetine ，3 cases of mirtazapine ，2 cases of amitriptyline ，1 case of sertraline ，1 case of paroxetine，1 case of mianserin and 1 case of imipramine. There were 9 cases of single drug and 10 cases of drug combination. All 19 patients suffered from thrombocytopenia at 3 d-10 years after medication ，14 of them had hemorrhage tendency. Main clinical manifestations included mucocutaneous hemorrhage ，gingival bleeding ，black stool ，hematochezia，vaginal bleeding ，ocular hemorrhage，alveolar hemorrhage. No bleeding was found in 5 cases. After drug withdrawal/changing drugs and other symptomatic treatment， platelet count of 19 patients recovered to normal ， and bleeding symptoms disappeared. CONCLUSIONS ： Thrombocytopenia caused by antidepressants has no obvious clinical features and is not easy to be found ，but it may lead to severe； bleeding symptoms if it is not found in time. The changes of platelet count should be closely monitored in clinical application of such drugs to ensure the safety of drug use.

Objective:To investigate the clinical effect of Jiedu Limai decoction in septic patients with syndrome of heat-toxin exuberance.Methods:A prospective randomized controlled trial was conducted. From March 2019 to April 2020, septic patients with syndrome of heat-toxin exuberance admitted to intensive care unit (ICU) of Shanghai General Hospital and Songjiang Branch of Shanghai General Hospital were enrolled as the research objects, and they were divided into routine treatment group and Jiedu Limai decoction group by the random number table method. Patients in both groups were given standard treatment in accordance with the guidelines, and patients in the Jiedu Limai decoction group were given Jiedu Limai decoction in addition to the standard treatment, once a day for 14 days. The 28-day survival of patients of the two groups were recorded, the acute physiology and chronic health evaluation Ⅱ (APACHEⅡ) score, sequential organ failure assessment (SOFA) score, coagulation indexes, infection indexes, inflammatory cytokines and organ function indicators before treatment and 7 days after treatment in both groups were recorded, and the prognosis of the two groups were recorded.Results:A total of 259 patients with infection or clinical diagnosis of infection admitted during the experimental observation period were included, and those who did not meet the Sepsis-3 diagnostic criteria, more than 80 years old or less than 18 years old, with multiple tumor metastases, autoimmune system diseases, with length of ICU stay less than 24 hours, with acute active gastrointestinal bleeding and with incomplete data were excluded. One hundred patients were finally enrolled, with 50 patients in the routine treatment group and 50 patients in the Jiedu Limai decoction group. There were no statistically significant differences in coagulation indexes, infection indicators, inflammatory cytokines and organ function indicators before treatment between the two groups. After 7 days of treatment, the coagulation indexes, infection biomarkers and inflammatory cytokines in the Jiedu Limai decoction group were significantly lower than those in the routine treatment group [D-dimer (mg/L): 2.2 (1.8, 8.5) vs. 4.0 (1.5, 8.7), fibrinogen (Fib, g/L): 3.7 (3.4, 4.3) vs. 4.2 (3.7, 4.3), fibrinogen degradation product (FDP, mg/L): 7.2 (5.4, 10.2) vs. 13.2 (9.2, 15.2), procalcitonin (PCT, μg/L): 0.4 (0.2, 2.9) vs. 0.5 (0.2, 0.9), C-reactive protein (CRP, mg/L): 50.1 (9.5, 116.0) vs. 75.1 (23.5, 115.2), interleukin-6 (IL-6, ng/L): 31.6 (21.6, 81.0) vs. 44.1 (14.0, 71.3), all P < 0.05], and the levels of B-type brain natriuretic peptide (BNP) and kidney injury molecule-1 (KIM-1) were significantly lowered [BNP (ng/L): 261.1 (87.5, 360.3) vs. 347.3 (128.8, 439.4), KIM-1 (μg/L): 0.86 (0.01, 1.40) vs. 1.24 (1.05, 1.57), both P < 0.05]. Compared with the routine treatment group, the number of new organ failure in the Jiedu Limai decoction group was decreased (30.0% vs. 50.0%, P < 0.05). Although there was no significant difference in 28-day mortality between the two groups ( P > 0.05), the 28-day mortality in the Jiedu Limai decoction group was lower than that in the routine treatment group (18.0% vs. 24.0%). Conclusion:Combining Jiedu Limai decoction to the sepsis guideline in treating syndrome of heat-toxin exuberance can effectively improve patients' coagulation function, the situation of heart and renal injury, reduce the level of inflammatory cytokines, and fewer people develop new organ failure after treatment.