Xanthine oxidase (XO) is an important therapeutic target for the treatment of hyperuricemia and gout. Based on the previously identified potent XO inhibitor 1, seventeen oxadiazoles and their ring-opening analogues were designed and synthesized via the bioisostere replacement strategy. Among them, compounds 2l, 2n, and 3b showed obvious XO inhibitory activity at the concentration of 10 μmol·L^-1, and compound 3b exhibited an IC₅₀ value of 1.45 μmol·L^-1.

Aim To investigate the neuroprotective effect of Takeda G protein-coupled receptor-5(TGR5)activated by INT-777 on hypoxic-ischemic encephalop-athy(HIE)in neonatal rats.Methods Seven-day-old SD rats were randomly divided into the sham opera-tion group(Sham,S),model group(HIE,G),INT-777 low-dose(L),medium-dose(M),and high-dose(H)groups.The modified Rice-Vanucci method was used to construct the HIE model and Intranasal admin-istration 1 h after modeling.Short-term neurobehavioral tests were performed 48 h after modeling to evaluate the neurological function of neonatal rats,TTC staining was used to determine the volume of cerebral infarction,dry and wet specific gravity was used to determine the brain water content,ferrous ion kit was used to deter-mine the brain ferrous ion content,HE staining was used to observe the pathological damage of brain tis-sue,Nissl staining was used to observe the loss of Nissl substance,Transmission electron microscopy(TEM)was used to observe the mitochondrial morphological changes of cortical neurons,and Western blot was em-ployed to detect the expression of ferroptosis-related proteins TFR1 and GPX4.Results Compared with group S,group G had increased short-term neurobehav-ioral test consumption time,higher scores,increased cerebral infarct volume,brain water content,and brain ferrous iron content,significant brain tissue damage on the affected side,severe loss of Nissl substance,smaller neuronal mitochondria,decreased mitochondrial cris-tae,and increased expression of TFR1 and reduced ex-pression of GPX4.Compared with group G,the INT-777 administration group had a shorter consumption time for short-term neurobehavioral tests,lower scores,the cerebral infarction volume,brain water content,and brain ferrous ion content decreased,the brain tissue damage on the affected side was reduced,and there was insignificant loss of Nissl substance,larger neuronal mi-tochondrial volume,increased mitochondrial cristae,re-duced expression of TFR1,and increased expression of GPX4.Conclusions INT-777 agonist TGR5 has a protective effect against hypoxic-ischemic encephalopa-thy in neonatal rats,and its mechanism of action may be related to the inhibition of neuronal ferroptosis.

Isoflavones which mainly distributed in leguminous plants have plenty of health benefits.Isoflavone synthase(IFS)is a membrane-associated cytochrome P450 enzyme(CYP450)which carries out the unique aryl-ring migration and hydroxylation.So far,few crystal structures of plant P450s have been obtained.We determined the crystal structure of IFS from Medicago truncatula at 1.9 ? by MAD method using a selenomethionine substituted crystal and conducted molecular docking and mutagenesis study.The structure of IFS complexed with imidazole exhibits the helix Ⅰa-loop-helix Ⅰβ motif which cor-responds to helix Ⅰ of other P450s.Compared with structures of common P450s,IFS/imidazole structure contains an extra domain,i.e.,the γ-domain.The structure reveals a homodimer in which the γ-domain of one molecule interacts with the β-domain of another.The plane of heme group makes an angle of ap-proximately 40° with the helix Ⅰa-loop-helix Ⅰβ motif.Molecular docking combined with mutagenesis study suggested that Trp-128 and Asp-300 might play important roles in substrate binding and recogni-tion.Phe-301,Ser-303 and Gly-305 from the helix Ⅰa-loop-helix Ⅰβ motif may play important roles in the aryl-ring migration.These novel structural features reveal insights into the unique reaction mechanism of IFS and provide a basis for engineering IFS in leguminous crops for health purpose.

Aim To investigate the neuroprotective effect of Takeda G protein-coupled receptor-5(TGR5)activated by INT-777 on hypoxic-ischemic encephalop-athy(HIE)in neonatal rats.Methods Seven-day-old SD rats were randomly divided into the sham opera-tion group(Sham,S),model group(HIE,G),INT-777 low-dose(L),medium-dose(M),and high-dose(H)groups.The modified Rice-Vanucci method was used to construct the HIE model and Intranasal admin-istration 1 h after modeling.Short-term neurobehavioral tests were performed 48 h after modeling to evaluate the neurological function of neonatal rats,TTC staining was used to determine the volume of cerebral infarction,dry and wet specific gravity was used to determine the brain water content,ferrous ion kit was used to deter-mine the brain ferrous ion content,HE staining was used to observe the pathological damage of brain tis-sue,Nissl staining was used to observe the loss of Nissl substance,Transmission electron microscopy(TEM)was used to observe the mitochondrial morphological changes of cortical neurons,and Western blot was em-ployed to detect the expression of ferroptosis-related proteins TFR1 and GPX4.Results Compared with group S,group G had increased short-term neurobehav-ioral test consumption time,higher scores,increased cerebral infarct volume,brain water content,and brain ferrous iron content,significant brain tissue damage on the affected side,severe loss of Nissl substance,smaller neuronal mitochondria,decreased mitochondrial cris-tae,and increased expression of TFR1 and reduced ex-pression of GPX4.Compared with group G,the INT-777 administration group had a shorter consumption time for short-term neurobehavioral tests,lower scores,the cerebral infarction volume,brain water content,and brain ferrous ion content decreased,the brain tissue damage on the affected side was reduced,and there was insignificant loss of Nissl substance,larger neuronal mi-tochondrial volume,increased mitochondrial cristae,re-duced expression of TFR1,and increased expression of GPX4.Conclusions INT-777 agonist TGR5 has a protective effect against hypoxic-ischemic encephalopa-thy in neonatal rats,and its mechanism of action may be related to the inhibition of neuronal ferroptosis.

Isoflavones which mainly distributed in leguminous plants have plenty of health benefits.Isoflavone synthase(IFS)is a membrane-associated cytochrome P450 enzyme(CYP450)which carries out the unique aryl-ring migration and hydroxylation.So far,few crystal structures of plant P450s have been obtained.We determined the crystal structure of IFS from Medicago truncatula at 1.9 ? by MAD method using a selenomethionine substituted crystal and conducted molecular docking and mutagenesis study.The structure of IFS complexed with imidazole exhibits the helix Ⅰa-loop-helix Ⅰβ motif which cor-responds to helix Ⅰ of other P450s.Compared with structures of common P450s,IFS/imidazole structure contains an extra domain,i.e.,the γ-domain.The structure reveals a homodimer in which the γ-domain of one molecule interacts with the β-domain of another.The plane of heme group makes an angle of ap-proximately 40° with the helix Ⅰa-loop-helix Ⅰβ motif.Molecular docking combined with mutagenesis study suggested that Trp-128 and Asp-300 might play important roles in substrate binding and recogni-tion.Phe-301,Ser-303 and Gly-305 from the helix Ⅰa-loop-helix Ⅰβ motif may play important roles in the aryl-ring migration.These novel structural features reveal insights into the unique reaction mechanism of IFS and provide a basis for engineering IFS in leguminous crops for health purpose.

Objective:To explore the relationship between the expression of cerebellar zinc finger structure 5(ZIC5)protein in breast cancer and its clinicopathological characteristics,surgical prognosis.Methods:A total of 128 breast cancer patients,who were admitted to our hospital be-tween June 2016 and December 2017,were enrolled in this study.Immunohistochemistry was employed to assess the expression of ZIC5 protein.The positive expression rate of ZIC5 protein in breast cancer tissues was compared with that in normal surgical margin tissues.Additionally,an analysis was conducted to explore the association between the expression of ZIC5 protein and various clinical pathological characteristics of breast cancer patients,as well as its correlation with prognosis.Results:The positive expression rate of ZIC5 protein in breast cancer tissue was higher than that in normal tissue of resection margin.The postoperative survival rate of breast can-cer patients was 81.37％.TNM stage Ⅲ～Ⅳ,undifferentiated/poorly differentiated,tumor diam-eter ≥ 2 cm,invasion depth T3～T4,lymph node metastasis,ZIC5 protein positive expression were all risk factors for poor prognosis of breast cancer surgery.(RR=4.405,5.153,4.520,2.211,3.137,6.079,P＜0.05).The survival rate of patients with negative ZIC5 protein expression in breast cancer tissue was higher than that of patients with positive ZIC5 protein expression(P＜0.05).Conclu-sion:The positive expression rate of ZIC5 protein in breast cancer tissue is higher than that in nor-mal tissue of resection margin,and the expression of ZIC5 protein in cancer tissue is related to clinical stage,tumor differentiation,tumor size,invasion depth,and lymph node metastasis.The above indicators are risk factors for poor prognosis of breast cancer surgery.

Aim To investigate the mechanism through which liraglutide (LRG) inhibited high glucose (HG)-induced cardiomyocyte hypertrophy. Methods Cultured H9c2 were divided into control (CON) group, HG group, low-, middle- and high-dose LRG (LRG-L, LRG-M and LRG-H) groups, LRG-H + autophagy inhibitor trimethyladenine (3-MA) group. The relative cell surface change was assessed phalloidin staining. Membrane bound Na, K

Objective: In this study, we aimed to investigate the prevalence of low anterior resection syndrome (LARS) in patients who had survived for more than 5 years after sphincter-preserving surgery for rectal cancer and to analyze its relationship with postoperative time. Methods: This was a single-center, retrospective, cross-sectional study. The study cohort comprised patients who had survived for at least 5 years (60 months) after undergoing sphincter- preserving radical resection of pathologically diagnosed rectal adenocarcinoma within 15 cm of the anal verge in the Department of Gastrointestinal Surgery, Peking University People's Hospital from January 2005 to May 2016. Patients who had undergone local resection, had permanent stomas, recurrent intestinal infection, local recurrence, history of previous anorectal surgery, or long- term preoperative defecation disorders were excluded. A LARS questionnaire was administered by telephone interview, points being allocated for incontinence for flatus (0-7 points), incontinence for liquid stools (0-3 points), frequency of bowel movements (0-5 points), clustering of stools (0-11 points), and urgency (0-16 points). The patients were allocated to three groups based on these scores: no LARS (0-20 points), minor LARS (21-29 points), and major LARS (30-42 points). The prevalence of LARS and major LARS in patients who had survived more than 5 years after surgery, correlation between postoperative time and LARS score, and whether postoperative time was a risk factor for major LARS and LARS symptoms were analyzed. Results: The median follow-up time of the 160 patients who completed the telephone interview was 97 (60-193) months; 81 (50.6%) of them had LARS, comprising 34 (21.3%) with minor LARS and 47 (29.4%) with major LARS. Spearman correlation analysis showed no significant correlation between LARS score and postoperative time (correlation coefficient α=-0.016, P=0.832). Multivariate analysis identified anastomotic height (RR=0.850, P=0.022) and radiotherapy (RR=5.760, P<0.001) as independent risk factors for major LARS; whereas the postoperative time was not a significant risk factor (RR=1.003, P=0.598). The postoperative time was also not associated with LARS score rank and frequency of bowel movements, clustering, or urgency (P>0.05). However, the rates of incontinence for flatus (3/31, P=0.003) and incontinence for liquid stools (8/31, P=0.005) were lower in patients who had survived more than 10 years after surgery. Conclusions: Patients with rectal cancer who have survived more than 5 years after sphincter-preserving surgery still have a high prevalence of LARS. We found no evidence of major LARS symptoms resolving over time.
Humans ; Rectal Neoplasms/pathology* ; Cross-Sectional Studies ; Low Anterior Resection Syndrome ; Postoperative Complications/etiology* ; Retrospective Studies ; Flatulence/complications* ; Anal Canal/pathology* ; Diarrhea ; Quality of Life

Aim To investigate the protective effect of mGluR5 activated by VU0360172 on germinal matrix hemorrhage in neonatal rats.Methods Seven day- old SD rats were randomly divided into Sham, GMH, and low-, medium-, and high-dose groups.The model was established by intracerebral injection of collagenase W-S.Then three doses of VU0360172 were injected intraperitoneal^ 3 h after surgery.Sham and GMH group were given the same amount of solvent.Neurobe- havioral tests were performed 24 h after surgery.Then the brain tissues were collected for evaluation of brain water content, brain hemoglobin content and HE stai¬ning.The expressions of Bcl-2 and cleaved-caspase-3 were determined by Western blot.Results Compared with Sham, GMH group had pooler behaviors in neuro- functional tests with increased brain water content and brain hemoglobin content (P < 0.01 ).And brain tis¬sues were destroyed significantly.WB results showed the expression level of Bcl-2 decreased ( P < 0.05 ) , while cleaved-caspase-3 being up-regulated ( P < 0.01).However, the administration of VU0360172 improved neurological function and ameliorated brain edema and hemorrhage ( P <0.01 ).Brain pathologi¬cal damage was reduced.Moreover, the stimulation of mGluR5 up-regulated Bcl-2 protein expression ( P < 0.05 ) and decreased the level of cleaved-caspase-3 ( P <0.01 ).Conclusion Activation of mGluR5 by VIJ0360172 protects against germinal matrix hemor¬rhage in neonatal rats.

Objective To investigate the contamination of Proteus mirabilis in cooked meat products sold in Zhongshan City from 2017 to 2020, and to analyze its drug resistance characteristics. Methods The detected positive strains of Proteus mirabilis were analyzed for drug resistance. The suspected strains of producing extended spectrum β-lactamases were detected by preliminary screening, then its genes were detected by using molecular biology methods and were finally sequenced. Results Among the 184 strains of Proteus mirabilis detected within 4 years, 117 strains were multi-drug resistant. 184 strains of Proteus mirabilis were highly resistant to tetracycline, polymyxin, minocycline, doxycycline and cefazolin, and they had a high sensitivity rate to ampicillin-sulbactam, cefotaxime, Ceftazidime, cefoxitin, gentamicin, ciprofloxacin, amoxicillin-clavulanic acid, and levofloxacin. In addition, all strains were sensitive to amikacin, meropenem and imipenem.Only one strain was isolated to produce extended spectrum β- Lactamase bacteria. Conclusion Comparing 2020 with 2017, the resistance rate of Proteus mirabilis in cooked meat to most antibiotics showed a downward trend, and the detection rate of multi-drug resistant bacteria decreased year by year. Compared with the clinically detected strains, the drug resistance rate of the detected strains in cooked meat is generally lower than that of the clinical strains. The monitoring of drug resistance of Proteus mirabilis should be continuously strengthened, which is of great significance for guiding the rational use of drugs in clinical practice and delaying the emergence of drug-resistant strains.