The aryl hydrocarbon receptor (AhR) plays a crucial role in regulating many physiological processes. Activating the AhR-CYP1A1 axis has emerged as a novel therapeutic strategy against various inflammatory diseases. Here, a practical in situ cell-based fluorometric assay was constructed to screen AhR-CYP1A1 axis modulators, via functional sensing of CYP1A1 activities in live cells. Firstly, a cell-permeable, isoform-specific enzyme-activable fluorogenic substrate for CYP1A1 was rationally constructed for in-situ visualizing the dynamic changes of CYP1A1 function in living systems, which was subsequently used for discovering the efficacious modulators of the AhR-CYP1A1 axis. Following screening of a compound library, LAC-7 was identified as an efficacious activator of the AhR-CYP1A1 axis, which dose-dependently up-regulated the expression levels of both CYP1A1 and AhR in multiple cell lines. LAC-7 also suppressed macrophage M1 polarization and reduced the levels of inflammatory factors in LPS-induced bone marrow-derived macrophages. Animal tests showed that LAC-7 could significantly mitigate DSS-induced ulcerative colitis and LPS-induced acute lung injury in mice, and markedly reduced the levels of multiple inflammatory factors. Collectively, an optimized fluorometric cell-based assay was devised for in situ functional imaging of CYP1A1 activities in living systems, which strongly facilitated the discovery of efficacious modulators of the AhR-CYP1A1 axis as novel anti-inflammatory agents.

Human carboxylesterase 2A (hCES2A) plays pivotal roles in prodrug activation and hydrolytic metabolism of ester-bearing chemicals. Targeted inhibition of intestinal hCES2A represents a feasible strategy to mitigate irinotecan-triggered gut toxicity (ITGT), but the orally active, selective, and efficacious hCES2A inhibitors are rarely reported. Here, a novel drug-like hCES2A inhibitor was developed via three rounds of structure-based drug design (SBDD) and structural optimization. Initially, donepezil was identified as a moderate hCES2A inhibitor from 2000 US Food and Drug Administration (FDA)-approved drugs. Following two rounds of SBDD and structural optimization, a donepezil derivative (B7) was identified as a strong reversible hCES2A inhibitor. Subsequently, nine B7 carbamates were rationally designed, synthesized and biologically assayed. Among all synthesized carbamates, C3 showed the most potent time-dependent inhibition on hCES2A (IC₅₀ = 0.56 nmol/L), excellent specificity and favorable drug-like properties. C3 could covalently modify the catalytic serine of hCES2A with high selectivity, while this agent also showed favorable safety profiles, high intestinal exposure, and impressive effects for ameliorating ITGT in both human intestinal organoids and tumor-bearing mice. Collectively, this study showcases a rational strategy for developing drug-like and serine-targeting covalent inhibitors against target serine hydrolase(s), while C3 emerges as a promising orally active drug candidate for ameliorating ITGT.

Objective:To evaluate the quality of guidelines and expert consensus on the prevention of urinary retention after vaginal delivery, so as to provide a reference for clinical prevention and management.Methods:We searched the website of Chinese and English guidelines, electronic literature database and professional society website by computer. The articles were evaluated by three researchers using the Appraisal of Guidelines for Research and EvaluationⅡ (AGREE Ⅱ) and the quality evaluation criteria for expert consensus of the Australian Joanna Briggs Institute Evidence-Based Health Care Center, and the recommendations of each guideline and expert consensus were summarized and analyzed.Results:A total of six guidelines and one expert consensus were included. The recommendation strength of four guidelines was A, and two guidelines were B, and the overall quality of the guidelines was relatively high. One expert consensus evaluation result was "included". Recommendations related to the prevention of urinary retention after vaginal delivery involved a total of 23 comments of risk screening and preventive measures.Conclusions:The quality of the included guidelines and expert consensus is generally high, and their recommendations can provide a reference for the prevention and management of urinary retention after vaginal delivery.

Objective:To investigate the anticoagulant causes, hemorrhagic susceptibility factors and clinical characteristics of patients with warfarin-related major bleeding in the emergency department of a general hospital.Methods:In a registry study from January 2017 to February 2020, 114 cases of warfarin-related major bleeding patients admitted to Department of Emergency Medicine, the First Affiliated Hospital of Wenzhou Medical University were enrolled. The descriptive methods were used to analyze anticoagulant causes, hemorrhagic susceptibility factors and clinical characteristics. Patients were divided into the international normalized ratio (INR) overrange group and the INR non-overrange group according to INR value during bleeding. The Chi-square test, Student’s t test, and Wilcoxon rank sum test were used to compare the differences between the INR overrange group and the INR non-overrange group. The Wilcoxon rank sum test and Student’s t test were used to analyze the characteristics of gastrointestinal tract bleeding and cerebral hemorrhage. Results:Warfarin-related major bleeding accounted for 0.36% (114/32 040) of first aid cases and 9.84% (114/1 158) of warfarin-taking cases, respectively. Seventy-seven cases (67.5%) of anticoagulant causes were related to atrial fibrillation (AF) and 32 cases (28.1%) were related to post-operative cardiac valve replacement. Of the bleeding susceptibility factors, HAS-BLED scored at 4.0 (3.0, 5.0), 84 cases (73.7%) had a history of drug use, 77 cases (67.5%) aged older than 65 years old, 65 cases (57.0%) had irregular INR monitoring, and 29 cases (25.4%) had recent increase in dose. Forty cases (35.1%) were gastrointestinal tract bleeding with the lowest hemoglobin (Hb) value and the highest score of HAS-BLED. Twenty-one cases (18.4%) were cerebral hemorrhage with the shortest prothrombin time (PT), the lowest INR value, the highest Hb, and the lowest score of HAS-BLED. Twelve cases (10.5%) died or gave up treatment in critical condition, including 6 cases of cerebral hemorrhage, 5 cases of gastrointestinal tract bleeding, and 1 case of hemoptysis. There were statistically significant differences in previous history of antiplatelet therapy, recent increase in dose, HAS-BLED score and bleeding site between the INR overrange group and the INR non-overrange group (all P<0.05). Conclusions:Among patients with warfarin-related major bleeding, AF and post-operative cardiac valve replacement are the main causes of warfarin anticoagulation. INR overrange is related to the previous history of antiplatelet therapy, recent increase in dose, and the high score of HAS-BLED. The gastrointestinal tract bleeding is the most common, with the lowest Hb value and the highest score of HAS-BLED. Cerebral hemorrhage is the second common, with the shortest PT, the lowest INR value, and the highest Hb. The incidence and mortality rates of warfarin-related major bleeding are relatively high.

Objective:To understand the current status of foreign dual-degree programs of Medical Doctor (MD) and Master of Public Health (MPH) and provide evidence-based decision-making reference for promoting the education of high-level applied public health talents in China.Methods:The list of involved institutions and information of foreign MD-MPH dual-degree programs was collected through literature retrieval, online information searching, and additional survey of key figures. We extracted the details of each project regarding professional fields, core competence, length of schooling, teaching and learning arrangement, internship eligibility, and graduation assessment. Python 3.8.0 was used for data cleaning, and the occurrence frequency of related items in each dimension was calculated.Results:A total of 99 MD-MPH programs from 104 foreign institutions were included, among which 97.1% of them were implemented in universities from the United States. The School of Public Health provided 42.4% (42/99) of the programs. Epidemiology was the major discipline set up among most programs, accounting for 12.0% (29/241) of all the specialties involved. Epidemiological research methods, health policy management and practice, and public health practice were the top 3 core competencies to be mastered. Of the 99 programs, 87 gave information on the length of the program, of which 74.7% (65/87) were five years, 6.9% (6/87) were four years, and 18.4% (16/87) included both 4-year and 5-year programs.Conclusions:The international MD-MPH programs were sophisticated and mainly organized by the School of Public Health alone or in conjunction with the School of Medicine. Epidemiology is the core course and competence objective, with a length of 4-5 years. Through learning experience from international MD-MPH programs and the Chinese unique medical development background, China should optimize its medical education system to develop a suitable talent training strategy for MD-MPH dual-degree programs in the new era.

Neoadjuvant therapy has been one of the standard therapies for borderline resectable pancreatic cancer and locally advanced pancreatic cancer, but it may deteriorate these patients′ nutritional status while controlling the progress of cancer, which inevitably influences these patients′ postoperative outcomes and prognosis.In this article, we tried to answer this problem by reviewing other studies.And we found that neoadjuvant therapy would influence patients′ postoperative outcomes and prognosis by deteriorating their nutritional status.But effective nutritional support can prevent it.It indicates that there is a need for these patients to receive nutritional support as soon as possible.However, in consideration of the limited number of relevant studies and their limitations, there is a need for more studies with strict design to answer this problem.And it can provide evidence for early nutritional support in pancreatic cancer patients who is going to undergo neoadjuvant therapy.

Neoadjuvant therapy has been one of the standard therapies for borderline resectable pancreatic cancer and locally advanced pancreatic cancer, but it may deteriorate these patients′ nutritional status while controlling the progress of cancer, which inevitably influences these patients′ postoperative outcomes and prognosis.In this article, we tried to answer this problem by reviewing other studies.And we found that neoadjuvant therapy would influence patients′ postoperative outcomes and prognosis by deteriorating their nutritional status.But effective nutritional support can prevent it.It indicates that there is a need for these patients to receive nutritional support as soon as possible.However, in consideration of the limited number of relevant studies and their limitations, there is a need for more studies with strict design to answer this problem.And it can provide evidence for early nutritional support in pancreatic cancer patients who is going to undergo neoadjuvant therapy.

Objective To assess the factors associated with the restoration of spontaneous circulation (ROSC) and 2-year survival prognosis in patients with cardiac arrest (CA) after acute myocardial infarction (AMI),and after ROSC,the effects of various factors on midian survival time and on 2-year survival.Methods In a registry study from January 2005 to January 2015,all consecutive AMI-induced CA patients treated with cardiopulmonary resuscitation (CPR) admitted to our hospital were enrolled.The survivors were followed-up for 2 years.Univariate analysis was applied to evaluate factors associated with rate of ROSC and 2-year survival.Multivariable logistic regression analysis was applied to evaluate statistically significant factors in the univariate analysis.Medians with inter-quartile ranges were used to describe 2-year survival time affected by various factors after ROSC.Kaplan-Meier survival curve analysis was used to evaluate the effect of factors on 2-year survival.Results A total of 254 cases with CA after AMI were enrolled,including 129 cases of ROSC and 71 cases of 2-year survival.Univariate analysis showed age ≥ 70 years,CA occurred during 22:00-8:00,the duration time ofCPR ≥ 15 min and adrenaline dosage ＞ 5 mg were unfavorable predictors of ROSC;while,left ventricular ejection fraction (LVEF) ≥ 40％ before CA,shockable rhythm and percutaneous coronary intervention (PCI) therapy were favorable predictors.Besides,age ≥ 70 years,intubation during CPR,adrenaline dosage ＞ 5 mg and cardiogenic shock were unfavorable predictors of 2-year survival;While,male,normal daily activity before CA and PCI treatment were favorable predictors.Multivariable analysis showed age,the duration of CPR,adrenaline dosage,LVEF before CA,the rhythm during CPR and PCI therapy were independent predictors of ROSC.Age and PCI therapy were independent predictors of 2-year survival.Among patients,the survival time was affected by various factors after ROSC,and the factors with minimum 25％ and small median value were associated with cardiac rupture,cancer,adrenaline dosage ＞ 5 mg and cardiogenic shock.The factor with maximum 25％ value was PCI treatment (216 days).Kaplan-Meier survival analysis suggested that age ≥ 70 years was an unfavorable factor of 2-years survival (Log-rank test,P=0.007);while,PCI treatment was a favorable factor (Log-rank test,P＜0.01).PCI-related prognosis analysis showed that the effectiveness of PCI was related to the timing of PCI,the number of infarctrelated artery and the difference in culprit lesion.Conclusions The age ≥ 70 years was disadvantageous to both ROSC and 2-year survival.PCI treatment was favorable to both ROSC and 2-year survival.

Objective To explore the effect of Kaolin combined with propranolol on matrix metalloproteinase-9 (MMP-9) in lungs of paraquate (PQ) intoxicated mice and the mechanism of protection for lung injury. Methods Fifty-four ICR mice were randomly divided into three groups, 18 mice in each group: namely control group, PQ intoxicated group and treatment group. The PQ intoxicated model was replicated by intra-gastric administration (ig) of PQ 100 mg/kg; after intoxication, 48 g/kg Kaolin combined with 3.2 mg/kg propranolol intra-gastric administration was immediately given to the treatment group, while in the control group, the same volume of normal saline ig was applied. All the mice were sacrificed at 6, 12 and 24 hours after disposal, and the lung was harvested to test the protein expression level of MMP-9 by Western Blot, and the lung tissue pathological changes were observed.Results There was no statistical significance in the protein expression levels of MMP-9 among the control group, PQ intoxicated group and treatment group at 6 hours after disposal (grey value: 0.655±0.045, 0.656±0.045, 0.641±0.036). The protein expression levels of MMP-9 in PQ intoxicated group were increased significantly compared with those in the control group at 12 hours and 24 hours after disposal (12 hours: 0.824±0.039 vs. 0.634±0.038, 24 hours: 0.742±0.039 vs. 0.658±0.041, bothP < 0.05), while the levels of treatment group were significantly lower than those in the intoxicated group (12 hours: 0.760±0.050 vs. 0.824±0.039, 24 hours: 0.686±0.041 vs. 0.742±0.039, bothP < 0.05). In PQ intoxicated group, early capillary dilation and congestion in lung tissue, a large number of inflammatory cells infiltration with mainly neutrophils in alveolar cavity and a small number of red blood cells exudation were seen at 12 hours; at 24 hours, capillary dilation at alveolar walls, congestion, swelling of endothelial cells, small flakes or large patches of inflammatory cell infiltration with mainly neutrophils in lungs were found. In the treatment group, the lung inflammatory cells infiltration, alveolar capillary dilatation, congestion, swelling of the endothelial cells, etc were also visible, but the degree of severity was significantly milder than those in the intoxicated group.Conclusion The interference of Kaolin combined with propranolol can significantly decrease the protein expression level of MMP-9 in lung tissue of acute paraquat poisoned mice that is possibly one of the mechanisms for prevention and treatment of lung injury in paraquat poisoning.

Objective To observe the expression changes in apoptosis-related microRNA(miRNA) in cerebral cortex after cardiac arrest-cardiopulmonary resuscitation(CA-CPR)in rats and explore the factors that may affect the mechanism of CPR. Methods 24 clean male Sprague-Dawley(SD)rats were randomly divided into three groups,the normal control group,sham operation group and CA-CPR group(each n=8). The animal model of CA induced by asphyxia was established and CPR was performed. In the normal control group,no special management was performed. In the sham operation group,only abdominal cavity anesthesia,tracheotomy,vascular puncture and electrocardiogram(ECG)were performed without clamping the trachea and resuscitating. Normal feeding in normal control group and 24 hours after tracheotomy in sham operation group,at 24 hours after recovery of spontaneous circulation(ROSC)in CA-CPR group,cerebral cortex specimens were obtained for detection of the expression of miRNA by using real time fluorescence quantitative reverse transcription - polymerase chain reaction(RT-PCR). Flow cytometry(FCM)was used to detect the neurocyte apoptotic rate. Results Compared between normal control and sham operation groups,there were no significant differences in the expression of apoptosis-related miRNA and neurocyte apoptosis rate of cerebral cortex(both P>0.05). Compared with sham operation group,in CA-CPR group, 16 miRNA expressions were up-regulated,including Let-7c,miR-15a,miR-21,miR-24,miR-29,miR-29b, miR-34a, miR-103, miR-200a, miR-200b, miR-200c, miR-210, miR-326, miR-338-3p, miR-494 and miR-497,and there were 22 down-regulated,being Let-7a,Let-7b,Let-7d,Let-7e,miR-19a,miR-19b-1, miR-20a,miR-20b,miR-23a,miR-23b,miR-25,miR-98,miR-107,miR-122a,miR-125a,miR-125b, miR-145,miR-181a,miR-181c,miR-335,miR-384-5p and miR-422a. Eight miRNA had significant changes at 24 hours after ROSC,in which miR-15a,miR-21,miR-34a,miR-497 were up-regulated respectively for 6.831±2.625,8.122±3.442,5.349±2.010,6.590±3.689 times,and miR-125b,miR-145,Let-7a,Let-7e were down-regulated respectively for 0.122±0.039,0.199±0.096,0.191±0.069,0.160±0.082 times. The apoptosis rate of cerebral cortex was increased significantly in CA-CPR group〔(32.23±5.31)%〕compared with that in normal control group〔(3.66±1.34)%〕and sham operation group〔(4.98±1.84)%,both P<0.01〕. Conclusions In early period after CA-CPR,obvious neurocyte apoptosis may be found in brain tissue of rats,and in the mean time, changes in apoptosis-related miRNA expression in cerebral cortex occur. The various types of miRNA with significant changes possibly play important roles in cerebral protection after CA-CPR in rats.
down-regulated respectively for 0.122±0.039,0.199±0.096,0.191±0.069,0.160±0.082 times. The apoptosis rate of cerebral cortex was increased significantly in CA-CPR group〔(32.23±5.31)%〕compared with that in normal control group〔(3.66±1.34)%〕and sham operation group〔(4.98±1.84)%,both P<0.01〕. Conclusions In early period after CA-CPR,obvious neurocyte apoptosis may be found in brain tissue of rats,and in the mean time, changes in apoptosis-related miRNA expression in cerebral cortex occur. The various types of miRNA with significant changes possibly play important roles in cerebral protection after CA-CPR in rats.