Objective:To explore the alteration of brain‐derived neurotrophic factor (BDNF) signaling and the influ‐ence of irbesartan on it in hippocampus of angiotensin‐converting enzyme 2 (ACE2) knock‐out (KO) mice . Meth‐ods:The 10~11‐week ACE2 KO (Ace2/y ) mice received daily treatment with angiotensin II (Ang II) type 1 (AT1) receptor blocker irbesartan (50 mg/kg) or placebo for two weeks. The wild‐type mice (WT ,Ace2+ /y ) were regarded as normal control. Western blotting method was used to measure levels of BDNF and extracellular signal regulated kinase 1/2 (ERK1/2) in the mice hippocampus. Radioimmunoassay was used to measure plasma Ang level in mice . Results :Compared with normal WT control mice ,there were significant down‐regulations of BDNF protein expres‐sion [ (1 ± 0.16) vs .(0.54 ± 0.16)] in hippocampus and plasma Ang‐ (1‐7) level [ (55.6 ± 7.5) pg/ml vs .(42.8 ± 5.8) pg/ml] ,and significant rise in ERK1/2 phosphorylation [ (1 ± 0.28) vs .(1.79 ± 0.29)] in ACE2 KO mice (P<0.01 all). After irbesartan treatment ,there were significant rise in BDNF protein expression (0.88 ± 0.13) in hippocampus and plasma Ang‐ (1‐7) level [(59.4 ± 8.4) pg/ml] ,and significant reduction in ERK1/2 phosphoryla‐tion level (1.33 ± 0.19) in ACE2 KO mice (P<0.05 or <0.01) .Conclusion:There are BDNF protein expression down‐regulation and enhanced ERK1/2 phosphorylation in hippocampus of ACE2 KO mice. AT1 receptor blockade irbesartan can improve Ang‐ (1‐7 ) level and hippocampus BDNF expression , while reducing hippocampus ERK phosphorylation signal in ACE2 KO mice ,suggesting that AT1 receptor blockade possesses certain brain protective effect.

Objective To investigate the potential relationship between the paroxysmal Atrial Fibrillation(PAF) and serum uric acid level.Methods Consecutive patients with (patient group,n =65) and without(control group,n =41) PAF,who were hospitalized in the Second Hospital of Tianjin Medical University from September 2011 to June 2012,were included in this study.We excluded subjects with congestive heart failure,acute coronary syndrome,congenital heart disease,valvular heart disease,cardiomyopathy,thyroid dysfunction and acute infection or inflammatory conditions.Baseline clinical data,complications and laboratory examination results were collected.Left atrium diameter (LAD),left ventricular end-diastolic dimension (LVEDD) and left ventricular ejection fraction (LVEF) were determined by echocardiography.Univariate and logistic regression was conducted to detect risk factors for PAF.Results Serum uric acid level were significantly increased in patients with PAF compared with controls ((360.2 ± 103.9) μmol/L vs (296.0 ±68.1) μmol/L,P =0.001).Multivariate logistic regression analysis showed that higher level of serum uric acid (OR:1.007,95％ CI:1.000-1.015) and LAD (OR:1.142,95％ CI:1.031-1.265) were independent risk factors for the occurrence of PAF.Conclusion High serum uric acid level is an independent risk factor for the development of PAF.Future larger studies should further evaluate this potential association as well as the underlying mechanisms.

AIM:To investigate regulatory roles of Apelin in adventitial remodeling and fibrosis in rats with transverse aortic constriction ( TAC) .METHODS:The male Sprague-Dawley rats with TAC were randomized to daily deliver either pyroglutamyl Apelin-13 ( 50μg/kg) or saline for 4 weeks.RESULTS:Histomorphometric analysis by HE and Masson Trichrome staining revealed increased medi -al and adventitial thicknesses , especially in the adventitia , in ascending aortas in rats with TAC when compared with the sham-operated rats.Downregulation of APJ receptor and elevations in phosphorylated mTOR and ERK 1/2 levels were observed in rats with TAC . There are marked increases in heart weight ( HW) , HW/body weight ratio , and aortic fibrosis in rats with TAC .The pressure over-load-mediated pathological adventitial remodeling was strikingly rescued by Apelin-13, associated with attenuation of aortic fibrosis and reduced mRNA expression of TGF-β1, fibronectin and collagen I .CONCLUSION:Our results demonstrate the importance of Apelin-13 in amelioration of aortic adventitial remodeling and fibrosis in rats with TAC via modulation of the mTOR /ERK signaling , thus indi-cating potential therapeutic strategies by enhancing Apelin /APJ action for preventing pressure overload-and fibrosis-associated cardio-vascular disorders .

OBJECTIVE:To establish the method for content determination of cantharidin in Lytta caraganae,and to use the result as the extract screening evidence of L. caraganae source material. METHODS:Ultrasonic extraction method was used to extract cantharidin from L. caraganae using acetone as solvent. HPLC method was adopted to determine the content of cantharidin. The determination was performed on C18column with mobile phase consisted of methanol-water(23:77)at flow rate of 1.0 mL/min. The detection wavelength was set 230 nm,the column temperature was set at 35 ℃,and sample size was 10 μL. The content of cantharidin in L. caraganae was determined and compared with the results of content determination by the method stated in Chinese Pharmacopeia(using chloroform as extraction solvent). RESULTS:The liner range of cantharidin were 0.2-1.0 mg/mL (r=0.998 8)with average methodology recovery rates of 101.1%(RSD=1.7%,n=6). The average content of cantharidin in L. caraganae was 0.932%(n=3),while the content of cantharidin was 0.793%(n=3)determined by the method stated in Chinese Pharmacopeia. Both were higher than the requirement of Chinese Pharmacopeia that the content of cantharidin in scource material of cantharidin was higher than 0.35%. CONCLUSIONS:Established method is accurate and reliable for the content determination cantharidin in L. caraganae. The content of cantharidin is up to the standard of Chinese Pharmacopeia,and can be used as source material for exacting cantharidin.

Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide, such as the on-going outbreak of the novel coronavirus SARS-CoV-2. Herein, we identified two potent inhibitors of human DHODH, S312 and S416, with favorable drug-likeness and pharmacokinetic profiles, which all showed broad-spectrum antiviral effects against various RNA viruses, including influenza A virus, Zika virus, Ebola virus, and particularly against SARS-CoV-2. Notably, S416 is reported to be the most potent inhibitor so far with an EC of 17 nmol/L and an SI value of 10,505.88 in infected cells. Our results are the first to validate that DHODH is an attractive host target through high antiviral efficacy in vivo and low virus replication in DHODH knock-out cells. This work demonstrates that both S312/S416 and old drugs (Leflunomide/Teriflunomide) with dual actions of antiviral and immuno-regulation may have clinical potentials to cure SARS-CoV-2 or other RNA viruses circulating worldwide, no matter such viruses are mutated or not.
Animals ; Antiviral Agents ; pharmacology ; therapeutic use ; Betacoronavirus ; drug effects ; physiology ; Binding Sites ; drug effects ; Cell Line ; Coronavirus Infections ; drug therapy ; virology ; Crotonates ; pharmacology ; Cytokine Release Syndrome ; drug therapy ; Drug Evaluation, Preclinical ; Gene Knockout Techniques ; Humans ; Influenza A virus ; drug effects ; Leflunomide ; pharmacology ; Mice ; Mice, Inbred BALB C ; Orthomyxoviridae Infections ; drug therapy ; Oseltamivir ; therapeutic use ; Oxidoreductases ; antagonists & inhibitors ; metabolism ; Pandemics ; Pneumonia, Viral ; drug therapy ; virology ; Protein Binding ; drug effects ; Pyrimidines ; biosynthesis ; RNA Viruses ; drug effects ; physiology ; Structure-Activity Relationship ; Toluidines ; pharmacology ; Ubiquinone ; metabolism ; Virus Replication ; drug effects