Objective:To explore the causal relationship between body mass index (BMI) and hypothyroidism using the two-sample Mendelian randomization model.Methods:A large-scale anthropometric genome-wide association study published in the GIANT database was used to select single nucleotide polymorphisms (SNPs) which were statistically significantly associated with BMI as an instrumental variable ( P<5×10 -8, linkage disequilibrium r 2<0.1). The causal relationship between BMI and hypothyroidism was determined by the inverse variance weighted (IVW), weighted median method and the MR-Egger method, respectively. A heterogeneity test, gene pleiotropy test, and sensitivity analysis were performed to evaluate the stability and reliability of the results. Results:A total of 89 SNPs related to BMI were screened out as instrumental variables. IVW analysis suggested that for every standard deviation increase in BMI, the risk of hypothyroidism increased by 0.9% (odd ratio ( OR)=1.009, 95% confidence interval ( CI): 1.006-1.012, P<0.001). Similar results were obtained with the weighted median method ( OR=1.007, 95% CI: 1.002-1.011, P=0.003) and the MR-Egger method ( OR=1.008, 95% CI: 1.001-1.015, P=0.006). The MR-Egger analysis showed that genetic pleiotropy did not bias the results (intercept=0.000 1, P=0.776), the one-by-one exclusion method did not show that a single instrumental variable SNP had a significant impact on the results, and the difference was not statistically significant ( P>0.05). Conclusion:Mendelian randomized analysis showed a positive causal relationship between BMI and hypothyroidism.

SARS-CoV-2 infection causes complicated clinical manifestations with variable multi-organ injuries, however, the underlying mechanism, in particular immune responses in different organs, remains elusive. In this study, comprehensive transcriptomic alterations of 14 tissues from rhesus macaque infected with SARS-CoV-2 were analyzed. Compared to normal controls, SARS-CoV-2 infection resulted in dysregulation of genes involving diverse functions in various examined tissues/organs, with drastic transcriptomic changes in cerebral cortex and right ventricle. Intriguingly, cerebral cortex exhibited a hyperinflammatory state evidenced by significant upregulation of inflammation response-related genes. Meanwhile, expressions of coagulation, angiogenesis and fibrosis factors were also up-regulated in cerebral cortex. Based on our findings, neuropilin 1 (NRP1), a receptor of SARS-CoV-2, was significantly elevated in cerebral cortex post infection, accompanied by active immune response releasing inflammatory factors and signal transmission among tissues, which enhanced infection of the central nervous system (CNS) in a positive feedback way, leading to viral encephalitis. Overall, our study depicts a multi-tissue/organ transcriptomic landscapes of rhesus macaque with early infection of SARS-CoV-2, and provides important insights into the mechanistic basis for COVID-19-associated clinical complications.
Animals ; COVID-19/genetics* ; Macaca mulatta ; SARS-CoV-2/genetics* ; Transcriptome

Objective: To analyze the clinical characteristics of children with Burkitt lymphoma (BL) and to summarize the mid-term efficacy of China Net Childhood Lymphoma-mature B-cell lymphoma 2017 (CNCL-B-NHL-2017) regimen. Methods: Clinical features of 436 BL patients who were ≤18 years old and treated with the CNCL-B-NHL-2017 regimen from May 2017 to April 2021 were analyzed retrospectively. Clinical characteristics of patients at disease onset were analyzed and the therapeutic effects of patients with different clinical stages and risk groups were compared. Survival analysis was performed by Kaplan-Meier method, and Cox regression was used to identify the prognostic factors. Results: Among 436 patients, there were 368 (84.4%) males and 68 (15.6%) females, the age of disease onset was 6.0 (4.0, 9.0) years old. According to the St. Jude staging system, there were 4 patients (0.9%) with stage Ⅰ, 30 patients (6.9%) with stage Ⅱ, 217 patients (49.8%) with stage Ⅲ, and 185 patients (42.4%) with stage Ⅳ. All patients were stratified into following risk groups: group A (n=1, 0.2%), group B1 (n=46, 10.6%), group B2 (n=19, 4.4%), group C1 (n=285, 65.4%), group C2 (n=85, 19.5%). Sixty-three patients (14.4%) were treated with chemotherapy only and 373 patients (85.6%) were treated with chemotherapy combined with rituximab. Twenty-one patients (4.8%) suffered from progressive disease, 3 patients (0.7%) relapsed, and 13 patients (3.0%) died of treatment-related complications. The follow-up time of all patients was 24.0 (13.0, 35.0) months, the 2-year event free survival (EFS) rate of all patients was (90.9±1.4) %. The 2-year EFS rates of group A, B1, B2, C1 and C2 were 100.0%, 100.0%, (94.7±5.1) %, (90.7±1.7) % and (85.9±4.0) %, respectively. The 2-year EFS rates was higher in group A, B1, and B2 than those in group C1 (χ²=4.16, P=0.041) and group C2 (χ²=7.21, P=0.007). The 2-year EFS rates of the patients treated with chemotherapy alone and those treated with chemotherapy combined with rituximab were (79.3±5.1)% and (92.9±1.4)% (χ²=14.23, P<0.001) respectively. Multivariate analysis showed that stage Ⅳ (including leukemia stage), serum lactate dehydrogenase (LDH)>4-fold normal value, and with residual tumor in the mid-term evaluation were risk factors for poor prognosis (HR=1.38,1.23,8.52,95%CI 1.05-1.82,1.05-1.43,3.96-18.30). Conclusions: The CNCL-B-NHL-2017 regimen show significant effect in the treatment of pediatric BL. The combination of rituximab improve the efficacy further.
Adolescent ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Burkitt Lymphoma/drug therapy* ; Child ; Disease-Free Survival ; Female ; Humans ; Lactate Dehydrogenases ; Lymphoma, B-Cell/drug therapy* ; Male ; Prognosis ; Retrospective Studies ; Rituximab/therapeutic use* ; Treatment Outcome

Objective: The relationship between serum uric acid (SUA) levels and glycemic indices, including plasma glucose (FPG), 2-hour postload glucose (2h-PG), and glycated hemoglobin (HbA1c), remains inconclusive. We aimed to explore the associations between glycemic indices and SUA levels in the general Chinese population. Methods: The current study was a cross-sectional analysis using the first follow-up survey data from The China Cardiometabolic Disease and Cancer Cohort Study. A total of 105,922 community-dwelling adults aged ≥ 40 years underwent the oral glucose tolerance test and uric acid assessment. The nonlinear relationships between glycemic indices and SUA levels were explored using generalized additive models. Results: A total of 30,941 men and 62,361 women were eligible for the current analysis. Generalized additive models verified the inverted U-shaped association between glycemic indices and SUA levels, but with different inflection points in men and women. The thresholds for FPG, 2h-PG, and HbA1c for men and women were 6.5/8.0 mmol/L, 11.0/14.0 mmol/L, and 6.1/6.5, respectively (SUA levels increased with increasing glycemic indices before the inflection points and then eventually decreased with further increases in the glycemic indices). Conclusion An inverted U-shaped association was observed between major glycemic indices and uric acid levels in both sexes, while the inflection points were reached earlier in men than in women.
Aged ; Asian Continental Ancestry Group ; Blood Glucose/analysis* ; China/epidemiology* ; Cohort Studies ; Diabetes Mellitus/blood* ; Female ; Glucose Tolerance Test ; Glycated Hemoglobin A/analysis* ; Glycemic Index ; Humans ; Male ; Middle Aged ; Uric Acid/blood*

According to human carboxylesterase 2(hCE2) inhibitors reported in the literature, the pharmacophore model of hCE2 inhibitors was developed using HipHop module in Discovery Studio 2016. The optimized pharmacophore model, which was validated by test set, contained two hydrophobic, one hydrogen bond acceptor, and one aromatic ring features. Using the pharmacophore model established, 5 potential hCE2 inhibitors(CS-1,CS-2,CS-3,CS-6 and CS-8) were screened from 20 compounds isolated from the roots of Paeonia lactiflora, which were further confirmed in vitro, with the IC_(50) values of 5.04, 5.21, 5.95, 6.64 and 7.94 μmol·L~(-1), respectively. The results demonstrated that the pharmacophore model exerted excellent forecasting ability with high precision, which could be applied to screen novel hCE2 inhibitors from Chinese medicinal materials.
Carboxylesterase/metabolism* ; Humans ; Hydrogen Bonding ; Hydrophobic and Hydrophilic Interactions

Objective:To explore the effects of Huanglian Wendantang （HLWDT） on pyroptosis of skeletal muscle in rats with impaired glucose tolerance （IGT） and to explain the mechanism based on NOD-like receptor protein 3 （NLRP3）/cysteine aspartate-specific protease-1 （Caspase-1）/gasdermin D （GSDMD）/interleukin-1β （IL-1β）/IL-18 signaling pathway. Method:The SD male rats were fed with 45% high-fat diet for 20 weeks to induce the IGT model. After modeling， the rats were randomly divided into a blank group， a model group， a positive control group （metformin hydrochloride， 0.05 g·kg^-1d^-1）， and an HLWDT （7.8 g·kg^-1d^-1） group based on the body weight of rats. The blank group and the model group were fed with the same volume of distilled water. The dose for each group was set as 10 mL·kg^-1d^-1. After four weeks of continuous gavage， blood was collected and serum was separated. The skeletal muscles of rats were stored in liquid nitrogen. Subsequently， serum IL-1β and IL-18 were detected by the enzyme-linked immunosorbent assay （ELISA）. The mRNA and protein expression levels of NLRP3， Caspase-1， and GSDMD were detected by real-time quantitative PCR （Real-time PCR） and Western blot， respectively. The expression of GSDMD， IL-1β， and IL-18 proteins in skeletal muscle tissues was detected by immunofluorescence. Hematoxylin-eosin （HE） staining was used to observe the pathological changes of skeletal muscles. Result:Compared with the blank group， the model group showed increased IL-1β and IL-18 in serum， and NLRP3， Caspase-1， and GSDMD gene and protein expression in skeletal muscle tissues （P<0.01）. Immunofluorescence assay showed that GSDMD， IL-18， and IL-1β protein expression in skeletal muscle tissues of the model group was significantly elevated （P<0.01）. HE staining showed obvious pathological changes in skeletal muscles. Compared with the model group， the HLWDT group and the positive control group could decrease IL-1β and IL-18 in serum and NLRP3， Caspase-1， and GSDMD gene and protein expression in skeletal muscle tissues （P<0.01）. In addition， immunofluorescence assay revealed that HLWDT could reduce protein expression levels of GSDMD， IL-1β， and IL-18 in skeletal muscles of IGT rats （P<0.01）. The results of HE staining showed that HLWDT could improve the pathological changes of skeletal muscles in IGT rats. Conclusion:HLWDT can inhibit skeletal muscle pyroptosis of IGT rats， and the mechanism may be closely related to NLRP3/Caspase-1/GSDMD/IL-18/IL-1β signaling pathway.

Objective: To evaluate the anti-inflammatory activity of Crotalaria ferruginea extract (CFE) and its mechanism. Methods: An intratracheal lipopolysaccharide (LPS) instillation-induced acute lung injury (ALI) model was used to study the anti-inflammatory activity of CFE in vivo. The LPS-induced shock model was used to analyze the effect of CFE on survival. LPS-stimulated RAW264.7 cell model was used to investigate the anti-inflammatory activity of CFE in vitro and the effects on mitogen-Activated protein kinase (MAPK) or nuclear factor-κB (NF-κB) signaling pathways. Results: CFE administration decreased the number of inflammatory cells, reduced the levels of tumor necrosis factor-α (TNF-A), monocyte chemotactic protein-1 (MCP-1), interleukin-6 (IL-6), and interferon-γ, and diminished protein content in the bronchoalveolar lavage fluid of mice. CFE also reduced lung wet-To-dry weight ratio, myeloperoxidase, and lung tissue pathological injury. CFE pre-Administration improved the survival rate of mice challenged with a lethal dose of LPS. CFE reduced LPS-Activated RAW264.7 cells to produce nitric oxide, TNF-α, MCP-1, and IL-6. Furthermore, CFE inhibited nuclear translocation and phosphorylation of NF-κB P65, extracellular signal-regulated kinase, c-Jun N-Terminal kinases, and P38 MAPKs. Conclusions: CFE exhibits potent anti-inflammatory activity in LPS-induced ALI mice, LPS-shock mice, and RAW264.7 cells, and its mechanism may be associated with the inhibition of NF-κB and MAPK signaling pathways. Crotalaria ferruginea may be a useful therapeutic drug for the treatment of ALI and other respiratory inflammations.

Pancreatic lipase (PL), a crucial enzyme in the digestive system of mammals, has been proven as a therapeutic target to prevent and treat obesity. The purpose of this study is to evaluate and characterize the PL inhibition activities of the major constituents from Fructus Psoraleae (FP), one of the most frequently used Chinese herbs with lipid-lowering activity. To this end, a total of eleven major constituents isolated from Fructus Psoraleae have been obtained and their inhibition potentials against PL have been assayed by a fluorescence-based assay. Among all tested compounds, isobavachalcone, bavachalcone and corylifol A displayed strong inhibition on PL (IC < 10 μmol·L). Inhibition kinetic analyses demonstrated that isobavachalcone, bavachalcone and corylifol A acted as mixed inhibitors against PL-mediated 4-methylumbelliferyl oleate (4-MUO) hydrolysis, with the K values of 1.61, 3.77 and 10.16 μmol·L, respectively. Furthermore, docking simulations indicated that two chalcones (isobavachalcone and bavachalcone) could interact with the key residues located in the catalytic cavity of PL via hydrogen binding and hydrophobic interactions. Collectively, these finding provided solid evidence to support that Fructus Psoraleae contained bioactive compounds with lipid-lowering effects via targeting PL, and also suggested that the chalcones in Fructus Psoraleae could be used as ideal leading compounds to develop novel PL inhibitors.

The peeled root,stem or twig of Syringa pinnatifolia is a representative Mongolian folk medicine with the effects of antidepression and pain relief. It has been used for the treatments of heart tingling,heart palpitations,upset,insomnia and other symptoms. Inspired by Mongolian medical theory and clinical practices,this study evaluated the analgesic effect of S. pinnatifolia ethanol extract( T) through three analgesic models including acetic acid writhing test,formalin test,and hot plate test,and the sedative effect of T was evaluated by locomotor activity and synergistic sleeping experiments,and furthermore the effects of T on the GABAergic nervous system were investigated by ELISA,immunohistochemistry,Western blot,and PCR methods. The results showed that T can significantly reduce the number of writhing,the time of paw licking and extend the thermal threshold of mice,suggesting the analgesic effect of T.T also can indicate its sedative effect by reducing the number of activities,decreasing latency of sleeping and extending sleeping time of mice. ELISA results showed that T can increase the content of GABA/Glu in rat cortex,hippocampus,and hypothalamus,and the most significant increase in hypothalamus. The immunohistochemistry and Western blot results showed that T can up-regulate the expression of GAD67 protein in hypothalamus,and the PCR results showed that T can up-regulate the expression of GABAA Rα1,α2,α3,α5,β1-3,γ1-3 genes,suggesting a sedative effect through the GABAergic nervous system. In conclusion,this study shed insight into the theoretical basis and clinical application of S. pinnatifolia,and also provides inspiration for subsequent development and application.
Analgesics ; pharmacology ; Animals ; Hypnotics and Sedatives ; pharmacology ; Medicine, Mongolian Traditional ; Mice ; Pain ; Plant Extracts ; pharmacology ; Rats ; Syringa ; chemistry

As part of systematic research of Corydalis hendersonii,a typical traditional Tibetan herbal medicine with clearing heat,relieving pain,and lowering blood pressure effects,a novel isoquinoline alkaloid,named hendersine G was isolated from the ethanol extract of the whole plant by various chromatographic techniques,including silica gel column,reverse phase column (ODS),Sephadex LH-20,and semi-preparative HPLC.Its structure was elucidated by MS,NMR and other spectroscopic data analysis.Hendersine G can be regarded as a condensation product of a tetrahydroberberine and a succinic acid,however,its absolute configuration has not been determined due to its structural complexity and less obtained amount.This present study provides an inspiration for further exploration of novel molecules from C.hendersonii.