As one of the most difficult-to-cure neuropsychiatric disorders in clinical practice， schizophrenia is mainly manifested by behavioral abnormalities and multidimensional cognitive dysfunction， and the recurrence rate and disability rate of the disease are increasing year by year， which seriously affects patients' social functioning and quality of life， and even threatens the physical and mental health of the surrounding population. At present， the treatment of schizophrenia is mainly based on antipsychotic drugs combined with psychotherapeutic techniques， which have limited long-term therapeutic effects and a high relapse rate. Traditional Chinese medicine （TCM） boasts the advantages of multi-targets， multi-pathways， multi-links， and multi-levels， and plays a crucial role in the prevention and treatment of schizophrenia and its prognosis. Phosphatidylinositol 3-kinase （PI3K） is widely present in cells and is involved in the regulation of protein synthesis and apoptosis， and the different isoforms of protein kinase B （Akt） are of great significance in cell growth， oxidative stress， neuronal development and other processes. In recent years， a large number of studies have found that the PI3K/Akt signaling pathway is closely related to schizophrenia. Through regulating the PI3K/Akt signaling pathway， TCM monomers and TCM compounds mainly affect key signaling molecules such as mammalian target of rapamycin （mTOR）， glycogen synthase kinase （GSK）， glucose transporter （GLUT） for glucose uptake and transport， and nuclear factor E₂-associated factor 2 （Nrf2）， which organize the intracellular network of centers and regulate the formation and plasticity of neuronal synapse， and they play an important role in mitigating schizophrenia by regulating the processes of cell proliferation， migration and apoptosis of neurons， and has the advantages of multi-targets， all-encompassing and low toxicity. This article analyzes and explains the mechanism of TCM intervention in the PI3K/Akt signaling pathway against schizophrenia， in order to provide a theoretical basis and reference for the prevention and treatment of schizophrenia by TCM.

Schizophrenia has various obstacles in cognition， thinking， emotion， behavior and other aspects； it belongs to the category of “madness” in traditional Chinese medicine （TCM）. Once schizophrenia occurs， multiple factors are often intertwined， and a single therapy is difficult to be effective. At present， TCM compounds and active ingredients have significant effects in the clinical treatment of schizophrenia， which is an important direction for the development of new drugs for schizophrenia. This article summarizes the molecular mechanism of TCM compounds and active ingredients in the treatment of schizophrenia. It is found that Wendan decoction and Yudian decoction can inhibit the apoptosis of hippocampal cells by activating BDNF/TrKB/CREB signaling pathway； quercetin and icariin can promote neural development and regeneration by activating NMDA/ERK signaling pathway； Wendan decoction and icariin can maintain neural cell homeostasis by activating PI3K/AKT signaling pathway； Bushen zhuangyang capsule can enhance learning and memory abilities by activating CaMKⅡ signaling pathway； formulas such as Huatan huoxue tongzhi formula can enhance intercellular information transmission by inhibiting PKC signaling pathway； α-humulene and others can restore nerve cell function by inhibiting NRG1/ErbB4 signaling pathway. TCM compounds and active ingredients can improve schizophrenia by intervening in the above-mentioned signaling pathways.

【Objective】 To construct a nomogram survival prediction model for patients with locally advanced renal cell carcinoma based on SEER database (n=7893), so as to provide reference for future prognosis study. 【Methods】 Case data were downloaded from the SEER database, and divided into the experimental group and validation group with a ratio of 7∶3 by simple randomization.The clinical information was analyzed, independent risk factors influencing prognosis were screened, and the overall survival (OS) and tumor-specific survival (CSS) were mapped.Model performance was evaluated using consistency index, area under the receiver operating characteristic curve (AUC), internal and external validation, and calibration curves. 【Results】 Patients’ age, tumor size, disease progression tpye, TNM stage, number of positive lymph nodes, marital status and pathological type were significantly correlated with OS and CSS (P<0.01).Based on the above predictors, the internal verification AUC of the 1-, 3- and 5- year OS nomogram model was 0.809, 0.721 and 0.715, respectively.The internal validation AUC of the nomogram model for 1-, 3- and 5- year CSS was 0.802, 0.745 and 0.735, respectively.The external validation AUC of the OS nomogram model was 0.792, 0.628 and 0.620 at 1, 3 and 5 years, respectively, and the external validation AUC of CSS was 0.943, 0.803 and 0.737 at 1.3 and 5 years, respectively, showing good model differentiation and accuracy. 【Conclusion】 The prediction performance of the nomogram model is good, and it can provide reference for individualized treatment.

【Objective】 A two-sample Mendelian randomization method was used to explore whether there is a causal relationship between the intake of alcohol, coffee, green tea and dairy products and the incidence of prostate cancer (PCa), in order to clarify the risk factors for the incidence of PCa and find a prevention pathway for PCa. 【Methods】 Data of alcohol, coffee, green tea, dairy products and prostate cancer were collected with genome-wide association study (GWAS).The causal relationship between their intake and the risk of PCa was analyzed with two-sample Mendelian randomization (2SMR).MR analysis was conducted with inverse-variance weighting (IVW).Sensitivity analysis was performed with weighted median, MR-Egger regression, Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) tests. 【Results】 Coffee intake (OR: 0.994, 95%CI: 0.990-0.999, P=0.014) and green tea intake (OR: 0.999, 95%CI: 0.998-0.999, P=0.036) were negatively correlated with the risk of PCa.Alcohol intake (OR: 0.997, 95%CI: 0.990-1.004, P=0.392) and dairy intake (OR: 1.025, 95%CI: 0.983-1.069, P=0.256) were not associated with the risk of PCa.In weighted median, MR-Egger regression, and retention one method analyses, the results were robust without heterogeneity or pleiotropy. 【Conclusion】 There was a causal association between coffee intake and green tea intake and the onset of PCa, but no causal association between alcohol intake and dairy intake and PCa onset.

[Objective] To explore the causal relationship between the body mass index (BMI) and the risk of urinary tumors using two-sample Mendelian randomization. [Methods] BMI data in IEU public database genome association and date of kidney cancer, prostate cancer, prostate cancer, bladder cancer were screened and analy through the inverse variance weighting method, MR-Egger regression analysis, weighted median analysis of two-sample mondel randomization method to evaluate the causal relationship between constitution index and urinary tumor.Finally, a sensitivity analysis was used to assess the stability and reliability of the results. [Results] Genetically-predicted BMI is positively related to the risk of kidney cancer (OR: 1.442 5, 95%CI: 1.082 1-1.923 0, P=0.012 5), negatively related to the risk of prostate cancer (OR: 0.992 6, 95%CI: 0.988 7-0.996 5, P=0.000 2), and had no causal relationship with the risk of bladder cancer (OR: 1.000 3, 95%CI: 0.999 4-1.001 1, P=0.526 9). Sensitivity analysis and pleiotropy analyses showed that the results of this study were reliable and there was no heterogeneity. [Conclusion] Genetically-predicted BMI is a risk factor for renal cancer and a protective factor for prostate cancer.It is not associated with the risk of bladder cancer.This finding can provide reference for the potential risk of common urological tumors and the development of prevention strategies.

Objective:To investigate alterations in brain functional connectivity (FC) in schizophrenia (SZ) model rats treated with Yudian decoction by using functional magnetic resonance imaging (fMRI).Methods:At 17th day of gestation in healthy SPF grade SD rats, a single intraperitoneal injection of methylazoxymethanol (MAM) (25 mg/kg) was used to induce abnormalities in monoamine neurotransmitters in pregnant female rats, thereby to establish a model of neural development abnormalities in the offspring. Four weeks old male offspring were selected as SZ model rats.Thirty SZ model rats were divided into model group, experimental group, and positive control group according to the body mass matching method, with 10 rats in each group. Additionally, 10 male offspring born to healthy female rats were selected as the blank control group.At 6 weeks of age, the rats in experimental group and positive control group were administered with Yudian decoction (1.54 g/kg) and risperidone (0.24 mg/kg) by gavage, respectively. The rats in blank control group and positive control group were administered with distilled water (6.7 mL/kg) by gavage.All the above interventions were conducted once a day for 14 consecutive days.The fMRI data were acquired from all samples using a 3.0 T MRI scanner. The bilateral hippocampus, bilateral prefrontal cortex, and bilateral striatum were designated as region of interest (ROI). FC comparisons between each pair of ROIs and whole-brain FC were conducted using two-sample t-test. Results:(1) Compared to the control group, the model group demonstrated enhanced whole-brain FC at the left cerebellar granular cell level (SIGMA: x=-2, y=-107, z=48) (cluster size=43, P<0.05, FWE adjusted under cluster-level). The experimental group exhibited increased whole-brain FC at the left cerebellar molecular layer (SIGMA: x=-5, y=-152, z=36) compared to the model group (cluster size=48, P<0.05, FWE adjusted under cluster-level). (2) Using the bilateral hippocampus as ROI, the positive control group exhibited enhanced FC at the deep layer of the superior colliculus (SIGMA: x=13, y=-77, z=27) compared to the model group (cluster size=88, P<0.05, FWE adjusted under cluster-level). The blank control group displayed decreased FC at the right granular insular cortex (SIGMA: x=43, y=19, z=9) compared to the model group (cluster size=125, P<0.05, FWE adjusted under cluster-level). Utilizing the bilateral prefrontal cortex as ROI, the experimental group showed reduced FC at the left cerebellar molecular layer (SIGMA: x=-14, y=-128, z=48) compared to the blank control group (cluster size=68, P<0.05 FWE adjusted under cluster-level). Conclusion:Schizophrenia is associated with abnormal whole-brain functional connectivity, notably characterized by enhanced functional connectivity in the hippocampal region.Yudian decoction demonstrates the capability to inhibit activity in the prefrontal cortex.

Female ; Humans ; Muscular Dystrophy, Duchenne/genetics*

OBJECTIVE: To investigate the protective effects and its possible mechanism of Wuzi Yanzong Pill (WYP) on Parkinson's disease (PD) model mice. METHODS: Thirty-six C57BL/6 male mice were randomly assigned to 3 groups including normal, PD, and PD+WYP groups, 12 mice in each group. One week of intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was used to establish the classical PD model in mice. Meanwhile, mice in the PD+WYP group were administrated with 16 g/kg WYP, twice daily by gavage. After 14 days of administration, gait test, open field test and pole test were measured to evaluate the movement function. Tyrosine hydroxylase (TH) neurons in substantia nigra of midbrain and binding immunoglobulin heavy chain protein (GRP78) in striatum and cortex were observed by immunohistochemistry. The levels of TH, GRP78, p-PERK, p-eIF2α, ATF4, p-IRE1α, XBP1, ATF6, CHOP, ASK1, p-JNK, Caspase-12, -9 and -3 in brain were detected by Western blot. RESULTS: Compared with the PD group, WYP treatment ameliorated gait balance ability in PD mice (P<0.05). Similarly, WYP increased the total distance and average speed (P<0.05 or P<0.01), reduced rest time and pole time (P<0.05). Moreover, WYP significantly increased TH positive cells (P<0.01). Immunofluorescence showed WYP attenuated the levels of GRP78 in striatum and cortex. Meanwhile, WYP treatment significantly decreased the protein expressions of GRP78, p-PERK, p-eIF2α, ATF4, p-IRE1 α, XBP1, CHOP, Caspase-12 and Caspase-9 (P<0.05 or P<0.01). CONCLUSIONS WYP ameliorated motor symptoms and pathological lesion of PD mice, which may be related to the regulation of unfolded protein response-mediated signaling pathway and inhibiting the endoplasmic reticulum stress-mediated neuronal apoptosis pathway.

Aim To observe the effect of epimedium on the proliferation and stem cell-like character expression of breast cancer cells, and investigate the relationship between the inhibition of stem cell-like character and miR-148a by epimedium, and its molecular mechanism. Methods After treatment with different concentrations of epimedium, cell viability and population dependence were detected by MTT assay and colony formation assay; the breast cancer stem cell-derived mammosphere formation was examined by Mammosphere assay; the expression levels of CD44,ALDH-1, Oct4,BMIl and EpCAM were detected by qPCR; the protein expression levels of EpCAM, SOX4, ZO-1, E-cadherin and vimentin were detected by Western blot; the protein localization of EpCAM was observed by im-munofluorescence assay; the effect of epimedium on migration was detected by wound healing assay. The miR-148a mimic was transfected into MDA-MB-231 cells, and the effects of epimedium on stem-like character expression of transfected MDA-MB-231 cells were observed. Results Epimedium significantly inhibited the proliferation and population dependence of MDA-MB-231 cells (P < 0.05 ), and reduced the breast cancer stem cell-derived mammosphere formation; compared with control group, epimedium significantly decreased mRNA levels of CD44, ALDH-1, Oct4, BMI1 and EpCAM (P <0.05) ,decreased protein contents of EpCAM, SOX4 and Vimentin (P < 0.05 ), up-regulated the protein expression of ZO-1 and e-cadherin ( P <0.05) ,and decreased the migration ability of MDA-MB-231 cells (P < 0.05). Epimedium up-regulated the expression of miR-148a in MDA-MB-231 cells (P <0.01). YYH + miR-148a mimic group significantly inhibited stem-like character expression and EMT process of breast cancer MDA-MB-231 cells compared with control group (P <0.05). Conclusions Epimedium can inhibit the proliferation of MDA-MB-231 cells, which may be related to the up-regulation of miR-148a, decrease of stem-like character expression of breast cancer cells,and inhibition of EMT.

Objective To investigate the brain age differences between Alzheimer's disease(AD)and mild cognitive impairment(MCI)patients,and further explore the correlations between brain age gap(BAG)and clinical features.Methods The clinical data and radiologic findings of 132 probable AD and AD-derived MCI patients diagnosed at Beijing Tiantan Hospital,Capital Medical University from December 2018 to July 2021 were retrospectively analyzed.According to the diagnostic criteria for AD and MCI,the patients were assigned into AD and MCI groups.In addition,156 volunteers without neurological diseases and other severe diseases were recruited as the control group.The general data,Montreal cognitive assessment(MoCA)score,and mini-mental state examination(MMSE)score were compared among the three groups.The deep learning-based brain age prediction model was employed to calculate the BAGs of the three groups.Spearman correlation analysis was conducted to explore the correlations between BAG and clinical features.Results The 132 patients included 106 patients in the AD group and 26 patients in the MCI group.The MoCA and MMSE scores followed an ascending trend of AD groupP<0.001).The predicted brain age and BAG in the AD group were higher than those in the MCI group(P=0.040,P=0.003)and control group(P=0.001,P<0.001).There was no significant difference in predicted brain age or BAG between MCI and control groups(P=0.352,P=0.224).BAG was negatively correlated with MoCA score(r=-0.341,P<0.001)and MMSE score(r=-0.324,P=0.001)in the AD group.Conclusion BAG can be used as an imaging biomarker to evaluate the degree of brain structural variation and the severity of brain injury in the patients with cognitive impairment.
Humans ; Alzheimer Disease ; Retrospective Studies ; Cognitive Dysfunction ; Brain/diagnostic imaging*