BACKGROUND: Epoxyeicosatrienoic acids (EETs), which are metabolites of arachidonic acid catalyzed by cytochrome P450 epoxygenase, are degraded into inactive dihydroxyeicosatrienoic acids by soluble epoxide hydrolase (sEH). Many studies have revealed that sEH gene deletion exerts protective effects against diabetes. Vascular calcification is a common complication of diabetes, but the potential effects of sEH on diabetic vascular calcification are still unknown. METHODS: The level of aortic calcification in wild-type and Ephx2-/- C57BL/6 diabetic mice induced with streptozotocin was evaluated by measuring the aortic calcium content through alizarin red staining, immunohistochemistry staining, and immunofluorescence staining. Mouse vascular smooth muscle cell lines (MOVAS cells) treated with β-glycerol phosphate (0.01 mol/L) plus advanced glycation end products (50 mg/L) were used to investigate the effects of sEH inhibitors or sEH knockdown and EETs on the calcification of vascular smooth muscle cells, which was detected by Western blotting, alizarin red staining, and Von Kossa staining. RESULTS: sEH gene deletion significantly inhibited diabetic vascular calcification by increasing levels of EETs in the aortas of mice. EETs (especially 11,12-EET and 14,15-EET) efficiently prevented the osteogenic transdifferentiation of MOVAS cells by decreasing nidogen-2 (NID2) expression. Interestingly, suppressing sEH activity by small interfering ribonucleic acid or specific inhibitors did not block osteogenic transdifferentiation of MOVAS cells induced by β-glycerol phosphate and advanced glycation end products. NID2 overexpression significantly abolished the inhibitory effect of sEH gene deletion on diabetic vascular calcification. Moreover, NID2 overexpression mediated by adeno-associated virus 9 vectors markedly increased insulin-like growth factor 2 (IGF2) and phospho-ERK1/2 expression in MOVAS cells. Overall, sEH gene knockout inhibited diabetic vascular calcification by decreasing aortic NID2 expression and, then, inactivating the downstream IGF2-ERK1/2 signaling pathway. CONCLUSIONS sEH gene deletion markedly inhibited diabetic vascular calcification through repressed osteogenic transdifferentiation of vascular smooth muscle cells mediated by increased aortic EET levels, which was associated with decreased NID2 expression and inactivation of the downstream IGF2-ERK1/2 signaling pathway.
Animals ; Mice ; Vascular Calcification/metabolism* ; Mice, Inbred C57BL ; Epoxide Hydrolases/metabolism* ; Diabetes Mellitus, Experimental/genetics* ; Male ; Gene Deletion ; MAP Kinase Signaling System/genetics* ; Cell Line ; Immunohistochemistry ; Muscle, Smooth, Vascular/metabolism* ; Signal Transduction/genetics* ; Mice, Knockout

Alzheimer's disease (AD) is the major form of dementia in the elderly and is closely related to the toxic effects of microglia sustained activation. In AD, sustained microglial activation triggers impaired synaptic pruning, neuroinflammation, neurotoxicity, and cognitive deficits. Accumulating evidence has demonstrated that aberrant expression of deubiquitinating enzymes is associated with regulating microglia function. Here, we use RNA sequencing to identify a deubiquitinase YOD1 as a regulator of microglial function and AD pathology. Further study showed that YOD1 knockout significantly improved the migration, phagocytosis, and inflammatory response of microglia, thereby improving the cognitive impairment of AD model mice. Through LC-MS/MS analysis combined with Co-IP, we found that Myosin heavy chain 9 (MYH9), a key regulator maintaining microglia homeostasis, is an interacting protein of YOD1. Mechanistically, YOD1 binds to MYH9 and maintains its stability by removing the K48 ubiquitin chain from MYH9, thereby mediating the microglia polarization signaling pathway to mediate microglia homeostasis. Taken together, our study reveals a specific role of microglial YOD1 in mediating microglia homeostasis and AD pathology, which provides a potential strategy for targeting microglia to treat AD.

Sigma-1 receptor (σ ₁R) has become a focus point of drug discovery for central nervous system (CNS) diseases. A series of novel 1-phenylethan-1-one O-(2-aminoethyl) oxime derivatives were synthesized. In vitro biological evaluation led to the identification of 1a, 14a, 15d and 16d as the most high-affinity (K _i < 4 nmol/L) and selective σ ₁R agonists. Among these, 15d, the most metabolically stable derivative exhibited high selectivity for σ ₁R in relation to σ ₂R and 52 other human targets. In addition to low CYP450 inhibition and induction, 15d also exhibited high brain permeability and excellent oral bioavailability. Importantly, 15d demonstrated effective antipsychotic potency, particularly for alleviating negative symptoms and improving cognitive impairment in experimental animal models, both of which are major challenges for schizophrenia treatment. Moreover, 15d produced no significant extrapyramidal symptoms, exhibiting superior pharmacological profiles in relation to current antipsychotic drugs. Mechanistically, 15d inhibited GSK3β and enhanced prefrontal BDNF expression and excitatory synaptic transmission in pyramidal neurons. Collectively, these in vivo proof-of-concept findings provide substantial experimental evidence to demonstrate that modulating σ ₁R represents a potential new therapeutic approach for schizophrenia. The novel chemical entity along with its favorable drug-like and pharmacological profile of 15d renders it a promising candidate for treating schizophrenia.

This article mainly elaborated the acupuncture and moxibustion treatment scheme of"eighteen needles for reproduction"based on Professor You Zhaoling's reproductive axis theory of"heart-kidney-Chong Ren-uterus".The"eighteen needles for reproduction"aims to regulate the disordered reproductive axis in gynecological reproductive diseases.It selects the acupoints on the main viscera and meridians of the reproductive axis as the main acupoints,and the acupoints regulating the qi and blood of the related viscera as the matching acupoints.Through specific manipulation,it can regulate the qi and blood,dredge the meridians,and treat the viscera,so as to nourish the essence and help pregnancy,and provide ideas and reference for the treatment of gynecological reproductive diseases with acupuncture and moxibustion.

Objective:To construct a model for predicting early recurrence of hepatocellular carcinoma (HCC) patients after radiofrequency ablation by different machine learning models based on multimodal MRI and clinical indicators, and to evaluate the predictive efficacy of the model.Methods:The data of patients with HCC who underwent radiofrequency ablation in Fourth Medical Center of Chinese PLA General Hospital and the First Medical Center of Chinese PLA General Hospital from January 2015 to December 2021 were retrospectively analyzed. A total of 169 patients with HCC were enrolled, including 152 males and 17 females, aged (57.2±9.2) years. The training set ( n=135) and the test set ( n=34) were randomly divided according to 8∶2. There were 49 cases recurrence in training set and 12 cases recurrence in test set. Based on the training set, the clinical influencing factors of early recurrence in patients with HCC after radiofrequency ablation were screened by univariated and multivariate logistic analysis, and the imaging features were sequentially screened by variance threshold method, select K-best and LASSO regression. Support vector machine (SVM), logistic regression and random forest (RFOREST) were used to construct the prediction models of early postoperative recurrence with simple imagomics alone or combined clinical features, respectively, and the receiver operating characteristic (ROC) curve was used to evaluate the prediction efficiency of the models. Results:Multivariate logistic regression analysis showed that preoperative alpha-fetoprotein >20 μg/L, platelet count >140×10 9 and tumor location were the influential factors for early recurrence of HCC patients after radiofrequency ablation (all P<0.05). Through variance threshold analysis, select K-best and LASSO regression, 16 optimal image omics features were selected. SVM, logistic regression and RFOREST were used to construct a simple imaging omics model for predicting early recurrence of HCC patients after radiofrequency ablation. The areas under ROC curve of the test set were 0.826, 0.830 and 0.826, respectively. And the areas under ROC curve of the constructed imagomics combined clinical model of test set were 0.830, 0.830 and 0.909, respectively. The area under ROC curve of RFOREST in the test set was better than that of SVM and logistic regression ( Z=2.19, 3.98, P=0.008, 0.008). Conclusion:The combined model constructed by SVM, logistic regression and RFOREST based on clinical indicators and image omics features is effective in predicting the early recurrence of patients with HCC after radiofrequency ablation, and the model constructed by RFOREST is the best.

Objective:To compare the clinical outcomes of endovascular therapy in acute stroke patients with anterior circulation tandem occlusions caused by atherosclerosis or dissection.Methods:A retrospective cohort study. A total of 98 patients with anterior circulation tandem lesions undergoing endovascular therapy in the Wuhan NO.1 Hospital (March 2016 to March 2022) were analyzed. Median age was 64(55,71) years old, and 82.7% (81/98 cases) were males. According to the lesion etiology, the patients were divided into atherosclerosis and dissection groups. The differences in clinical outcomes between the two groups were investigated, including favorable 90-day functional outcome (modified Rankin Scale score of 0-2), successful reperfusion (modified Thrombolysis in Cerebrovascular Infarction score of 2b-3), symptomatic intracranial hemorrhage, stroke-associated pneumonia, 90-day all-cause mortality, and average hospitalization days. Logistic regression analysis was used to adjust for potential confounders affecting functional outcomes in both groups, and to determine odds ratios and 95% confidence intervals.Results:Seventy-one patients were grouped into the atherosclerotic cause and 27 into the dissection cause cohorts. The rate of favorable 90-day functional outcome was 43.7% (31/71 cases) in the atherosclerosis group versus 55.6% (15/27 cases) in the dissection group (adjusted odds ratio=1.339; 95% confidence interval, 0.374-4.798; P=0.654). No significant differences were found in other clinical outcomes between the two groups (all P>0.05). Conclusion:The clinical prognosis of patients with tandem lesions caused by atherosclerotic stenosis or artery dissection was similar after endovascular therapy. Future studies are still needed to verify our results.

Objective To investigate the regulatory effect of poria cocos on gastrointestinal motility in mice. Methods A total of 130 Kunming mice were randomly divided into negative control group, low-dose and high-dose groups of raw poria cocos powder, low-dose and high-dose groups of cooked poria cocos powder, low-dose and high-dose groups of poria cocos surrogate culture powder, low-dose, medium-dose and high-dose groups of poria cocos water extract, and low-dose, medium-dose and high-dose groups of poria cocos alcohol extract, with 10 mice in each group. The animals were administered by gavage for 7 days, once a day. After the last administration, the intestinal propulsion function test and gastric solid emptying test were conducted to observe the regulating effect of poria cocos on gastrointestinal motility of mice. Results Compared with the negative control group, the small intestine propulsion rate in the low-dose group of poria cocos surrogate culture powder was significantly increased (P<0.01). Except the high-dose group of raw poria cocos powder, the other poria cocos groups had higher gastric residual rate (P<0.05). Conclusion Poria cocos does not promote intestinal propulsion of mice under normal physiological condition, but it can inhibit gastric empting and exert a moderating effect on gastrointestinal function in normal mice.

Objective To investigate the efficacy and safety of tenofovir alafenamide fumarate(TAF)in the treatment of patients with decompensated hepatitis B cirrhosis.Methods We retrospective analyzed 41 patients with decompensated hepatitis B cirrhosis receiving TAF antiviral therapy for 24 weeks at Wuwei Tumor Hospital in Gansu province from June 2022 to June 2023.Primary endpoint was proportion of patients achieving virologic response(HBV DNA<20 IU/mL).Other endpoints included changes in ALT,AST,TBIL,Child-Pugh score(CTP),and MELD score from baseline to week 24.In terms of safety,changes in Scr,eGFR and adverse events from baseline to week 24 were observed.Results Of 41 patients,73.2%were male(n = 30),with mean age of 53.49 years.24 weeks after treatment with TAF,HBV DNA was undetectable in 90.2%of the patients.The median levels of ALT,AST and total bilirubin(TBIL)were 50.70 U/L,48.70 U/L and 26.40 μmol/L respectively at base-line,and reduced significantly to 31.50 U/L,37.8 U/L and 23.8 μmol/L(P<0.05)respectively after 24-week therapy with TAF.CTP score was improved in 58.6%of the patients(n = 24),and so was MELD score in 63.4%of the patients(n = 26)at week 24.The median serum creatinine and eGFR were 58.5 μmol/L and 106.15 mL/(min·1.73 m2)respectively at baseline,and creatinine and eGFR were stable during treatment.No drug-related adverse events or severe adverse events occurred during treatment,neither did creatinine and eGFR liver transplan-tation,HCC or death.Conclusions Our clinical studies demonstrated better effectiveness and safety of TAF for decompensated CHB patients.

Radiation-induced brain injury (RBI) is one of the complications after radiotherapy for head and neck malignant tumors, which seriously affects the quality of life of patients. The pathophysiological mechanism of RBI is not completely clear. Current studies suggest that it is involved in a variety of cells in the central nervous system (CNS), whereas astrocyte, as the largest number of glial cells in the CNS, plays an important role in maintaining the CNS homeostasis and responding to CNS injury. In this article, the role of astrocytes in RBI was reviewed.

Objective:To explore the effect of applying SHOW mode of mindfulness meditation training in the psychological intervention of patients with advanced lung cancer.Methods:From June 2020 to May 2021, a total of 130 patients with advanced lung cancer who were hospitalized in Taizhou Central Hospital were selected as the research objects by the convenient sampling method. According to the random number table method, patients were divided into the study group and the control group, with 65 cases in each group. The control group was given routine mindfulness meditation intervention, while the study group was given SHOW model mindfulness meditation training on the basis of the control group. The degree of anxiety and depression, psychological resilience and self-management efficacy of patients in the two groups were observed before and after intervention.Results:After intervention, scores of Hamilton Anxiety Scale (HAMA-14) and Hamilton Depression Scale (HAMD-17) in the two groups were lower than those before intervention and scores of HAMA-14 and HAMD-17 in the study group were lower than those in the control group, and the differences were statistically significant ( P<0.05) . The scores of Connor-Davidson Resilience Scale (CD-RISC) and Strategies Used by People to Promote Health-Chinese (C-SUPPH) in two groups were higher than those before intervention and the scores of CD-RISC and C-SUPPH in the study group were higher than those in the control group, and the differences were statistically significant ( P<0.05) . Conclusions:The SHOW model mindfulness meditation training has a good application effect in the psychological intervention of patients with advanced lung cancer, which can effectively improve the degree of anxiety and depression of patients and enhance their psychological resilience and self-management efficacy.