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

The relationship between hyperuricemia (HUA) and erectile dysfunction (ED) remains inadequately understood. Given that HUA is often associated with various metabolic disorders, this study aims to explore the multivariate linear impacts of metabolic parameters on erectile function in ED patients with HUA. A cross-sectional analysis was conducted involving 514 ED patients with HUA in the Department of Andrology, Jiangsu Province Hospital of Chinese Medicine (Nanjing, China), aged 18 to 60 years. General demographic information, medical history, and laboratory results were collected to assess metabolic disturbances. Sexual function was evaluated using the 5-item version of the International Index of Erectile Function (IIEF-5) questionnaire. Based on univariate analysis, variables associated with IIEF-5 scores were identified, and the correlations between them were evaluated. The effects of these variables on IIEF-5 scores were further explored by multiple linear regression models. Fasting plasma glucose ( β = -0.628, P < 0.001), uric acid ( β = -0.552, P < 0.001), triglycerides ( β = -0.088, P = 0.047), low-density lipoprotein cholesterol ( β = -0.164, P = 0.027), glycated hemoglobin (HbA1c; β = -0.562, P = 0.012), and smoking history ( β = -0.074, P = 0.037) exhibited significant negative impacts on erectile function. The coefficient of determination ( R ²) for the model was 0.239, and the adjusted R ² was 0.230, indicating overall statistical significance ( F -statistic = 26.52, P < 0.001). Metabolic parameters play a crucial role in the development of ED. Maintaining normal metabolic indices may aid in the prevention and improvement of erectile function in ED patients with HUA.
Humans ; Male ; Erectile Dysfunction/metabolism* ; Hyperuricemia/metabolism* ; Adult ; Middle Aged ; Cross-Sectional Studies ; Glycated Hemoglobin/metabolism* ; Blood Glucose/metabolism* ; Uric Acid/blood* ; Young Adult ; Triglycerides/blood* ; Adolescent ; Cholesterol, LDL/blood* ; Penile Erection/physiology* ; Surveys and Questionnaires

Objective To identify lipid metabolism genes in cerebral infarction;To explore the intervention effect of Huoxue Rongluo Prescription.Methods Multi-chip combined differential analysis(GSE61616,GSE30655)was used to identify lipid metabolism genes in cerebral infarction in combination with Reactome database,and the expression differences of lipid metabolism genes in cerebral infarction were identified and verified in GSE97537 chip;Pearson correlation analysis was used to analyze the correlation of 51 cerebral infarction samples in GSE61616,GSE30655,GSE97537,GSE137595,GSE22255,GSE163614,and GSE78731 datasets;PPI,GO and KEGG analysis of lipid metabolism genes in cerebral infarction were performed through STRING database and R clusterProfiler package.SD rats were made to the model of cerebral infarction,and was administered with Huoxue Rongluo Prescription extract 11.7 g/kg by intragastric administration for 7 days.The symptoms of neurological deficit,the changes of Nissl bodies and the mRNA expressions of PLA2G4A,SPHK1,and PTGES key genes in lipid metabolism in cerebral infarction were observed.Results TSPO,CYP1B1,PLIN2,CH25H,PLA2G4A,ANGPTL4,PTGS1,SPHK1,and PTGES were identified as lipid metabolism genes in cerebral infarction,and were significantly highly expressed and positively correlated in cerebral infarction.Among them,PTGS1,PLA2G4A,and SPHK1 interacted with each other,which were the key genes of lipid metabolism in cerebral infarction;the lipid metabolism gene in cerebral infarction mainly exerted molecular functions such as oxidoreductase activity,iron ion binding,heme binding,etc.,mediating arachidonic acid metabolism,phospholipase D signaling pathway,VEGF signaling pathway,involved in regulation of lipid metabolism process,fatty acid metabolism process,fatty acid derivative metabolism process.The symptoms of neurological deficit in the model rats with cerebral infarction were severe(P<0.001),and Huoxue Rongluo Prescription could effectively improve the neurological deficit of model rats(P<0.001).The Nissl staining indicated that the neuronal structure was abnormal and the number was significantly reduced after cerebral infarction(P<0.001).Huoxue Rongluo Prescription could increase the number of neurons(P<0.001)and repair the neuronal structure.RT-qPCR showed that the key genes of lipid metabolism in cerebral infarction were significantly higher in cerebral infarction(P<0.001),corroborated with the bioinformatics results,and Huoxue Rongluo Prescription could reduce the expression of key lipid metabolism genes of PTGS1,PLA2G4A,and SPHK1(P<0.001,P<0.01,P<0.05).Conclusion Huoxue Rongluo Prescription can down-regulate the expressions of PTGS1,PLA2G4A,SPHK1,exert molecular functions such as oxidoreductase activity,iron ion binding,heme binding,and mediate arachidonic acid metabolism,phospholipase D signaling pathway,and VEGF signaling pathway.It participates in the process of lipid metabolism regulation,fatty acid metabolism,and fatty acid derivative metabolism,increases the number of Nissl bodies,improves the symptoms of neurological deficits,and exerts neuroprotective effects.

The essence-qi-spirit theory is an important part of traditional Chinese medicine， whose steady state is the material and functional basis for the balance of yin and yang in the body， making the essence， qi and spirit integrated， and body and spirit harmonized. Based on this theory， it is proposed that essence and qi depletion， spirit dissipation and qi dispersion， disharmony between yin and yang is the main pathogenesis of sleep disorders. Therefore， the method of regulating and harmonzing yin and yang by essence gathering， qi nourishing and spirit storing can be used to treat sleep disorder. The biological clock system of the circadian rhythm of sleep is regulated by the molecular oscillation that is generated by the transcription of the biological clock gene， and is a clock gradually formed by orga-nisms constantly adapting to the laws of nature. As the material basis， power， and embodiment of sound and peaceful sleep， essence， qi and spirit can perceive and transmit natural signals， whose functions are similar to what is recognized by modern science that oscillation amplifies the rhythm signal， and synchronously regulates the expression signal of the biological clock gene， thereby forming a biological clock system with “input-oscillation-output” as the feedback cycle. It is believed that the regulation method of yin and yang by essence gathering， qi nourishing and spirit storing may comprehensively regulate the physiological activities through brain/ muscle aryl hydrocarbon receptor nuclear translocator-like protein 1 （BMAL1）/circadian locomotor output cycles kaput （CLOCK）-period protein （PER）/ cryptochrome （CRY） transcriptional feedback loop， thereby adapting to the natural environment changes， playing an active role in the treatment of sleep disorders， and provideing a new idea for traditional Chinese medicine to reshape the molecular regulation system of the endogenous biological clock to prevent and treat sleep disorders.

Objective:To investigate the correlation of preoperative peripheral lymphocyte-to-monocyte ratio(LMR)with the biochemical relapse and prognosis in prostate cancer(PCa)patients treated with endocrine therapy after radical prostatectomy(RP).Methods:Clinical data of 306 prostate cancer patients treated with endocrine therapy after radical prostatectomy were retrospectively analyzed in our hospital from June 2008 to June 2019.The end point of observation was biochemical relapse-free survival(RFS)in all patients receiving RP.The best cutoff value of preoperative LMR was calculated by receiver operating characteristic(ROC)curve.All patients were divided into the high LMR group(LMR≥2.8, n=93, 30.4%)and the low LMR group(LMR<2.8, n=213, 69.6%). The differences in clinical indicators of PCa were compared between high and low LMR groups.CoX regression model on the risk ratio of single and multiple factors were used to analyze the survival effect of preoperative LMR on the prognosis of PCa patients undergoing endocrine therapy after operation.Results:The median follow-up time was ranged from 4 to 132 months.The area under the ROC curve of LMR was 0.582(95% CI: 0.511-0.652, P<0.05), and the cutoff value of the preoperative LMR was 2.8, which was significantly associated with clinical T stage( P=0.023)and lymphatic metastasis( P=0.031). Kaplan-Meier analysis demonstrated that the low LMR group had a short RFS and a poor prognosis(31.0 months vs.38.5 months)than those in the high LMR group( P<0.05). Lymphatic metastasis and preoperative LMR were independent predictors for RFS in PCa patients treated with endocrine therapy after radical prostatectomy. Conclusions:Preoperative peripheral LMR can be used as an auxiliary indicator of the prognosis in PCa patients treated with endocrine therapy after radical prostatectomy.

Objective:To evaluate the prognostic value of preoperative red cell distribution width to platelet ratio on prostate cancer patients treated with endocrine therapy after radical prostatectomy.Methods:The clinical data of 349 prostate cancer patients treated with endocrine therapy after radical prostatectomy in our hospital from October 2007 to October 2018 were retrospectively analyzed.Among all the patients, the average age was 67 years old(ranged 42 to 84 years). The preoperative newly diagnosed PSA level was 4.2-499.2 ng/ml(average 30.6 ng/ml). 158 cases had a Gleason score of more than 8. 191 cases had a Gleason score of below than 8. According to tumorous staging, 151 patients were staged less than or equal to stage T 2b, 110 patients were staged as stage T 2c, 88 patients were staged equal or greater than stage T 3a. 295 patients were staged less than 1.15 ng/(ml·cm 3)of prostate specific antigen density, 54 patients were staged equal or greater than 1.15 ng/(ml·cm 3). There were 86 cases of seminal vesicle invasion and 263 cases of non-seminal vesicle invasion. There were 121 patients with low risk of prostate cancer, 83 patients with medium risk, and 145 patients with high risk. All patients received endocrine therapy after radical prostatectomy with androgen deprivation therapy (ADT). End point of observation was biochemical recurrence-free survival (RFS) with PCa patients treated with endocrine therapy after radical prostatectomy. Patients were categorized in two groups with high RPR and low RPR values using a cut-off point as calculated by the receiver-operating curve analysis.Correlations between RPR and clinical characteristics were analyzed.The prognostic analysis of preoperative RPR on prostate cancer patients treated with endocrine therapy after radical prostatectomy was estimated using Kaplan-Meier analysis and Cox proportional hazards models. Kaplan-Meier method was used to draw the survival curve. Meanwhile, univariate and multivariate Cox regression were used to explore factors influencing the prognosis of PCa patients. Results:of the 349 cases, ranging 4-132 months. Biochemical recurrence with PCa patients occurred in 93 cases, and 256 patients were not biochemical recurrence.The ideal cutoff value of preoperative RPR was 0.27(95% CI 0.502-0.653, P<0.05)determined by the ROC curve, by which the 349 patients was divided into the high RPR group of 66 patients(18.9 %) and the low RPR group of 283 patients(81.1 %). Preoperative RPR was significantly associated with Gleason score ( P=0.005), newly diagnosed tPSA value ( P=0.000), tumor T stage ( P=0.031), PCa risk scale ( P=0.037), positive margin ( P=0.030). The RFS in the high RPR group(26.0 months)was shorter than that in the low RPR group(35.0 months)( P<0.001). In univariate analysis, Gleason score ( HR=1.579, 95% CI 1.049-2.376, P=0.028), serum newly diagnosed tPSA ( HR=2.979, 95% CI 1.655-5.362, P=0.000), tumor T stage( HR=1.292, 95% CI 1.009-1.653, P=0.042), preoperative RPR value ( HR=3.555, 95% CI 2.339-5.401, P=0.000) were prognostic factors ( P<0.05). Cox multivariate analysis showed that higher newly diagnosed tPSA value( HR=1.917, 95% CI 1.033-3.558, P=0.039)and higher RPR value( HR=3.086, 95% CI 1.994-4.775, P=0.000) were independent predictors for endocrine therapy after radical prostatectomy of PCa( P<0.05). Conclusions:Preoperative RPR was an independent predictor for poor prognosis in PCa patients treated with endocrine therapy after radical prostatectomy.

Objective To investigate the consistency in 18F-deoxyglucose positron emission tomography (18F-FDG PET-CT) examination and histopathological analyses in the diagnoses of resectable lung tumors. Methods Retrospective reviews over the clinical data of lung tumor patients by preoperative PET-CT diagnosis and postoperative histopathological diagnosis were conducted to investigate the effects of the two diagnostic methods in terms of lung tumor properties , mediastinal lymph node metastasis , and pulmonary hilar lymph node metastasis. Results The diagnoses by preoperative PET-CT was consistent in differentiation of non-malignancy and malignancy of pathologic lung tumors by 87.3%, at a medium level (κ = 0.401, P < 0.001). McNemar test showed P = 0.508, indicating the two diagnostic methods were insignificantly different in the diagnosis of pulmonary tumors. The preoperative PET-CT was consistent in the diagnosis of the metastasis of pathologic mediastinal lymph node by 85.9%, at a medium level (κ = 0.697, P < 0.001). McNemar test showed P =0.754, indicating no significant difference between the diagnostic methods. The preoperative PET-CT was consistent with postoperative pathological examinations in the differentiations of the metastasis of pulmonary and hilar lymph node by 77.4%, at a medium level (κ=0.523, P < 0.001). McNemar test showed P = 0.454, indicating the two diagnostic methods were no significantly different. Conclusion Preoperative PET-CT and histopathologic examinations may be consistent in lung tumor diagnosis , which provides a basis for a certain significance in the surgical options.

Objective:To investigate the role of sterol regulatory element binding protein-1 (SREBP1) in atorvastatin-induced reduction of nucleotide-binding oligomerization domain-like receptor protein 1 ( NLRP1 ) inflammasome expression. Methods:THP-1 cells were treated with phorbol 12-myristate 13-acetate (160 nmol/L) for 12 h to be differentiated into macrophages. The medium was then replaced with serum-free medium containing lipopolysaccharide and ( or ) atorvastatin. The mRNA expression of NLRP1 and SREBP1 were detected by Real-time PCR. The protein expression of NLRP1 and SREBP1 were determined by Western blot. Furthermore, we observed the effect of SREBP1 siRNA on atorvastatin-induced reduction of NLRP1 expression. Results:Atorvastatin inhibited the mRNA and protein expression of NLRP1 and SREBP1 in the THP-1 macrophages. SREBP1 siRNA showed no significant difference on lowering NLRP1 expression when compared with atorvastatin. Treating cells with SREBP1 siRNA and atorvastatin at the same time resulted in more obvious reduction of NLRP1 expression than single use of SREBP1 siRNA or atorvastatin. Conclusion:Atorvastatin might exert anti-inflammatory effect by repressing NLRP1 expression through the SREBP1 path-way.