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.

Notum, a negative feedback regulator of the Wnt signaling, has emerged as a promising target for treating glucocorticoid-induced osteoporosis (GIOP). This study showcases an efficient strategy for discovering the anti-Notum constituents from herbal medicines (HMs) as novel anti-GIOP agents. Firstly, a rapid-responding near-infrared fluorogenic substrate for Notum was rationally engineered for high-throughput identifying the anti-Notum HMs. The results showed that Bu-Gu-Zhi (BGZ), a known anti-osteoporosis herb, potently inhibited Notum in a competitive-inhibition manner. To uncover the key anti-Notum constituents in BGZ, an efficient strategy was adapted via integrating biochemical, phytochemical, computational, and pharmacological assays. Among all identified BGZ constituents, three furanocoumarins were validated as strong Notum inhibitors, while 5-methoxypsoralen (5-MP) showed the most potent anti-Notum activity and favorable safety profiles. Mechanistically, 5-MP acted as a competitive inhibitor of Notum via creating strong hydrophobic interactions with Trp128 and Phe268 in the catalytic cavity of Notum. Cellular assays showed that 5-MP remarkably promoted osteoblast differentiation and activated Wnt signaling in dexamethasone (DXMS)-challenged MC3T3-E1 osteoblasts. In dexamethasone-induced osteoporotic mice, 5-MP strongly elevated bone mineral density (BMD) and improved cancellous and cortical bone thickness. Collectively, this study constructs a high-efficient platform for discovering key anti-Notum constituents from HMs, while 5-MP emerges as a promising anti-GIOP agent.

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 investigate the association between serum ferritin (SF), blood lipid levels and hyperuricemia in middle-aged and elderly individuals with normal body mass(BMI).Methods:A retrospective study was conducted on 1 671 participants with normal BMI from health check-ups at Wusong Hospital of Zhongshan Hospital, Fudan University from January 2019 to December 2021. Collected data included fasting plasma glucose (FPG), uric acid, creatinine (CREA), triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and SF levels. SF, TC, LDL-C, and HDL-C were grouped by quartiles, linear regression and Pearson correlation analysis used to assess their associations with hyperuricemia.Results:Among 1 671 normal-weight middle-aged and elderly individuals, 250 cases of hyperuricemia were identified, yielding a prevalence of 14.96% (250/1 671). Pearson analysis revealed: a moderate positive correlation between SF and uric acid levels ( r = 0.500, P<0.01); a weak positive correlation between TC and uric acid levels ( r = 0.250, P<0.01); a moderate negative correlation between HDL-C and uric acid levels ( r = - 0.333, P<0.01); a weak-to-moderate positive correlation between LDL-C and uric acid levels ( r = 0.380, P<0.01). Additionally, male gender showed a moderate positive correlation with uric acid levels ( r = 0.575, P<0.01), while CREA demonstrated a positive correlation with uric acid ( r = 0.620, P<0.05). Conclusions:In normal-weight middle-aged and elderly populations, gender, TG, TC, LDL-C and SF exhibite positive correlations with uric acid levels, with stronger associations observed for gender, CREA, and SF. HDL-C show a negative correlation with uric acid levels.

Objective:To investigate the association between serum ferritin (SF), blood lipid levels and hyperuricemia in middle-aged and elderly individuals with normal body mass(BMI).Methods:A retrospective study was conducted on 1 671 participants with normal BMI from health check-ups at Wusong Hospital of Zhongshan Hospital, Fudan University from January 2019 to December 2021. Collected data included fasting plasma glucose (FPG), uric acid, creatinine (CREA), triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and SF levels. SF, TC, LDL-C, and HDL-C were grouped by quartiles, linear regression and Pearson correlation analysis used to assess their associations with hyperuricemia.Results:Among 1 671 normal-weight middle-aged and elderly individuals, 250 cases of hyperuricemia were identified, yielding a prevalence of 14.96% (250/1 671). Pearson analysis revealed: a moderate positive correlation between SF and uric acid levels ( r = 0.500, P<0.01); a weak positive correlation between TC and uric acid levels ( r = 0.250, P<0.01); a moderate negative correlation between HDL-C and uric acid levels ( r = - 0.333, P<0.01); a weak-to-moderate positive correlation between LDL-C and uric acid levels ( r = 0.380, P<0.01). Additionally, male gender showed a moderate positive correlation with uric acid levels ( r = 0.575, P<0.01), while CREA demonstrated a positive correlation with uric acid ( r = 0.620, P<0.05). Conclusions:In normal-weight middle-aged and elderly populations, gender, TG, TC, LDL-C and SF exhibite positive correlations with uric acid levels, with stronger associations observed for gender, CREA, and SF. HDL-C show a negative correlation with uric acid levels.

Multiple thrombosis in the coronary arteries need to be characterized by a thorough determination of the source of the thrombus to distinguish them as thrombosis or coronary embolism.This case was a 38-year-old male patient with chest pain and an electrocardiogram showing acute inferior wall and right ventricular myocardial infarction.Emergency coronary angiography showed thrombosis in the proximal middle of the left anterior descending artery,the opening of the first diagonal artery,and the middle of the right coronary artery,but no obvious stenosis was seen.Postoperative electrocardiogram showed acute inferior wall,right ventricular and anterior wall myocardial infarction,and intensive antithrombotic treatment was applied,elective re-examination of coronary angiography and intraluminal imaging showed mixed plaques and suspicious intimal dissection,indicating the possibility of thrombosis secondary to unstable plaque and coronary dissection,and intensive drug treatment was given.After discharge,the patient was stable during the regular follow-up visits.

Conventional 1.5T and 3.0T cardiac MRI(CMRI)had been widely used.The ultrahigh field MR behaved better in image resolution and signal-to-noise ratio.The domestic 5.0T whole-body ultrahigh field MRI had better balance between the field strength and quality in CMRI,which was expected to improve imaging quality and efficiency.The status challenges and future of 5.0T CMRI were reviewed in this paper.

Objective To investigate the indicators of thrombolytic therapy in patients with acute ischemic stroke,find out the early warning value,and provide guidance for decision-making of emergency doctors.Methods Patients with acute ischemic stroke who were treated with thrombolytic therapy from January,2010 to August,2017 in our hospital were enrolled in this study.According to the modified Rankin scale,patients were divided into the good prognosis group and poor prognosis group.Logistic regression model was used to evaluate the relative dependent risk factors.Results Totally 210 patients were enrolled in the good prognosis group and 152 patients in the poor prognosis group.Multivariate logistic regression analysis showed that NIHSS score on admission,blood glucose,systolic blood pressure before thrombolytic therapy,homocysteine,onset-to-needle time and previous history of diabetes mellitus were independent risk factor for poor prognosis (P＜0.05).Conclusions Risk factors as NIHSS score on admission,blood glucose,systolic blood pressure before thrombolytic therapy,homocysteine,onsetto-needle time and previous history of diabetes mellitus are early warning indicators of poor prognosis in patients with acute ischemic stroke treated with thrombolytic therapy.

Objective To investigate the feasibility of hydrogen proton magnetic resonance spectroscopy (1 H-MRS)for detection of Wallerian degeneration of the pyramidal tract after cerebral infarction.Methods Multiple metabolic indices including NAA,Cho, Cr of the bilateral cerebral peduncle were detected by using 1 H-MRS in 1 5 patients with unilateral middle cerebral artery infarction and 1 5 age-matched healthy volunteers,NAA/Cr,Cho/Cr were also calculated.Comparing the difference between cerebral infarction group and the control group ,the ROC curve was analyzed.Results The values of NAA/Cr in the ipsilateral cerebral peduncle of cerebral infarction patients were significantly lower than that of the contralateral,and there were significant differences between the two groups(P <0.05).The values of NAA/Cr in the ipsilateral cerebral peduncle of cerebral infarction patients decreased (P <0.05),as compared with that of the control group.The area under the ROC curve was 0.947,the truncation point was 1.63.The NAA/Cr val-ues of the contralateral cerebral peduncle of cerebral infarction patients had no significant differences compared with the control group (P >0.05),the Cho/Cr values of the ipsilateral and the contralateral cerebral peduncle had no significant difference compared with the control group (P >0.05).Conclusion 1 H-MRS can detect Wallerian degeneration of the pyramidal tract after cerebral infarction.