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.

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 investigate the influence of oral midazolam on postoperative behavioral changes(NPOBCs)in preschool children undergoing laparoscopic inguinal hernia sac ligation.Methods A total of 197 preschool children,118 males and 79 females,aged 1-6 years,BMI 14.0-24.5 kg/m2,ASA physical status Ⅰ or Ⅱ,who undergoing laparoscopic inguinal hernia sac ligation from July 2022 to A-pril 2023 were selected.The children were divided into two groups by random number table method:the oral midazolam group(group M,n=100)and the oral saline group(group C,n=97).In the observation room,group M received an oral dose of 0.5 mg/kg midazolam while group C received an oral dose of 5％sa-line 0.25 ml/kg before being accompanied by a clown doctor to the operating room after 30 minutes.Modi-fied Yale preoperative anxiety scale(m-YPAS)scores before entering the observation room and before ente-ring the operating room,as well as induction compliance checklist(ICC)scores before anesthesia induction were recorded.Postoperatively,FLACC and PAED scores were recorded at immediately,6,and 24 hours after surgery along with occurrences of postoperative nausea and vomiting and hypoxemia.Family members of the children were followed up at 1 day,7,14,and 30 days after discharge using PHBQ to record NPOBCs occurrence in children.Results Compared with group C,m-YPAS score,ICC score before anesthesia in-duction,PAED score immediately after surgery,and the incidence of NPOBCs 1 day,7,14,and 30 days after surgery were significantly reduced in group M(P＜0.05).There were no significant differences in YPAS scores before entering the observation room,6 and 24 hours PAED scores,incidence of postoperative nausea and vomiting,hypoxemia between the two groups.Conclusion Preoperative oral administration of midazolam to children undergoing laparoscopic inguinal hernia sac ligation can effectively alleviate periopera-tive anxiety and reduce the incidence of NPOBCs.It does not increase the risk of delayed awakening or post-operative adverse reactions in children.

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