Background/Aims: Ubiquitination is widely involved in the progression of hepatocellular carcinoma (HCC) by regulating various cellular processes. However, systematic strategies for screening core ubiquitin-related genes, clarifying their functions and mechanisms, and ultimately developing potential therapeutics for patients with HCC are still lacking. Methods: Cox and LASSO regression analyses were performed to construct a ubiquitin-related gene prediction model for HCC. Loss- and gain-of-function studies, transcriptomic and metabolomics analysis were used to explore the function and mechanism of UBE2S on HCC cell glycolysis and growth. Results: Based on 1,423 ubiquitin-related genes, a four-gene signature was successfully constructed to evaluate the prognosis of patients with HCC. UBE2S was identified in this signature with the potential to predict the survival of patients with HCC. E2F2 transcriptionally upregulated UBE2S expression by directly binding to its promoter. UBE2S positively regulated glycolysis in a HIF-1α-dependent manner, thus promoting the proliferation of HCC cells. Mechanistically, UBE2S enhanced K11-linkage polyubiquitination at lysine residues 171 and 196 of VHL independent of E3 ligase, thereby indirectly stabilizing HIF-1α protein levels by mediating the degradation of VHL by the proteasome. In particular, the combination of cephalomannine, a small molecule compound that inhibits the expression of UBE2S, and PX-478, an inhibitor of HIF-1α, significantly improved the anti-tumor efficacy. Conclusions UBE2S is identified as a key biomarker in HCC among the thousands of ubiquitin-related genes and promotes glycolysis by E3 enzyme-independent ubiquitination, thus serving as a therapeutic target for the treatment of HCC.

Schizophrenia is a serious mental disease. The diagnosis of schizophrenia so far relies heavily on subjective evidence, including self-reported experiences by patients, manifestations described by relatives, and abnormal behaviors assessed by psychiatrists. The diagnosis, monitoring of the disease progression and therapy efficacy assessment are challenging due to the lack of established laboratory biomarkers. Based on the current literature, clinical consensus, guidelines, and expert recommendations, this review highlighted evidence-based potential laboratory biomarkers for the diagnosis of schizophrenia, including genetic biomarkers, neurotransmitters, neurodevelopmental-related proteins, and intestinal flora, and discussed the potential future directions for the application of these biomarkers in this field, aiming to provide an objective basis for the use of these biomarkers in the early and accurate diagnosis, treatment, and prognosis and rehabilitation assessment of schizophrenia.

Humans ; COVID-19 ; Consensus ; SARS-CoV-2 ; China

Objective To explore whether Rho kinase inhibitor protects endotoxemia mice from kidney injury,and to investigate the mechanism underlying this effect. Methods Adult male C57BL/6 mice were randomly divided into three groups (n = 8 for each group): control,lipopolysaccharide (LPS),and LPS+ Y-27632 (Rho kinase inhibitor). For induction of acute kidney injury,mice were administered 30 mg/kg LPS intraperitoneally. Y-27632 (10 mg/kg body weight) was injected intraperitoneally 18 h and 1 h before injection of LPS,and an equal volume of sterile saline was administered at the corresponding time point in each group. The mice were killed 8 h after LPS administration. Blood samples and kidney tissues were taken and preserved for subsequent analysis. Results Pretreatment with Y-27632 significantly attenuated LPS-induced kidney injury;pretreatment with Y-27632 markedly reduced renal expression of inflammatory cytokines (TNF-α and IL-1β) in endotoxemia mouse,and also significantly inhibited LPS-induced caspase-3 expression in the kidney; and Y-27632 pretreatment dramatically reduced TLR4 protein expression and NF-κBp65 phosphorylation in kidney tissues of endotoxemia mouse. Conclusion Rho kinase inhibitor may inhibit TLR4 and NF-κB signaling pathway to reduce the inflammatory response in the kidneys of endotoxemia mice and alleviate acute renal injury induced by LPS.

Objective: To investigate the clinical effect and safety of Wanfeile in the treatment of erectile dysfunction (ED). METHODS: Totally 100 ED patients received oral Wanfeile at 100 mg, once every 3 days, for a course of 3 months. We compared the IIEF-5 scores of the patients before and after medication and among the patients with different degrees of ED. We evaluated the total clinical effectiveness of Wanfeile and analyzed adverse reactions. RESULTS: The total effectiveness rate of Wanfeile was 95.6%. All the patients showed significant improvement in the IIEF-5 scores after treatment as compared with the baseline (P <0.05). Adverse reactions were observed in 5 cases (5.50%), all mild and transient. CONCLUSIONS Wanfeile is safe and efficacious for the treatment of ED.
Double-Blind Method ; Drug Administration Schedule ; Erectile Dysfunction ; drug therapy ; Humans ; Male ; Phosphodiesterase 5 Inhibitors ; administration & dosage ; adverse effects ; Sildenafil Citrate ; administration & dosage ; adverse effects ; Surveys and Questionnaires ; Treatment Outcome

Objective To investigate the content of intestinal fatty acid binding protein (IFABP) and its clinical significance in patients with severe sepsis.Methods A prospective observational study was conducted.Fifty patients with severe sepsis admitted to intensive care unit (ICU) of the First Affiliated Hospital of China Medical University from July to December 2012 were enrolled,and 20 healthy patients served as control group.The concentrations of serum IFABP,interleukin-6 (IL-6),and tumor necrosis factor-α (TNF-α) were determined with enzyme-linked immunosorbent assay (ELISA) on days 0,1 and 3 after ICU admission.Acute physiology and chronic health evaluation Ⅱ (APACHE Ⅱ) and sequential organ failure assessment (SOFA) score,28-day prognosis,acute gastrointestinal injury (AGI) grade were recorded at the same time.Furthermore,the contents of IFABP were compared between control group and the severe sepsis group,abdominal infection group and non-abdominal infection group,the survival group and the death group,as well as among different AGI-grade groups.Correlation analysis of IFABP and inflammatory factors,IFABP and two scores,and IFABP and time of stay in ICU and mechanical ventilation were studied.Multivariate logistic regression and analysis of 28-day outcome of the patients were also studied.Results IFABP levels were increased in severe sepsis patients on days 0,1 and 3 compared with those of healthy control group (mg/L:731.90 ±53.91,592.07 ±41.94,511.85 ±47.97 vs.439.88 ±23.68,all P =0.000).There was no statistical significance of IFABP levels between abdominal infection group and non-abdominal infection group,the survival group and the death group,or among different AGI-grade groups.The correlation analysis showed that IFABP was statistically related with IL-6 (r=0.794,P=0.000),TNF-α (r=0.878,P=0.010),APACHE Ⅱ score (r=0.428,P=0.000) in patients with severe sepsis.Significant correlations were also found between IFABP and IL-6 (r=0.812,P=0.000),TNF-α (r=0.885,P=0.000) in abdominal infection group,as well as in non-abdominal infection group (IL-6:r=0.739,P=0.000; TNF-α:r=0.828,P=0.000).As shown by multivariate logistic regression analysis,SOFA scores on days 0,1,3 were the independent risk factors for death [odds ratio (OR) was 1.624 (P=0.004),1.411 (P=0.027),1.740 (P=0.012),respectively],but IFABP level,AGI grade,and APACHE Ⅱ score had no influence on death rate.Conclusion IFABP concentrations in patients with severe sepsis were significantly increased,and it is correlated well to IL-6,TNF-α and APACHE Ⅱ score,but did not related obviously with AGI grade and the prognosis of the patients.

Objective To explore the role of MAPK and NF-?B in the increase of Toll-like receptor 4(TLR4) expression induced by lipopolysaccharide(LPS) in pulmonary micro-vascular endothelial cells(PMVECs) of mouse.Methods PMVECs were isolated,cultured and exposed to the different concentration LPS at(2 h),and(100 ?g/L) LPS in different time.The concentration of TNF-? in culture supernatant was detected using ELISA.(Using) PD98059 inhibitor for ERK,SB203580 inhibitor for P38 MAPK and PDTC inhibitor for NF-?B pretreated(PMVECs).RT-PCR was used to detect the levels of TLR4 and TNF-? mRNA.Western-blot was used to detect the protein expression of nuclear factor-kappa B(NF-?B) P65 subunit and ERK / P38 MAPK in nuclear extract after LPS exposure for 6 h respectively.Results With the treatment of 50～(500 ng /mL) LPS for(2 h) or(100 ?g /L)(LPS exposure) in different time,the concentration of TNF-?in culture supernatant of PMVECs was increased by a time and dosage dependent style(P

BACKGROUND:Lung injury can be induced after injection of lipopolysaccharide(LPS) into the vein of aging rats,and with the development of lung injury,the kidney function can be influenced.Ginkgo biloba extract(GBE) has some effects such as clearing the free radicals,improving hemorrheology,protecting the vascular endothelial cells and so on. OBJECTIVE:To investigate whether renal function damage is induced by acute lung injury(ALI) in aging rats so as to support the hypothesis that lung is the start-up organ in multiple organ dysfunction syndrome in the elderly and the protective effect of GBE on it. DESIGN:Randomized controlled experimental trial based on the experimental animals. SETTING:Laboratory of Department of Pathophysiology,Institute of Basic Medical Science,Peking Union Medical College. MATERIALS:The study has been completed from May 2001 to January 2003 in the Laboratory of Department of Pathophysiology,Institute of Basic Medical Science,Peking Union Medical College.Thirty-six Wistar male rats were involved. INTERVENTIONS:For reproducing the mimic aging rats models,the rats were injected intraperitoneally,D-gal 50 mg/kg,once a day,for 6weeks totally,and randomly divided into 3 groups, namely: ①control group(saline ,intravenous injection);② LPS group( LPS,5 mg/kg intravenous injection) ③ GBE+LPS group (GBE was used 7 days prior to LPS,31 mg/kg ,once a day).Samples(blood,lung and kidney tissue) were collected at 2 or 6 hours after LPS or saline administration. MAIN OUTCOME MEASURES:Contents of creatinine(Cr),blood urea nitrogen (BUN),lactic acid (LA),NO (its metabolite is NO2-/NO3-) and methane dicarboxylic aldehyde(MDA);and activities of glutathione peroxi-dase(GSH-Px) and Na+-K+-ATPase were measured. RESULTS:Compared with control group,there was obviously ALI at 2or 6 hours after LPS administration.Cr [(94.7±10.3) μmol/L]and BUN [(l1.4 1.9)mmol/L]contents in blood were increased significantly until 6 hours after LPS administration.In LPS group,MDA[(22.5 2.6) nmol/L]and NO2-/NO3-[(25.8 2.9) μmol/g] contents in blood and in lung tissue were all increased significantly at 2 hours.But GSH-PX [(355.145.0)μkat/g],Na+-K+-ATPase [(886.3 97.2) nkat/g] activities in lung tissue were decreased significantly at 2 hours after LPS administration.The above changes lasted for 6 hours.However,significant change did not occur until 6 hours after LPS administration in renal tissue.All the above changes were markedly attenuated by pretreatment of GBE. CONCLUSION:ALI was caused by LPS intravenous injection in aging rats.Renal function damage could be induced by ALI in aging rats.GBE showed a protective effect on ALI and renal function damage in this animal model.

ObjectiveTo investigate the effect of α-Zearalanol(α-ZAL) on lipometabolism and hemorheology in ovariectomized(OVX) hyperlipidemia rabbits.Methods44 adult virgin female rabbits were divided into 5 groups,group A: normal control;group B: sham+CHO;group C: OVX+CHO;group D: OVX+CHO+17βE_2;group E: OVX+CHO+α-ZAL.Cholesterol(CHO) was fed to rabbits for 12 weeks.Before and after feeding CHO,the serum lipid(TC,TG,LDL-C,HDL-C) were measured;Blood viscosity,plasma viscosity,aggregation index of RBC(AIRC) and fibrinogen were also assayed respectively.ResultsThe serum levels of TC,TG and LDL-C in group B and E were significantly decreased compared with those in group C(P<0.05);the level of blood viscosity,plasma viscosity and AIRC platelet aggregation rate in group D and E were also significantly decreased compared with those in group C(P<0.05).Conclusionα-ZAL can improve vascular function through the adjustment of lipometabolism and hemorheology.

ObjectiveTo investigate the effect of Jiuqiang Naoliqing(JNQ)-containing serum on secretion of nitric oxide(NO) and endothelin-1(ET-1) in human umbilical vein endothelial cells(HUVECs), in order to explore the effect of JNQ on regulation of vascular active factors in HUVECs.MethodsThe HUVECs were explored to different volume fractions of JNQ containing serum after being isolated and cultured. The levels of cultured medium of NO and ET-1 were measured.ResultsThe cultured medium content of NO and ET-1 in different volume fractions of JNQ containing serum was significantly increased compared with normal serum control (P<0.05), while the ratio of NO to ET-1 were increased in comparison with normal control (P<0.05).Conclusion JNQ can be promoted secretion of NO and ET-1 in HUVECs, preserving endothelial function, and maintaining the balance of NO/E-1.