Objective To study the effect of aerobic exercise and dietary intervention on lipid metabolism in metabolic syndrome rats, and investigate the possible mechanism mediated by peroxisome proliferator-activated receptorα(PPARα). Methods After one-week feed-ing, Sprague-Dawley rats were randomly divided into blank control group (CC group) and model group which were feed in high-fat-and-salt diet for 18 weeks to establish a metabolic syndrome model. Then, the metabolic syndrome rats were randomly divided into model control group (MC), the model high-fat diet group (MHE) and the model general died exercise group (ME). ME and MHE groups were forced to run on a treadmill for twelve weeks at the same time. The weight of perirenal fat, blood free fat acid (FFA), and blood lipid were determined. The expression of PPARαmRNA in myocardium was detected by RT-PCR. Western blotting was applied to detect the protein expression of PPARαin myocardium. Results Compared with CC group, MC group showed significant increase in body weight, perirenal fat weigh, FFA, and blood lipid (P<0.05), and significant decrease in PPARαmRNA and protein expression (P<0.01) in myocardium. Compared with MC group, ME and MHE groups showed significant decrease in body weight, perirenal fat weight, triglyceride (TG), and showed significant in-crease in high-density lipoprotein (HDL), and the expression of PPARαmRNA and protein in myocardium (P<0.05). Compared with MHE group, ME group showed decrease in low-density lipoprotein (LDL) (P<0.05), and increase in the expression of PPARαmRNA and protein (P<0.01). Conclusion Aerobic exercise may activate the expression of PPARα, enhance the utilization of fatty acid, reduce body mass and visceral fat mass, improve the dyslipidemia and then regulate lipid metabolism in metabolic syndrome rats.

The BCCIP (BRCA2- and CDKN1A-interacting protein) is an important cofactor for BRCA2 in tumor suppression. Although the low expression of BCCIP is observed in multiple clinically diagnosed primary tumor tissues such as ovarian cancer, renal cell carcinoma and colorectal carcinoma, the mechanism of how BCCIP is regulated in cells is still unclear. The human INO80/YY1 chromatin remodeling complex composed of 15 subunits catalyzes ATP-dependent sliding of nucleosomes along DNA. Here, we first report that BCCIP is a novel target gene of the INO80/YY1 complex by presenting a series of experimental evidence. Gene expression studies combined with siRNA knockdown data locked candidate genes including BCCIP of the INO80/YY1 complex. Silencing or over-expressing the subunits of the INO80/YY1 complex regulates the expression level of BCCIP both in mRNA and proteins in cells. Also, the functions of INO80/YY1 complex in regulating the transactivation of BCCIP were confirmed by luciferase reporter assays. Chromatin immunoprecipitation (ChIP) experiments clarify the enrichment of INO80 and YY1 at +0.17 kb downstream of the BCCIP transcriptional start site. However, this enrichment is significantly inhibited by either knocking down INO80 or YY1, suggesting the existence of both INO80 and YY1 is required for recruiting the INO80/YY1 complex to BCCIP promoter region. Our findings strongly indicate that BCCIP is a potential target gene of the INO80/YY1 complex.
Calcium-Binding Proteins ; genetics ; metabolism ; Cell Cycle Proteins ; genetics ; metabolism ; Chromatin Assembly and Disassembly ; physiology ; DNA Helicases ; genetics ; metabolism ; HeLa Cells ; Humans ; Multiprotein Complexes ; genetics ; metabolism ; Nuclear Proteins ; genetics ; metabolism ; Promoter Regions, Genetic ; physiology ; Transcription, Genetic ; physiology ; YY1 Transcription Factor ; genetics ; metabolism

Objective To investigate DNA methylation markers in the whole blood of patients with systemic lupus erythematosus(SLE),in hope to facilitate the evaluation of SLE severity.Methods Whole blood samples were obtained from 58 patients with SLE(including 14 cases of severe SLE,25 moderate SLE,19 inactive SLE)and 50 healthy controls.Bisulphite sequencing was performed to determine the methylation status of interleukin-2 common receptor gamma chain(IL-2RG)promoter region,and real-time reverse transcriptionPCR to quantify the expression level of IL-2RG mRNA,in these subjects.Results The methylation level of IL2RG promoter region was 0.217 ± 0.140,0.325 ± 0.230,0.342 ± 0.085 and 0.175 ± 0.036 in the patients withsevere,moderate and inactive SLE and healthy controls,respectively.A significant increase was observed in the methylation level of IL-2RG promoter region in the patients with inactive SLE compared with the patients with severe SLE and healthy controls(both P ＜ 0.01),and in the patients with SLE compared with the healthy controls(0.263 ± 0.047 vs.0.175 ± 0.036,P ＜ 0.05).The expression level of IL-2RG mRNA was significantly lower in the patients with SLE than in the healthy controls(2.550 ± 0.823 vs.4.293 ± 1.283,P ＜ 0.05).A negative correlation was observed between the expression level of IL-2RG mRNA and methylation level of IL2RG promoter region in 20 patients with SLE(r =-0.44,P ＜ 0.05).Conclusion The methylation status of IL2RG promoter region is statistically higher in patients with SLE than in healthy controls,and significantly different between patients with active SLE and those with stable SLE.

AIM:To explore the therapeutic effect of a novel Rho kinase inhibitor WAR 5 on the experimental autoimmune encephalomyelitis (EAE) and its possible mechanism.METHODS: Female C57BL/6 mice were randomly divided into EAE group and WAR5 group.EAE model was induced by the application of MOG 35-55 peptide.WAR5 was in-jected intraperitoneally every other day from post-immunization (PI) day 3 to PI day 27.The clinical score and body weight were recorded every other day .On PI day 28, the animals were sacrificed and spinal cords were obtained for HE and mye-lin staining .The splenocytes were isolated and the expression of CD 16/32 and CD206 were analyzed by flow cytometry . The protein extracts from the brains and spinal cords were collected for the measurement of inducible nitric oxide synthase ( iNOS) by Western blotting .RESULTS:The administration of WAR 5 delayed the onset of EAE and attenuated the clini-cal symptoms .The results of the pathological examination revealed that WAR 5 inhibited the infiltration of inflammatory cells and improved myelination in spinal cords , accompanied with the poralization of M 1 macrophages to M2 phenotype in the spleen.WAR5 inhibited the expression of iNOS in the central nervous system , especially in the spinal cords .CON-CLUSION:The therapeutic effect of WAR5 on EAE may be related to the shift of M1 macrophages to M2 phenotype and inhibition of inflammation in the central nerve system .

Objective To studyexplore the reversal effect of S-adenosylmethionine(SAM)on chemotherapy resistancechemoresis-tance of pancreatic cancer and explore its related mechanisms.Methods After treatment of human pancreatic cancer resistant cell lines PANC-1/GEM with SAM,the cell proliferation activity of PANC-1/GEM cells and their resistance to gemcitabine(GEM)were ana-lyzed by MTT assay;The the effect of SAM on apoptosis rate of PANC-1/GEM cells was detected by flow cytometry;the change of SAM on the migration activity of drug-resistant cell lines was detected by cell scratch assay;the expression of NEDD4-1 protein in drug-re-sistant cell lines and the changes of NEDD4-1,p-JAK2,p-STAT3 and P-gp protein levels after SAM treatment were detected by Western blot.Results SAM could inhibit the activity of pancreatic cancer PANC-1/GEM resistant cell lines and significantly decreased its resistance to GEM chemotherapy.The IC50 value decreased from 1557.50±201.10nmol/L to 218.39±20.61 nmol/L(P＜0.01);SAM can obviously induced the apoptosis of drug-resistant cell lines and inhibited their migration activity;the expression of NEDD4-1 protein was up-regulated in drug-resistant cell lines,and SAM could inhibit the activation levels of NEDD4-1,p-JAK2,p-STAT3 and P-gp proteins.Conclusion SAM can reduce the chemotherapy resistance of PANC-1/GEM cells to GEM by regulating NEDD4-1 to inhibit the activity of JAK2/STAT3 pathway and regulate the activity of P-gp protein,which provides some experimental evidence for the clinical application of SAM in the treatment of chemotherapy resistance in tumor patients.

Objective To investigate the safety and efficacy of bybrid surgery in the treatment of cerebral arteriovenous malformation(CAVM)and possible factors for postoperative symptom progression.Methods A total of 61 patients with CAVM admitted to the Department of Neurosurgery,Xuanwu Hospital,Capital Medical University from January 1,2016 to December 31,2021 who underwent bybrid surgery were retrospectively included.Demographic information(sex,age),incidence(first diagnosis of CAVM by imaging and/or first appearance of CAVM-related symptoms such as hemorrhage and epilepsy),time from onset to hybrid surgery,modified Rankin scale(mRS)score at admission,history of previous CAVM treatment(surgical removal of previous CAVM and intravascular treatment),CAVM imaging data(lesion location,size,drainage),Spetzler-Martin grade,lesion density(loose,dense),CAVM combined with aneurysm or aneurysmal structure,surgical method(microsurgery+intraoperative DSA,microsurgery+intraoperative DSA+endovascular embolism),treatment-related complications(intracranial hemorrhage and/or ischemic events and/or edema in surgery-related areas,puncture site hematoma and/or fistula and/or pseudoaneurysm,gastrointestinal and/or gingival bleeding and/or epistaxis,contrast hypersensitivity,all-cause death),clinical and radiological follow-up data were recorded.The safety(treatment-related complications,symptom progression[positive difference between the mRS score at 6 months postoperatively and the baseline mRS score])and effectiveness(occlusion,complete absence of the malformation on DSA at 6 months postoperatively;good prognosis,mRS score≤2 at 6months postoperatively)of hybrid surgery treatment were evaluated.Based on the clinical follow-up results at 6 months after surgery,patients who underwent hybrid surgery for CAVM were divided into the progressive group and the non-progressive group,and their baseline and clinical characteristics were compared.Results(1)Among the 61 patients who underwent hybrid surgery for CAVM,37(60.7％)were male,with a median age of 25(13,42)years;11(18.0％)were asymptomatic,and 39(63.9％)had hemorrhage as their initial symptom,while 11(18.0％)had seizures as their initial symptom.At admission,54(88.5％)patients had an mRS score of ≤2,including 38(62.3％)patients who had undergone previous endovascular embolization and had residual or recurrent CAVM;the Spetzler-Martin grade of the CAVM lesion was Ⅰ,Ⅱ,Ⅲ,or Ⅳ in 13(21.3％),22(36.1％),21(34.4％),and 5(8.2％)patients,respectively;24 patients underwent DSA verification during surgery using a hybrid surgical platform,and 37 patients underwent DSA verification and assisted endovascular embolization using a hybrid surgical platform.(2)Clinical follow-up completion rate was 77.0％(47/61);the follow-up time ranged from 6 to 24 months and the median follow-up time was 12(6,24)months.The good prognosis rate was 91.5％(43/47),there was no death.The incidence of treatment-related complications was 10.6％(5/47).The completion rate of imaging follow-up was 72.1％(44/61)and the median follow-up time was 15(10,22)months.There were 40(90.9％)of CAVM occlusion,2(4.5％)of residual CAVM and 2(4.5％)of recurrent CAVM.(3)Among the 47 patients who completed clinical follow-up,15 patients developed symptoms and 32 patients did not develop symptoms.There were no significant differences in sex,age,onset symptoms,mRS score at admission,lesion location,lesion density and aneurysm or aneurysmal structure between the two groups(all P＞0.05).In the progressive group,the proportion of lesions with the largest diameter＜3 cm,3-6 cm and＞6 cm were 3/15,10/15 and 2/15,respectively,and the largest diameter was mainly 3-6 cm.In the non-progressive group,the proportion of the largest diameter＜3 cm and 3-6 cm were 18/32 and 14/32,respectively,and the largest diameter＜3 cm was the main proportion(x2=8.321).Deep venous drainage(x2=11.937)and residual and/or recurrence(x2=8.507)were present in the progressive group,and the differences between the groups were statistically significant(all P＜0.05).Conclusions Hybrid surgery has certain safety and effectiveness in the treatment of CAVM.Patients with CAVM who experienced progression after undergoing composite surgery have characteristics such as larger maximum diameter,the presence of deep venous drainage and residual and/or recurrence,and the factors affecting progression need to be further explored in the future.

Background::Atopic dermatitis (AD) affects approximately 10% of adults worldwide. CM310 is a humanized monoclonal antibody targeting interleukin-4 receptor alpha that blocks interleukin-4 and interleukin-13 signaling. This trial aimed to evaluate the efficacy and safety of CM310 in Chinese adults with moderate-to-severe AD.Methods::This multicenter, randomized, double-blind, placebo-controlled, phase 2b trial was conducted in 21 medical institutions in China from February to November 2021. Totally 120 eligible patients were enrolled and randomized (1:1:1) to receive subcutaneous injections of 300 mg CM310, 150 mg CM310, or placebo every 2 weeks for 16 weeks, followed by an 8-week follow-up period. The primary endpoint was the proportion of patients achieving ≥75% improvement in the Eczema Area and Severity Index (EASI-75) score from baseline at week 16. Safety and pharmacodynamics were also studied.Results::At week 16, the proportion of EASI-75 responders from baseline was significantly higher in the CM310 groups (70% [28/40] for high-dose and 65% [26/40] for low-dose) than that in the placebo group (20%[8/40]). The differences in EASI-75 response rate were 50% (high vs. placebo, 95% CI 31%–69%) and 45% (low vs. placebo, 95% CI 26%–64%), with both P values <0.0001. CM310 at both doses also significantly improved the EASI score, Investigator’s Global Assessment score, daily peak pruritus Numerical Rating Scale, AD-affected body surface area, and Dermatology Life Quality Index compared with placebo. CM310 treatment reduced levels of thymus and activation-regulated chemokine, total immunoglobulin E, lactate dehydrogenase, and blood eosinophils. The incidence of treatment-emergent adverse events (TEAEs) was similar among all three groups, with the most common TEAEs reported being upper respiratory tract infection, atopic dermatitis, hyperlipidemia, and hyperuricemia. No severe adverse events were deemed to be attributed to CM310. Conclusion::CM310 at 150 mg and 300 mg every 2 weeks demonstrated significant efficacy and was well-tolerated in adults with moderate-to-severe AD.Trial Registration::ClinicalTrials.gov, NCT04805411.