This study adopted a three-dimensional "effect-dose-mechanism" evaluation system to screen the optimal regimen of Yuxuebi Tablets(YXB) combined with ibuprofen(IBU) for chronic musculoskeletal pain(CMP) intervention and elucidate its pharmacological mechanism, so as to provide a scientific basis for the clinical application of the regimen. The experiments were conducted using 8-week-old ICR mice, which were randomly divided into sham operation(sham) group, model(CFA) group, IBU group, YXB group, stasis paralysis tablets combined with ibuprofen low-dose group(IBU-L-YXB), stasis paralysis combined with ibuprofen high-dose group(IBU-H-YXB), stasis paralysis tablets combined with ibuprofen high-dose with ibuprofen discontinuation on the 10th day of administration(IBU-10-YXB), and stasis paralysis tablets combined with ibuprofen high-dose with ibuprofen halving on the 10th day of administration(IBU-1/2-YXB) group. An animal model was established using the CFA plantar injection method. On D0(the second day post-modeling), the success of model establishment was assessed, followed by continuous drug administration for 18 consecutive days from D1 to D18. During this period, mechanical pain threshold was measured by the Von Frey test; thermal hyperalgesia was detected by the hot plate test, and depression-like behavior was observed by the tail suspension test. After treatment, peripheral blood was collected from all groups for complete blood biochemical analysis, and the injected feet of the sham, CFA, IBU, YXB, IBU-YXB, and IBU-10-YXB groups were subjected to oxylipin metabolomics analysis. Immunofluorescence double staining was further performed to detect the co-expression of key oxylipin metabolic enzymes(COX2, LTA4H, and 5/12/15-LOX) and macrophage marker CD68 in the sham, CFA, IBU, and YXB-L/M/H groups. Subsequently, confirmatory analysis of positive indicators was conducted in the sham, CFA, IBU, YXB, IBU-YXB, and IBU-10-YXB groups. On D6(acute phase), mechanical pain sensitivity data showed that compared with the CFA group, only the three combination groups(IBU-YXB, IBU-10-YXB, and IBU-1/2-YXB) exhibited significantly increased paw withdrawal thresholds. On D17(chronic phase), only the IBU-10-YXB group showed a mechanical pain threshold significantly higher than all other monotherapy and combination groups. On D17, thermal pain data showed that compared with the CFA group, all groups except IBU-1/2-YXB had significantly prolonged paw withdrawal latency. On D18, tail suspension data showed that compared with the CFA group, the YXB, IBU-YXB, and IBU-10-YXB groups had significantly reduced immobility time. In summary, IBU-10-YXB stably improved the core symptoms of acute and chronic inflammatory pain. Complete blood count data showed that compared with the sham group, the CFA group had significantly increased mean platelet volume(MPV), while compared with the CFA group, the IBU-YXB and IBU-10-YXB groups had significantly reduced MPV. Moreover, the platelet distribution width(PDW) of the IBU-10-YXB group was further reduced compared with the CFA group. These data suggest that the IBU-10-YXB combination regimen has superior effects on inflammation and blood circulation improvement compared with other treatment groups. At the mechanistic level, each treatment group differentially regulated pro-inflammatory and pro-resolving oxylipin(SPM). Specifically, compared with the CFA group, the IBU and IBU-YXB groups significantly inhibited the synthesis of the prostaglandin family downstream of COX2, reducing pro-inflammatory oxylipins PGD2 and 6-keto-PGF1α but inhibiting PGE1 and PGE2, which played positive roles in peripheral circulation, vasodilation, and inflammation resolution. Compared with the CFA group, the YXB group tended to inhibit the pro-inflammatory oxylipin LTB4 downstream of LTA4H and increase SPMs such as LXA4. The IBU-10-YXB group bidirectionally regulated pro-inflammatory oxylipins and SPMs. Compared with IBU, IBU-10-YXB significantly inhibited the pro-inflammatory mediator 5-HETE. Meanwhile, IBU-10-YXB broadly upregulated SPMs, as evidenced by significant upregulation of LXA4 compared with the CFA group, significant upregulation of LXA5 compared with the IBU and IBU-YXB groups, significant upregulation of RvD1 compared with the CFA group and all other treatment groups, and significant upregulation of RvD5 compared with the sham group. Immunofluorescence double staining results were as follows: compared with the CFA group, the IBU group specifically inhibited the oxylipin metabolic enzyme COX2. In the YXB group, COX2, LTA4H, and 5/12-LOX were significantly inhibited. Within the optimal analgesic dose range, YXB's inhibitory effects on COX2 and LTA4H were dose-dependent, while its inhibitory effects on 5/12-LOX were inversely dose-dependent. The two combination groups(IBU-YXB and IBU-10-YXB) inhibited COX2 and LTA4H without significantly affecting 5-LOX, while IBU-10-YXB further significantly inhibited 12-LOX. These results suggest that the IBU-10-YXB combination regimen effectively maintains stable inhibition of COX2, LTA4H, and 12-LOX while enhancing 5-LOX expression. This combinatorial strategy effectively suppresses pro-inflammatory oxylipins and promotes SPM biosynthesis, overcoming IBU's analgesic ceiling effect and its blockade of pain resolution pathways while compensating for YXB's inability to effectively intervene in acute pain and inflammation. Therefore, it achieves more stable anti-inflammatory, analgesic, and antidepressant effects.
Animals ; Ibuprofen/administration & dosage* ; Mice ; Mice, Inbred ICR ; Drugs, Chinese Herbal/administration & dosage* ; Male ; Musculoskeletal Pain/immunology* ; Tablets ; Humans ; Chronic Pain/metabolism* ; Drug Therapy, Combination ; Disease Models, Animal

OBJECTIVE: To evaluate the dynamic changes of glucocorticoid (GC) dose and the feasibility of GC discontinuation in rheumatoid arthritis (RA) patients under the background of Chinese medicine (CM). METHODS: This multicenter retrospective cohort study included 1,196 RA patients enrolled in the China Rheumatoid Arthritis Registry of Patients with Chinese Medicine (CERTAIN) from September 1, 2019 to December 4, 2023, who initiated GC therapy. Participants were divided into the Western medicine (WM) and integrative medicine (IM, combination of CM and WM) groups based on medication regimen. Follow-up was performed at least every 3 months to assess dynamic changes in GC dose. Changes in GC dose were analyzed by generalized estimator equation, the probability of GC discontinuation was assessed using Kaplan-Meier curve, and predictors of GC discontinuation were analyzed by Cox regression. Patients with <12 months of follow-up were excluded for the sensitivity analysis. RESULTS: Among 1,196 patients (85.4% female; median age 56.4 years), 880 (73.6%) received IM. Over a median 12-month follow-up, 34.3% (410 cases) discontinued GC, with significantly higher rates in the IM group (40.8% vs. 16.1% in WM; P<0.05). GC dose declined progressively, with IM patients demonstrating faster reductions (median 3.75 mg vs. 5.00 mg in WM at 12 months; P<0.05). Multivariate Cox analysis identified age <60 years [P<0.001, hazard ratios (HR)=2.142, 95% confidence interval (CI): 1.523-3.012], IM therapy (P=0.001, HR=2.175, 95% CI: 1.369-3.456), baseline GC dose ⩽7.5 mg (P=0.003, HR=1.637, 95% CI: 1.177-2.275), and absence of non-steroidal anti-inflammatory drugs use (P=0.001, HR=2.546, 95% CI: 1.432-4.527) as significant predictors of GC discontinuation. Sensitivity analysis (545 cases) confirmed these findings. CONCLUSIONS RA patients receiving CM face difficulties in following guideline-recommended GC discontinuation protocols. IM can promote GC discontinuation and is a promising strategy to reduce GC dependency in RA management. (Trial registration: ClinicalTrials.gov, No. NCT05219214).
Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Arthritis, Rheumatoid/drug therapy* ; Glucocorticoids/therapeutic use* ; Medicine, Chinese Traditional ; Retrospective Studies

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 investigate the distribution and antimicrobial resistance profiles of common pathogens isolated from cerebrospinal fluid(CSF)in CHINET program from 2015 to 2021.Methods The bacterial strains isolated from CSF were identified in accordance with clinical microbiology practice standards.Antimicrobial susceptibility test was conducted using Kirby-Bauer method and automated systems per the unified CHINET protocol.Results A total of 14 014 bacterial strains were isolated from CSF samples from 2015 to 2021,including the strains isolated from inpatients(95.3％)and from outpatient and emergency care patients(4.7％).Overall,19.6％of the isolates were from children and 80.4％were from adults.Gram-positive and Gram-negative bacteria accounted for 68.0％and 32.0％,respectively.Coagulase negative Staphylococcus accounted for 73.0％of the total Gram-positive bacterial isolates.The prevalence of MRSA was 38.2％in children and 45.6％in adults.The prevalence of MRCNS was 67.6％in adults and 69.5％in children.A small number of vancomycin-resistant Enterococcus faecium(2.2％)and linezolid-resistant Enterococcus faecalis(3.1％)were isolated from adult patients.The resistance rates of Escherichia coli and Klebsiella pneumoniae to ceftriaxone were 52.2％and 76.4％in children,70.5％and 63.5％in adults.The prevalence of carbapenem-resistant E.coli and K.pneumoniae(CRKP)was 1.3％and 47.7％in children,6.4％and 47.9％in adults.The prevalence of carbapenem-resistant Acinetobacter baumannii(CRAB)and Pseudomonas aeruginosa(CRPA)was 74.0％and 37.1％in children,81.7％and 39.9％in adults.Conclusions The data derived from antimicrobial resistance surveillance are crucial for clinicians to make evidence-based decisions regarding antibiotic therapy.Attention should be paid to the Gram-negative bacteria,especially CRKP and CRAB in central nervous system(CNS)infections.Ongoing antimicrobial resistance surveillance is helpful for optimizing antibiotic use in CNS infections.

Objective To investigate the antimicrobial resistance of clinical isolates from elderly patients(≥65 years)in major medical institutions across China.Methods Bacterial strains were isolated from elderly patients in 52 hospitals participating in the CHINET Antimicrobial Resistance Surveillance Program during the period from 2015 to 2021.Antimicrobial susceptibility test was carried out by disk diffusion method and automated systems according to the same CHINET protocol.The data were interpreted in accordance with the breakpoints recommended by the Clinical and Laboratory Standards Institute(CLSI)in 2021.Results A total of 514 715 nonduplicate clinical isolates were collected from elderly patients in 52 hospitals from January 1,2015 to December 31,2021.The number of isolates accounted for 34.3％of the total number of clinical isolates from all patients.Overall,21.8％of the 514 715 strains were gram-positive bacteria,and 78.2％were gram-negative bacteria.Majority(90.9％)of the strains were isolated from inpatients.About 42.9％of the strains were isolated from respiratory specimens,and 22.9％were isolated from urine.More than half(60.7％)of the strains were isolated from male patients,and 39.3％isolated from females.About 51.1％of the strains were isolated from patients aged 65-＜75 years.The prevalence of methicillin-resistant strains(MRSA)was 38.8％in 32 190 strains of Staphylococcus aureus.No vancomycin-or linezolid-resistant strains were found.The resistance rate of E.faecalis to most antibiotics was significantly lower than that of Enterococcus faecium,but a few vancomycin-resistant strains(0.2％,1.5％)and linezolid-resistant strains(3.4％,0.3％)were found in E.faecalis and E.faecium.The prevalence of penicillin-susceptible S.pneumoniae(PSSP),penicillin-intermediate S.pneumoniae(PISP),and penicillin-resistant S.pneumoniae(PRSP)was 94.3％,4.0％,and 1.7％in nonmeningitis S.pneumoniae isolates.The resistance rates of Klebsiella spp.(Klebsiella pneumoniae 93.2％)to imipenem and meropenem were 20.9％and 22.3％,respectively.Other Enterobacterales species were highly sensitive to carbapenem antibiotics.Only 1.7％-7.8％of other Enterobacterales strains were resistant to carbapenems.The resistance rates of Acinetobacter spp.(Acinetobacter baumannii 90.6％)to imipenem and meropenem were 68.4％and 70.6％respectively,while 28.5％and 24.3％of P.aeruginosa strains were resistant to imipenem and meropenem,respectively.Conclusions The number of clinical isolates from elderly patients is increasing year by year,especially in the 65-＜75 age group.Respiratory tract isolates were more prevalent in male elderly patients,and urinary tract isolates were more prevalent in female elderly patients.Klebsiella isolates were increasingly resistant to multiple antimicrobial agents,especially carbapenems.Antimicrobial resistance surveillance is helpful for accurate empirical antimicrobial therapy in elderly patients.

Objective To summarize the changing prevalence of carbapenem resistance in Enterobacterales based on the data of CHINET Antimicrobial Resistance Surveillance Program from 2015 to 2021 for improving antimicrobial treatment in clinical practice.Methods Antimicrobial susceptibility testing was performed using a commercial automated susceptibility testing system according to the unified CHINET protocol.The results were interpreted according to the breakpoints of the Clinical & Laboratory Standards Institute(CLSI)M100 31st ed in 2021.Results Over the seven-year period(2015-2021),the overall prevalence of carbapenem-resistant Enterobacterales(CRE)was 9.43％(62 342/661 235).The prevalence of CRE strains in Klebsiella pneumoniae,Citrobacter freundii,and Enterobacter cloacae was 22.38％,9.73％,and 8.47％,respectively.The prevalence of CRE strains in Escherichia coli was 1.99％.A few CRE strains were also identified in Salmonella and Shigella.The CRE strains were mainly isolated from respiratory specimens(44.23±2.80)％,followed by blood(20.88±3.40)％and urine(18.40±3.45)％.Intensive care units(ICUs)were the major source of the CRE strains(27.43±5.20)％.CRE strains were resistant to all the β-lactam antibiotics tested and most non-β-lactam antimicrobial agents.The CRE strains were relatively susceptible to tigecycline and polymyxins with low resistance rates.Conclusions The prevalence of CRE strains was increasing from 2015 to 2021.CRE strains were highly resistant to most of the antibacterial drugs used in clinical practice.Clinicians should prescribe antimicrobial agents rationally.Hospitals should strengthen antibiotic stewardship in key clinical settings such as ICUs,and take effective infection control measures to curb CRE outbreak and epidemic in hospitals.

Objective To characterize the changing species distribution and antibiotic resistance profiles of respiratory isolates in hospitals participating in the CHINET Antimicrobial Resistance Surveillance Program from 2015 to 2021.Methods Commercial automated antimicrobial susceptibility testing systems and disk diffusion method were used to test the susceptibility of respiratory bacterial isolates to antimicrobial agents following the standardized technical protocol established by the CHINET program.Results A total of 589 746 respiratory isolates were collected from 2015 to 2021.Overall,82.6％of the isolates were Gram-negative bacteria and 17.4％were Gram-positive bacteria.The bacterial isolates from outpatients and inpatients accounted for(6.0±0.9)％and(94.0±0.1)％,respectively.The top microorganisms were Klebsiella spp.,Acinetobacter spp.,Pseudomonas aeruginosa,Staphylococcus aureus,Haemophilus spp.,Stenotrophomonas maltophilia,Escherichia coli,and Streptococcus pneumoniae.Each microorganism was isolated from significantly more males than from females(P＜0.05).The overall prevalence of methicillin-resistant S.aureus(MRSA)was 39.9％.The prevalence of penicillin-resistant S.pneumoniae was 1.4％.The prevalence of extended-spectrum β-lactamase(ESBL)-producing E.coli and K.pneumoniae was 67.8％and 41.3％,respectively.The overall prevalence of carbapenem-resistant E.coli,K.pneumoniae,Enterobacter cloacae,Pseudomonas aeruginosa,and Acinetobacter baumannii was 3.7％,20.8％,9.4％,29.8％,and 73.3％,respectively.The prevalence of β-lactamase was 96.1％in Moraxella catarrhalis and 60.0％in Haemophilus influenzae.The H.influenzae isolates from children(＜18 years)showed significantly higher resistance rates to β-lactam antibiotics than the isolates from adults(P＜0.05).Conclusions Gram-negative bacteria are still predominant in respiratory isolates associated with serious antibiotic resistance.Antimicrobial resistance surveillance should be strengthened in clinical practice to support accurate etiological diagnosis and appropriate antimicrobial therapy based on antimicrobial susceptibility testing results.

In order to investigate whether the effect of Yuxuebi Tablets on the peripheral and central inflammation resolution of mice with inflammatory pain is related to their regulation of G protein-coupled receptor 37(GPR37), an inflammatory pain model was established by injecting complete Freund's adjuvant(CFA) into the paws of mice, with a sham-operated group receiving a similar volume of normal saline. The mice were assigned randomly to the sham-operated group, model group, ibuprofen group(91 mg·kg~(-1)), and low-, medium-, and high-dose groups of Yuxuebi Tablets(60, 120, and 240 mg·kg~(-1)). The drug was administered orally from days 1 to 19 after modeling. Von Frey method and the hot plate test were used to detect mechanical pain thresholds and heat hyperalgesia. The levels of interleukin-10(IL-10) and transforming growth factor-beta(TGF-β) in the spinal cord were quantified using enzyme-linked immunosorbent assay(ELISA), and the mRNA and protein expression of GPR37 in the spinal cord was measured by real-time quantitative reverse transcription PCR(qRT-PCR) and Western blot. Additionally, immunofluorescence was used to detect the expression of macrosialin antigen(CD68), mannose receptor(MRC1 or CD206), and GPR37 in dorsal root ganglia, as well as the expression of calcium-binding adapter molecule 1(IBA1), CD206, and GPR37 in the dorsal horn of the spinal cord. The results showed that compared with those of the sham-operated group, the mechanical pain thresholds and hot withdrawal latency of the model group significantly declined, and the expression of CD68 in the dorsal root ganglia and the expression of IBA1 in the dorsal horn of the spinal cord significantly increased. The expression of CD206 and GPR37 significantly decreased in the dorsal root ganglion and dorsal horn of the spinal cord, and IL-10 and TGF-β levels in the spinal cord were significantly decreased. Compared with those of the model group, the mechanical pain thresholds and hot withdrawal latency of the high-dose group of Yuxuebi Tablets significantly increased, and the expression of CD68 in the dorsal root ganglion and IBA1 in the dorsal horn of the spinal cord significantly decreased. The expression of CD206 and GPR37 in the dorsal root ganglion and dorsal horn of the spinal cord significantly increased, as well as IL-10 and TGF-β levels in the spinal cord. These findings indicated that Yuxuebi Tablets may reduce macrophage(microglial) infiltration and foster M2 macrophage polarization by enhancing GPR37 expression in the dorsal root ganglia and dorsal horn of the spinal cord of CFA-induced mice, so as to improve IL-10 and TGF-β levels, promote resolution of both peripheral and central inflammation, and play analgesic effects.
Inflammation/genetics* ; Pain/genetics* ; Drugs, Chinese Herbal/administration & dosage* ; Animals ; Mice ; Freund's Adjuvant/pharmacology* ; Ibuprofen ; Pain Threshold/drug effects* ; Hyperalgesia/genetics* ; Ganglia, Spinal ; Interleukin-10/genetics* ; Transforming Growth Factor beta/genetics* ; Reverse Transcriptase Polymerase Chain Reaction ; Tablets ; Receptors, G-Protein-Coupled

Cardiac surgery patients often present with multiple comorbidities,the risk of periop-erative complications and the complexity of postoperative rehabilitation have significantly increased,posing higher demands on comprehensive perioperative management.Preoperative exercise pre-reha-bilitation,as a multidisciplinary collaborative intervention strategy,has been demonstrated to signifi-cantly improve the clinical prognosis of patients undergoing elective cardiac surgery by enhancing their cardiopulmonary function,muscle strength,and overall physiological functional reserve,thereby in-creasing the body's tolerance to surgical stress.Although phase-specific research achievements have been made domestically and internationally in the field of exercise pre-rehabilitation,its standardized implementation and clinical translation on a global scale still face numerous obstacles,necessitating systematic review and in-depth exploration.Therefore,this study aimed to conduct a systematic re-view of the intervention protocols,clinical efficacy,safety,and feasibility of preoperative exercise pre-rehabilitation in patients undergoing elective cardiac surgery,with the goal of providing theoretical evidence and practical references for optimizing perioperative management pathways and promoting the implementation of enhanced recovery after surgery concepts.

Liver failure （LF） is a severe clinical syndrome characterized by severe impairment or decompensation of liver function. At present， the key role of immune molecules in the pathogenesis of LF has been well established. These molecules not only directly participate in the pathological process of LF， but also influence the course of LF by modulating the behavior of immune cells. In addition， immune molecules can be used as potential biomarkers for evaluating the prognosis of LF. This article summarizes the role of immune molecules in LF and explores the therapeutic strategies based on these immune molecules， in order to provide new directions for the diagnosis and treatment of LF.