Aim To identify the underlying target of bullatine A(BA)against rheumatoid arthritis(RA)u-sing limited proteolysis-small molecule mapping(LiP-SMap)drug target proteomics and to provide a scientif-ic basis for clinical application of Aconiti brachypodi Radix in the treatment of RA.Methods LiP-SMap drug target proteomics was employed to perform bioin-formatics analysis for comparing and validating the dif-ferential protein expression after BA intervention.A collagen-induced arthritis(CIA)model was estab-lished in DBA/1 mice using bovine type Ⅱ collagen.The mice were then divided into the CIA model group,methotrexate-positive control group(MTX group),and BA groups(10 mg·kg-1 and 20 mg·kg-1)based on their clinical scores.After drug intervention,the thera-peutic efficacy against RA was assessed by joint index scores and foot thickness measurements.Histopatholog-ical changes in the arthritic joints of CIA mice were e-valuated using hematoxylin and eosin(HE)staining.Enzyme-linked immunosorbent assay(ELISA)was employed to detect inflammatory cytokines interleukin-17(IL-17)and total IgG and IgG3 anti-collagen-spe-cific antibodies levels from the serum of CIA mice.Flow cytometry was used to detect the expression levels of intracellular Th17 cells(IL-17+CD4+T cells)and Th1 cells(IFN-γ+CD4+T cells).Fluorescent quanti-tative PCR was performed to detect the expression of genes related to differential proteins.Results The proteomic analysis identified Serpinb1a as a protein with strong binding affinity to BA,and KEGG enrich-ment analysis indicated IL-17 signaling pathway was a crucial pathway of BA in against RA.BA treatment significantly reduced clinical scores and foot thickness,improved local arthritis symptoms in CIA mice,and al-leviated inflammatory cell infiltration into arthritic joints(P＜0.05).Differential protein validation re-sults showed that BA had strong affinity with Serpinb1a(-5.92 kJ·mol-1)and downregulated the expres-sion of Serpinb1a mRNA.Furthermore,the administra-tion of BA markedly reduced serum IL-17 A levels from CIA mice,inhibited the expression of intracellular IL-17 A and IFN-γ cytokines in splenic CD4+T cells(P＜0.05),and significantly downregulated the transcrip-tional expression of IL-17F(P＜0.05).Conclusion BA exhibits therapeutic effects on collagen-induced arthritis,and its mechanism of action may involve the regulation of Serpinb1a and the IL-17 signaling path-way.

Aim To identify the underlying target of bullatine A(BA)against rheumatoid arthritis(RA)u-sing limited proteolysis-small molecule mapping(LiP-SMap)drug target proteomics and to provide a scientif-ic basis for clinical application of Aconiti brachypodi Radix in the treatment of RA.Methods LiP-SMap drug target proteomics was employed to perform bioin-formatics analysis for comparing and validating the dif-ferential protein expression after BA intervention.A collagen-induced arthritis(CIA)model was estab-lished in DBA/1 mice using bovine type Ⅱ collagen.The mice were then divided into the CIA model group,methotrexate-positive control group(MTX group),and BA groups(10 mg·kg-1 and 20 mg·kg-1)based on their clinical scores.After drug intervention,the thera-peutic efficacy against RA was assessed by joint index scores and foot thickness measurements.Histopatholog-ical changes in the arthritic joints of CIA mice were e-valuated using hematoxylin and eosin(HE)staining.Enzyme-linked immunosorbent assay(ELISA)was employed to detect inflammatory cytokines interleukin-17(IL-17)and total IgG and IgG3 anti-collagen-spe-cific antibodies levels from the serum of CIA mice.Flow cytometry was used to detect the expression levels of intracellular Th17 cells(IL-17+CD4+T cells)and Th1 cells(IFN-γ+CD4+T cells).Fluorescent quanti-tative PCR was performed to detect the expression of genes related to differential proteins.Results The proteomic analysis identified Serpinb1a as a protein with strong binding affinity to BA,and KEGG enrich-ment analysis indicated IL-17 signaling pathway was a crucial pathway of BA in against RA.BA treatment significantly reduced clinical scores and foot thickness,improved local arthritis symptoms in CIA mice,and al-leviated inflammatory cell infiltration into arthritic joints(P＜0.05).Differential protein validation re-sults showed that BA had strong affinity with Serpinb1a(-5.92 kJ·mol-1)and downregulated the expres-sion of Serpinb1a mRNA.Furthermore,the administra-tion of BA markedly reduced serum IL-17 A levels from CIA mice,inhibited the expression of intracellular IL-17 A and IFN-γ cytokines in splenic CD4+T cells(P＜0.05),and significantly downregulated the transcrip-tional expression of IL-17F(P＜0.05).Conclusion BA exhibits therapeutic effects on collagen-induced arthritis,and its mechanism of action may involve the regulation of Serpinb1a and the IL-17 signaling path-way.

Objective To study the clinical characteristics and bacterial antimicrobial susceptibility testing results of patients with clinically isolated Ralstonia pickettii(R.pickettii),and provide basis for the rational use of antimi-crobial agents.Methods Inpatients with R.pickettii infection who were treated at the Tianjin First Central Hospi-tal from January 2014 to December 2023 were analyzed retrospectively.Clinical characteristics and antimicrobial sus-ceptibility testing results were analyzed.Results A total of 80 strains of Ralstonia spp.were isolated over 10-year period,including 42(52.5％)non-repetitive strains of R.pickettii.Among 42 R.pickettii strains,64.3％were isolated from male patients.The strains isolated from sputum,catheter,blood,throat swabs,and drainage fluid specimens accounted for 38.1％,28.6％,19.0％,4.8％,and 2.4％,respectively.The clinical distribution of R.pickettii was highest in the intensive care unit(ICU),with a proportion of 52.4％.The number of infected patients first increased and then decreased with the years,followed by a slight fluctuation.There was no statistically signifi-cant difference in the number of infected patients in each department over the years(P＞0.05).R.pickettii had higher susceptibility rates to doxycycline,levofloxacin,ciprofloxacin,and minocycline,susceptibility rates were 78.3％-90.9％,but was completely resistant to compound sulfamethoxazole and cefazolin(100％),it also had higher resistance rates to aztreonam,colistin,cefotetan,tobramycin,amikacin,ceftazidime,and gentamicin(80.0％-97.4％).There was no statistically significant difference in the resistance rates to 21 antimicrobial agents among different years(all P＞0.05).Conclusion R.pickettii is mainly from ICU,and the majority of the infected population are adult males.Most strains are isolated from sputum and catheter.R.pickettii presents multidrug re-sistance.Attention should be paid to the changes in the resistance rates of antimicrobial agents,strengthen the dy-namic monitoring of bacterial resistance and guide the rational selection of antimicrobial agents in clinic,implement early and effective treatment to improve the prognosis of the patients.

This study aims to evaluate the methodological and reporting quality of diagnosis and treatment guidelines for hyperuricemia as well as the expert consensuses and promote the understanding and application of the diagnosis and treatment guidelines for hyperuricemia. With "hyperuricemia" "guidelines" "consensus" "recommendations" as the key words in titles, the authors searched for the published clinical guidelines on hyperuricemia in Chinese against CNKI, Wanfang, VIP, Medlive and the official website of the industry association. The retrieval time limit was until May 31, 2021. The appraisal of guidelines for research and evaluation Ⅱ(AGREEⅡ) and the reporting items for practice guidelines in health care(RIGHT) were employed to evaluate the methodological quality and reporting quality of 14 guidelines/consensuses included. The average scores of the guidelines/consensuses were 80.85%(48.61%-98.61%) for the domain of scope and purpose, 34.52%(0-69.44%) for the domain of stakeholder involvement, 35.53%(6.25%-92.19%) for the domain of rigor of development, 55.85%(23.61%-86.11%) for the domain of clarity of presentation, 26.19%(0-76.04%) for the domain of applicability, and 21.42%(0-50.00%) for the domain of editorial independence. Nine guidelines/consensuses were of medium overall quality with grade B recommendation, and five guidelines/consensuses were of poor quality with grade C recommendation. The RIGHT classified the fourteen guidelines/consensuses into one of high reporting quality, three of medium reporting quality, and ten of low reporting quality. The results of this study indicate that the standardization and rigor of the methodological quality and the reporting quality of the clinical guidelines/consensuses for hyperuricemia in China remain to be strengthened.
China ; Consensus ; Humans ; Hyperuricemia/drug therapy* ; Publications ; Reference Standards

Objective: To investigate the functional changes of key gut microbiota (GM) that produce lipopolysaccharide (LPS) in atrial fibrillation (AF) patients and to explore their potential role in the pathogenesis of AF. Methods: This was a prospective cross-sectional study. Patients with AF admitted to Beijing Chaoyang Hospital of Capital Medical University were enrolled from March 2016 to December 2018. Subjects with matched genetic backgrounds undergoing physical examination during the same period were selected as controls. Clinical baseline data and fecal samples were collected. Bacterial DNA was extracted and metagenomic sequencing was performed by using Illumina Novaseq. Based on metagenomic data, the relative abundances of KEGG Orthology (KO), enzymatic genes and species that harbored enzymatic genes were acquired. The key features were selected via the least absolute shrinkage and selection operator (LASSO) analysis. The role of GM-derived LPS biosynthetic feature in the development of AF was assessed by receiver operating characteristic (ROC) curve, partial least squares structural equation modeling (PLS-SEM) and logistic regression analysis. Results: Fifty nonvalvular AF patients (mean age: 66.0 (57.0, 71.3), 32 males(64%)) were enrolled as AF group. Fifty individuals (mean age 55.0 (50.5, 57.5), 41 males(82%)) were recruited as controls. Compared with the controls, AF patients showed a marked difference in the GM genes underlying LPS-biosynthesis, including 20 potential LPS-synthesis KO, 7 LPS-biosynthesis enzymatic genes and 89 species that were assigned as taxa harbored nine LPS-enzymatic genes. LASSO regression analysis showed that 5 KO, 3 enzymatic genes and 9 species could be selected to construct the KO, enzyme and species scoring system. Genes enriched in AF group included 2 KO (K02851 and K00972), 3 enzymatic genes (LpxH, LpxC and LpxK) and 7 species (Intestinibacter bartlettii、Ruminococcus sp. JC304、Coprococcus catus、uncultured Eubacterium sp.、Eubacterium sp. CAG:251、Anaerostipes hadrus、Dorea longicatena). ROC curve analysis revealed the predictive capacity of differential GM-derived LPS signatures to distinguish AF patients in terms of above KO, enzymatic and species scores: area under curve (AUC)=0.957, 95%CI: 0.918-0.995, AUC=0.940, 95%CI 0.889-0.991, AUC=0.972, 95%CI 0.948-0.997. PLS-SEM showed that changes in lipopolysaccharide-producing bacteria could be involved in the pathogenesis of AF. The key KO mediated 35.17% of the total effect of key bacteria on AF. After incorporating the clinical factors of AF, the KO score was positively associated with the significantly increased risk of AF (OR<0.001, 95%CI:<0.001-0.021, P<0.001). Conclusion: Microbes involved in LPS synthesis are enriched in the gut of AF patients, accompanied with up-regulated LPS synthesis function by encoding the LPS-enzymatic biosynthesis gene.
Aged ; Atrial Fibrillation/complications* ; Cross-Sectional Studies ; Gastrointestinal Microbiome ; Humans ; Lipopolysaccharides ; Male ; Middle Aged ; Prospective Studies

ObjectiveTo explore the pharmacodynamic effect of gramine on 2，4-dinitrochlorobenzene （DNCB）-induced atopic dermatitis （AD） in mice and its potential mechanism. MethodThe mice were divided into the normal control group， model group， dexamethasone （0.05 g·kg^-1） group， and high- and low-dose （0.12，0.06 g·kg^-1） gramine groups. Mice in all groups except for the normal control group were stimulated with DNCB， followed by medication 13 d later. The changes in skin lesions were then observed， and the skin thickness， moisture content， and transepidermal water loss （TWEL） in each group were measured. The pathological changes in skin lesions were observed by hematoxylin-eosin （HE） staining， and the effects of drugs on CD4⁺/CD8⁺T-cell ratio in the spleen were detected by flow cytometry. The levels of immunoglobulin E （IgE）， interleukin （IL）-4， and IL-6 in serum were detected by enzyme-linked immunosorbent assay （ELISA）， and the changes in serum alanine aminotransferase （ALT）， aspartate aminotransferase （AST）， blood urea nitrogen （BUN）， and creatinine （CRE） by microplate method. The mRNA expression levels of inflammatory cytokines γ-interferon（IFN-γ）， IL-13， IL-17， IL-1β， IL-6， and tumor necrosis factor-α （TNF-α） in skin lesions were assayed by real-time polymerase chain reaction （Real-time PCR）， and the protein expression levels of nuclear transcription factor -κB (NF-κB) and NF-κB inhibitory protein α (IκBα) in skin lesions by Western blot. ResultCompared with the normal control group， the model group showed skin edema， erythema， scab， scratch， and lymphocyte and neutrophil infiltration， decreased skin moisture content， as well as increased skin thickness， TWEL （P<0.01）， spleen index， CD4⁺/CD8⁺ T-cell ratio in the spleen （P<0.05）， mRNA expression of IFN-γ， IL-13， IL-17， IL-1β， IL-6， and TNF-α in the skin lesions （P<0.05）， serum contents of IgE， IL-4， and IL-6 （P<0.05）， and protein expression of IκBα and NF-κB in skin lesions （P<0.05）. Compared with the model group， dexamethasone and gramine at different doses alleviated skin erythema， scale， scab， and inflammatory cell infiltration， elevated skin moisture content， inhibited skin thickening and TWEL， and decreased spleen index， CD4⁺/CD8⁺T-cell ratio in the spleen， mRNA expression of inflammatory factors in the skin lesions， serum contents of IgE and inflammatory factors， and protein expression of IκBα and NF-κB in skin lesions， especially in the dexamethasone group and the high- dose gramine group（P<0.05，P<0.01）. ConclusionGramine can inhibit the expression of related inflammatory factors and regulate the immune function of AD mice via the IκBα/NF-κB pathway， enabling it become a potential drug for treating AD.

Animals ; Apoptosis ; Bridged Bicyclo Compounds, Heterocyclic/pharmacology* ; Cell Line ; Hypoxia ; MicroRNAs/genetics* ; Myocardial Reperfusion Injury/drug therapy* ; Myocytes, Cardiac ; Oxidative Stress ; Rats ; Reperfusion Injury ; Tetrahydronaphthalenes/pharmacology*

Preclinical studies suggest that the GABA receptor is a potential target for treatment of substance use disorders. Baclofen (BLF), a prototypical GABA receptor agonist, is the only specific GABA receptor agonist available for application in clinical addiction treatment. The nucleus accumbens shell (AcbSh) is a key node in the circuit that controls reward-directed behavior. However, the relationship between GABA receptors in the AcbSh and memory reconsolidation was unclear. The aim of this study was to investigate the effect of intra-AcbSh injection of BLF on the reconsolidation of morphine reward memory. Male C57BL/6J mice were used to establish morphine conditioned place preference (CPP) model and carry out morphine reward memory retrieval and activation experiment. The effects of intra-AcbSh injection of BLF on morphine-induced CPP, reinstatement of CPP and locomotor activity were observed after environmental cues activating morphine reward memory. The results showed that intra-AcbSh injection of BLF (0.06 nmol/0.2 μL/side or 0.12 nmol/0.2 μL/side), rather than vehicle or BLF (0.01 nmol/0.2 μL/side), following morphine reward memory retrieval abolished morphine-induced CPP by disrupting its reconsolidation in mice. Moreover, this effect persisted for more than 14 days, which was not reversed by a morphine priming injection. Furthermore, intra-AcbSh injection of BLF without morphine reward memory retrieval had no effect on morphine-associated reward memory. Interestingly, administration of BLF into the AcbSh had no effect on the locomotor activity of mice during testing phase. Based on these results, we concluded that intra-AcbSh injection of BLF following morphine reward memory could erase morphine-induced CPP by disrupting its reconsolidation. Activating GABA receptor in AcbSh during drug memory reconsolidation may be a potential approach to prevent drug relapse.
Animals ; Baclofen ; administration & dosage ; Conditioning, Classical ; GABA-B Receptor Agonists ; administration & dosage ; Locomotion ; Male ; Memory ; Mice ; Mice, Inbred C57BL ; Morphine ; Nucleus Accumbens ; drug effects ; Opioid-Related Disorders ; Reward

Objective: To compare the safety profile, angiographic and clinical outcomes between drug-coated balloon(DCB) only strategy versus drug eluting stent(DES) implantation in primary percutaneous coronary intervention(PCI) for acute myocardial infarction(AMI) patients. Methods: A total of 380 AMI patients who underwent primary PCI in Beijing Chaoyang Hospital from January 2016 to May 2019 were enrolled. They were allocated into DEB group(n=180) or DES group(n=200). The Primary endpoint was the major adverse cardiac events(MACE) in hospital and within 3 months after discharge, the composite event of cardiac death, non-fatal myocardial infarction(MI), target vessel revascularization(TVR) and in stent thrombosis. The secondary endpoints included: (1)TIMI blood flow grade and myocardial perfusion grade (TMP grade) of infarct-related vessels before and after PCI. (2)The degree of ST segment resolution(STR) between half hour and two hours after PCI, and STR was represented by percentage of summed ST-segment reduction between baseline and post-PCI. Using the most significant lead of ST segment elevation, calculating the rate of decline in the ST segment after treatment; or the most significant lead of the ST segment depression, to calculate the rate of recovery in the ST segment after treatment. STR<50% was defined as incomplete STR. (3)The occurrence of coronary artery dissection during operation. (4)The peak value of myocardial enzymes. (5)The incidence of bleeding in hospital and within 3 months after discharge. The inverse probability weighting method based on propensity score (IPTW) was used to compare the effects of the two treatments on MACE occurrence in the logistic regression model. Results: There was no significant difference in sex, age, risk factors of coronary heart disease, type and site of AMI, interventional therapy data(P>0.05) between the two groups. The ratio of bifurcation lesions in DCB group was significantly higher than that in DES group, and the diameter of the DCB was smaller while the length was longer than that of DES (all P<0.05). One death occurred in each group during hospitalization. Compared with the DES group, the incidence of MI ［2.8%(5/180) vs. 0.5% (1/200), P=0.10］ and TVR ［2.8%(5/180) vs. 0.5%(1/200), P=0.10］ in the DCB group during hospitalization showed an increasing trend, and were mostly associated with delayed coronary dissection. The incidence of MACE was similar between the two groups (3.3%(6/180) and 1.0%(2/200), P=0.15) during hospitalization. There was no MACE occurred in the two groups within 3 months after discharge. There was no significant difference between the two groups in TIMI grade, TMP grade, incomplete STR rate and peak value of myocardial enzyme (all P>0.05). The incidence of coronary artery dissection was significantly higher in DCB group than in DES group (8.3%(15/180) and 3.0%(6/200), P=0.02), but most of them were type B or A dissection and did not need special treatment. There was no significant difference in bleeding event between the two groups(P=0.91). Logistic regression analysis showed that there was no difference in the risk of MACE during hospitalization between DES and DCB groups for AMI patients receiving PCI (compared with DCB, OR=0.35, 95%CI 0.08-1.43, P=0.13). Conclusions: The initial safety and efficacy profiles of DCB are similar with those of DES for the AMI patients during PCI. The study highlights that the incidence of coronary dissection (type A or B) is higher post DCB treatment than post DES, but it does not affect blood flow. However, the incidence of in-hospital MI due to delayed coronary dissection trends to be higher post DCB. So we should pay close attention to the risk of delayed coronary dissection after DCB in AMI patients with de novo lesion.
Drug-Eluting Stents ; Humans ; Myocardial Infarction ; Percutaneous Coronary Intervention ; Stents ; Treatment Outcome

Background: Although the use of extra-corporeal membrane oxygenation (ECMO) has been rapidly increasing, the benefit of ECMO in patients with acute respiratory distress syndrome (ARDS) remains unclear. Our objective was to investigate the effect of venovenous ECMO (VV-ECMO) on adult patients with severe ARDS. Methods: We conducted a multi-center, retrospective, cohort study in the intensive care units (ICUs) of six teaching hospitals between January 2013 and December 2018. Patients with severe ARDS who received VV-ECMO support were included. The detailed demographic data and physiologic data were used to match ARDS patients without ECMO. The primary endpoint was the 28-day mortality. Results: Ninety-nine patients with severe ARDS supported by VV-ECMO and 72 patients without ECMO were included in this study. The acute physiology and chronic health evaluation II score was 23.1 ± 6.3 in the ECMO group and 24.8 ± 8.5 in the control group (P = 0.1195). The sequential organ failure assessment score was 12.8 ± 3.4 in the ECMO group and 13.7 ± 3.5 in the control group (P = 0.0848). The 28-day mortality of patients with ECMO support was 39.4%, and that of the control group was 55.6%. The survival analysis curve showed that the 28-day mortality in the ECMO group was significantly lower than that in the control group (P = 0.0097). Multivariate Cox regression analysis showed that the independent predictors of the 28-day mortality were the requirement of vasopressors before ECMO (hazard ratio [HR]: 1.006; 95% confidence interval [CI]: 1.001–1.013; P = 0.030) and duration of mechanical ventilation before ECMO (HR: 3.299; 95% CI: 1.264–8.609; P = 0.034). Conclusions This study showed that ECMO improved the survival of patients with severe ARDS. The duration of mechanical ventilation and the requirement of vasopressors before ECMO might be associated with an increased risk of death.