Enterovirus 71 Activates Plasmacytoid Dendritic Cell-Dependent PSGL-1 Binding Independent of Productive Infection.

Enterovirus 71 (EV71) is a significant causative agent of hand, foot, and mouth disease, with potential serious neurologic complications or fatal outcomes. The lack of effective treatments for EV71 infection is attributed to its elusive pathogenicity. Our study reveals that human plasmacytoid dendritic cells (pDCs), the main type I IFN-producing cells, selectively express scavenger receptor class B, member 2 (SCARB2) and P-selectin glycoprotein ligand 1 (PSGL-1), crucial cellular receptors for EV71. Some strains of EV71 can replicate within pDCs and stimulate IFN-α production. The activation of pDCs by EV71 is hindered by Abs to PSGL-1 and soluble PSGL-1, whereas Abs to SCARB2 and soluble SCARB2 have a less pronounced effect. Our data suggest that only strains binding to PSGL-1, more commonly found in severe cases, can replicate in pDCs and induce IFN-α secretion, highlighting the importance of PSGL-1 in these processes. Furthermore, IFN-α secretion by pDCs can be triggered by EV71 or UV-inactivated EV71 virions, indicating that productive infection is not necessary for pDC activation. These findings provide new insights into the interaction between EV71 and pDCs, suggesting that pDC activation could potentially mitigate the severity of EV71-related diseases.

Identification and Verification of Novel Biomarkers Involving Rheumatoid Arthritis with Multimachine Learning Algorithms: An In Silicon and In Vivo Study.

Background: Rheumatoid arthritis (RA) remains one of the most prevalent chronic joint diseases. However, due to the heterogeneity among RA patients, there are still no robust diagnostic and therapeutic biomarkers for the diagnosis and treatment of RA. Methods: We retrieved RA-related and pan-cancer information datasets from the Gene Expression Omnibus and The Cancer Genome Atlas databases, respectively. Six gene expression profiles and corresponding clinical information of GSE12021, GSE29746, GSE55235, GSE55457, GSE77298, and GSE89408 were adopted to perform differential expression gene analysis, enrichment, and immune component difference analyses of RA. Four machine learning algorithms, including LASSO, RF, XGBoost, and SVM, were used to identify RA-related biomarkers. Unsupervised cluster analysis was also used to decipher the heterogeneity of RA. A four-signature-based nomogram was constructed and verified to specifically diagnose RA and osteoarthritis (OA) from normal tissues. Consequently, RA-HFLS cell was utilized to investigate the biological role of CRTAM in RA. In addition, comparisons of diagnostic efficacy and biological roles among CRTAM and other classic biomarkers of RA were also performed. Results: Immune and stromal components were highly enriched in RA. Chemokine- and Th cell-related signatures were significantly activated in RA tissues. Four promising and novel biomarkers, including CRTAM, PTTG1IP, ITGB2, and MMP13, were identified and verified, which could be treated as novel treatment and diagnostic targets for RA. Nomograms based on the four signatures might aid in distinguishing and diagnosing RA, which reached a satisfactory performance in both training (AUC = 0.894) and testing (AUC = 0.843) cohorts. Two distinct subtypes of RA patients were identified, which further verified that these four signatures might be involved in the immune infiltration process. Furthermore, knockdown of CRTAM could significantly suppress the proliferation and invasion ability of RA cell line and thus could be treated as a novel therapeutic target. CRTAM owned a great diagnostic performance for RA than previous biomarkers including MMP3, S100A8, S100A9, IL6, COMP, LAG3, and ENTPD1. Mechanically, CRTAM could also be involved in the progression through immune dysfunction, fatty acid metabolism, and genomic instability across several cancer subtypes. Conclusion: CRTAM, PTTG1IP, ITGB2, and MMP13 were highly expressed in RA tissues and might function as pivotal diagnostic and treatment targets by deteriorating the immune dysfunction state. In addition, CRTAM might fuel cancer progression through immune signals, especially among RA patients.

[Statistics and Analysis of 136 Cases of Adverse Events of International Medical Devices].

To explore the law and characteristics of adverse events of medical devices and to provide research methods and basis for reducing the recurrence of similar adverse events, we collect medical devices safety information from five representative countries in the world, and make statistics and analysis on the types of events, the types of management and the causes of events. The results show that among 136 serious adverse events, the top three causes of recall are product design factors, software factors, and component defects. In order to reduce the application risk of medical devices, it is suggested that product designers, operating users and medical institutions should correctly implement the monitoring and evaluation system of medical devices.

MicroRNA-143-3p inhibits colorectal cancer metastases by targeting ITGA6 and ASAP3.

MicroRNAs, which regulate mRNAs, operate through a variety of signaling pathways to participate in the development of colorectal cancer (CRC). In this study, we found that microRNA (miR)-143-3p expression was significantly lower in both CRC and liver metastatic CRC tissues from liver compared with normal colonic tissues. Functional assays showed that miR-143-3p inhibited CRC cell invasion and migration in vitro. Using a bioinformatics approach, we identified miR-143-3p target mRNAs. Among the candidate targets, only the expression of integrin alpha 6 (ITGA6) and ArfGAP with the SH3 domain and ankyrin repeat and PH domain 3 (ASAP3) were significantly reduced by miR-143-3p mimics as examined by western blot, and the metastasis potential of CRC cells was attenuated by endogenous ITGA6 and ASAP3 knockdown, determined by migration and invasion assays. Both ITGA6 and ASAP3 were upregulated in CRC tissues compared to normal tissues. Analysis of the relationship between clinicopathological features and ITGA6/ASAP3 protein expression in 200 patients with CRC showed a significant difference in positive ITGA6 expression between the early stage (I + II) and the advanced stage (III + IV), and ASAP3 expression levels positively correlated with metastasis in the lymph nodes. These results indicate that miR-143-3p acts as an anti-oncogene by downregulating ITGA6/ASAP3 protein expression and could offer new insight into potential therapeutic targets for CRC.

Identification of a Critical and Conformational Neutralizing Epitope in Human Adenovirus Type 4 Hexon.

Human adenovirus type 4 (HAdV-4) is an epidemic virus that contributes to serious acute respiratory disease (ARD) in both pediatric and adult patients. However, no licensed drug or vaccine is currently available to the civilian population. The identification of neutralizing epitopes of HAdV-4 should allow the development of a novel antiviral vaccine and a novel gene transfer vector, and an effective neutralizing monoclonal antibody (MAb) will be useful in developing appropriate antiviral drugs. In this study, we report that MAb MN4b shows strong neutralizing activity against HAdV-4. MN4b recognizes a conformational epitope (418AGSEK422) within hypervariable region 7 (HVR7). Mutations within this site permitted HAdV-4 mutants to escape neutralization by MN4b and to resist neutralization by animal and human anti-HAdV-4 sera. A recombinant virus, rAd3-A4R7-1, containing the identified neutralizing epitope in the HVR7 region of HAdV-3 hexon, successfully induced antiserum that inhibited HAdV-4 infection. These results indicate that a small surface loop of HAdV-4 hexon is a critical neutralization epitope for this virus. The generation of MN4b and the identification of this neutralizing epitope may be useful in developing therapeutic treatment, a subunit vaccine, and a novel vector that can escape preexisting neutralization for HAdV-4.IMPORTANCE Neutralizing antibodies are considered good tools for the prevention of human adenovirus type 4 (HAdV-4) infections. The identification of the epitopes recognized by such neutralizing antibodies is important for the generation of recombinant antiviral vaccines. However, until now, no neutralizing epitope has been reported for HAdV-4. Here, we developed a serotype-specific neutralizing MAb directed against HAdV-4, MN4b. We provide evidence that MN4b recognizes a conformational epitope within HVR7 of HAdV-4 hexon. Antisera generated to this conformational epitope displayed on HAdV-3 hexon inhibited infection of AD293 cells by HAdV-4. Our findings are very important for the development of therapeutic treatment, a subunit vaccine, and a novel vector for HAdV-4.

polyPK: an R package for pharmacokinetic analysis of multi-component drugs using a metabolomics approach.

Summary: Pharmacokinetics (PK) is a long-standing bottleneck for botanical drug and traditional medicine research. By using an integrated phytochemical and metabolomics approach coupled with multivariate statistical analysis, we propose a new strategy, Poly-PK, to simultaneously monitor the performance of drug constituents and endogenous metabolites, taking into account both the diversity of the drug's chemical composition and its complex effects on the mammalian metabolic pathways. Poly-PK is independent of specific measurement platforms and has been successfully applied in the PK studies of Puerh tea, a traditional Chinese medicine Huangqi decoction and many other multi-component drugs. Here, we introduce an R package, polyPK, the first and only automation of the data analysis pipeline of Poly-PK strategy. polyPK provides 10 functions for data pre-processing, differential compound identification and grouping, traditional PK parameters calculation, multivariate statistical analysis, correlations, cluster analyses and resulting visualization. It may serve a wide range of users, including pharmacologists, biologists and doctors, in understanding the metabolic fate of multi-component drugs. Availability and implementation: polyPK package is freely available from the R archive CRAN (https://CRAN.R-project.org/package=polyPK). Contact: wjia@cc.hawaii.edu or chentianlu@sjtu.edu.cn. Supplementary information: Supplementary data are available at Bioinformatics online.

Human Blood CD1c+ Dendritic Cells Encompass CD5high and CD5low Subsets That Differ Significantly in Phenotype, Gene Expression, and Functions.

There are three major dendritic cell (DC) subsets in both humans and mice, that is, plasmacytoid DCs and two types of conventional DCs (cDCs), cDC1s and cDC2s. cDC2s are important for polarizing CD4+ naive T cells into different subsets, including Th1, Th2, Th17, Th22, and regulatory T cells. In mice, cDC2s can be further divided into phenotypically and functionally distinct subgroups. However, subsets of human cDC2s have not been reported. In the present study, we showed that human blood CD1c+ cDCs (cDC2s) can be further separated into two subpopulations according to their CD5 expression status. Comparative transcriptome analyses showed that the CD5high DCs expressed higher levels of cDC2-specific genes, including IFN regulatory factor 4, which is essential for the cDC2 development and its migration to lymph nodes. In contrast, CD5low DCs preferentially expressed monocyte-related genes, including the lineage-specific transcription factor MAFB. Furthermore, compared with the CD5low subpopulation, the CD5high subpopulation showed stronger migration toward CCL21 and overrepresentation among migratory DCs in lymph nodes. Additionally, the CD5high DCs induced naive T cell proliferation more potently than did the CD5low DCs. Moreover, CD5high DCs induced higher levels of IL-10-, IL-22-, and IL-4-producing T cell formation, whereas CD5low DCs induced higher levels of IFN-γ-producing T cell formation. Thus, we show that human blood CD1c+ cDC2s encompass two subsets that differ significantly in phenotype, that is, gene expression and functions. We propose that these two subsets of human cDC2s could potentially play contrasting roles in immunity or tolerance.

Strategy for an Association Study of the Intestinal Microbiome and Brain Metabolome Across the Lifespan of Rats.

There is increased appreciation for the diverse roles of the microbiome-gut-brain axis on mammalian growth and health throughout the lifespan. Numerous studies have demonstrated that the gut microbiome and their metabolites are extensively involved in the communication between brain and gut. Association study of brain metabolome and gut microbiome is an active field offering large amounts of information on the interaction of microbiome, brain and gut but data size and complicated hierarchical relationships were found to be major obstacles to the formation of significant, reproducible conclusions. This study addressed a two-level strategy of brain metabolome and gut microbiome association analysis of male Wistar rats in the process of growth, employing several analytical platforms and various bioinformatics methods. Trajectory analysis showed that the age-related brain metabolome and gut microbiome had similarity in overall alteration patterns. Four high taxonomical level correlated pairs of "metabolite type-bacterial phylum", including "lipids-Spirochaetes", "free fatty acids (FFAs)-Firmicutes", "bile acids (BAs)-Firmicutes", and "Neurotransmitters-Bacteroidetes", were screened out based on unit- and multivariant correlation analysis and function analysis. Four groups of specific "metabolite-bacterium" association pairs from within the above high level key pairs were further identified. The key correlation pairs were validated by an independent animal study. This two-level strategy is effective in identifying principal correlations in big data sets obtained from the systematic multiomics study, furthering our understanding on the lifelong connection between brain and gut.

Association of IL-6 Gene (-174 and -572 G/C) Polymorphisms with Proliferative Diabetic Retinopathy of Type 2 Diabetes in a Chinese Population.

PURPOSE: To investigate the association of interleukin (IL)-6 with proliferative diabetic retinopathy (PDR) of type 2 diabetes (T2D) in a Chinese population. METHODS: Two subtypes of the IL-6 promoter (-174 and -572 G/C) were genotyped in 215 T2D patients with PDR and 207 T2D patients with a normal retinal function (controls) using the PCR-RFLP method. The mRNA and protein expression of IL-6 was examined by real-time PCR. RESULTS: T2D patients with PDR had a significantly higher frequency of IL-6 -174 GC (OR 0.58; 95% CI 0.34-0.99; p = 0.011) and IL-6 -572 GG (OR 0.53; 95% CI 0.24-1.14; p = 0.016) than T2D controls. The mRNA expressions of the rs1800795 GC and rs1800796 GG genotype were significantly increased compared to other cases (Fsig = 0.002, p = 0.001, respectively), followed by a relative increase in IL-6 in protein. CONCLUSIONS: IL-6 genotypes of rs1800795 GC and rs1800796 GG might point to a relatively high risk for T2D patients suffering from PDR in a Chinese population and they were associated with elevation of IL-6 expression in both mRNA and protein.

Cilostazol Suppresses IL-23 Production in Human Dendritic Cells via an AMPK-Dependent Pathway.

BACKGROUND/AIMS: Cilostazol has been previously demonstrated to inhibit IL-23 production in human synovial macrophages via a RhoA/ROCK-dependent pathway. However, whether cilostazol affects IL-23 production in human dendritic cells remains largely unknown. The present study was designed to investigate this question and elucidate the possible underlying mechanisms. METHODS: Human monocyte-derived dendritic cells (mo-DCs) were pretreated with or without cilostazol and then incubated with zymosan. Enzyme-linked immunosorbent assay (ELISA) and real time PCR analyses were used to measure IL-23 protein expression and RNA levels, respectively, whereas Western blotting was used to measure the expression and phosphorylation level of AMPK. RESULTS: Our results demonstrated that cilostazol suppressed zymosan-induced IL-23 protein production in a concentration dependent manner without affecting dendritic cell viability. In addition, it was found that cilostazol suppressed the expression of the p19 and p40 subunits of IL-23. Moreover, cilostazol mimicked the effect of the AMPK agonist A-769662, as demonstrated by the fact that IL-23 production was also inhibited by A-769662, and the effect of cilostazol on IL-23 production was blocked by the AMPK antagonist Compound C. More importantly, Western blotting demonstrated that cilostazol led to an increased phosphorylation of AMPK. CONCLUSION: Collectively, our data suggest that cilostazol inhibits the production of IL-23 in human mo-DCs, potentially via the activation of AMPK. This suggests that cilostazol could be an effective anti-inflammatory agent in IL-23- and dendritic cell-related diseases.

MicroRNAs, TGF-ß signaling, and the inflammatory microenvironment in cancer.

Inflammatory cells and mediators form a major part of the tumor microenvironment and play important roles in the regulation of cancer initiation, tumor cell proliferation, and metastasis. MicroRNAs (miRNAs) play important roles in several physiological and pathological processes, including the regulation of the inflammatory microenvironment in cancer. Transforming growth factor-ß (TGF-ß) is an inflammation-related cytokine that functions in both tumor suppression and promotion; however, its underlying molecular mechanisms remain unclear. Recent evidence indicates an association between miRNAs and TGF-ß signaling, providing new insight into the nature of the inflammatory microenvironment in cancer. The present review is an overview of the interaction between miRNAs and inflammatory cytokines, with emphasis on the cross talk between TGF-ß signaling and miRNAs and their influence on cancer cell behavior. The emerging roles of miRNAs in cancer-related inflammation and the potential to target miRNA signaling pathways for cancer therapy are also discussed.

The safety and effectiveness of bivalirudin in female patients with acute myocardial infarction undergoing primary angioplasty: A subgroup analysis of the BRIGHT trial.

BACKGROUND: Being female is an independent predictor of adverse events during percutaneous coronary interventions (PCI). OBJECTIVE: To evaluate the safety and efficiency of bivalirudin during emergency PCI in female patients with acute myocardial infarction (AMI). METHODS: The present study was a subgroup analysis of the randomized Bivalirudin in Acute Myocardial Infarction vs. Heparin and GPI plus Heparin (BRIGHT) trial. A total of 392 female patients enrolled in the BRIGHT trial were assigned to receive bivalirudin with post-procedure dose infusion (n = 127) or heparin with or without tirofiban (n = 265). The primary efficiency endpoint was 30-day net adverse clinical events (NACEs). The secondary efficiency endpoints were 30-day major cardiac and cerebral events (MACCEs) and bleeding events defined according to Bleeding Academic Research Consortium (BARC) definitions. RESULTS: For female patients, bivalirudin treatment was associated with significantly lower incidences of 30-day NACEs (6.3% vs. 21.5%, P < 0.001), any bleeding (2.4% vs. 12.8%, P = 0.001) and BARC 2-5 type bleeding (1.6% vs. 7.2%, P = 0.021) compared with the control regimen. The incidence of MACCEs (3.4% vs. 9.4%, P = 0.055) and stent thrombosis (0% vs. 1.1%, P = 0.229) were comparable between the two groups. Multivariate analysis showed that bivalirudin (OR: 0.245, 95% CI: 0.113-0.532, P < 0.001), transradial access (OR: 0.119, 95% CI: 0.067-0.211, P < 0.001), and statin (OR: 0.254, 95% CI: 0.08-0.807, P = 0.02) were independent protective factors for 30-day NACEs in female patients. CONCLUSIONS: The use of bivalirudin during emergency PCI for AMI in female patients significantly reduced the bleeding risk with anticoagulation effects compared with heparin with or without tirofiban.

Development and Characterization of VEGF165-Chitosan Nanoparticles for the Treatment of Radiation-Induced Skin Injury in Rats.

Radiation-induced skin injury, which remains a serious concern in radiation therapy, is currently believed to be the result of vascular endothelial cell injury and apoptosis. Here, we established a model of acute radiation-induced skin injury and compared the effect of different vascular growth factors on skin healing by observing the changes of microcirculation and cell apoptosis. Vascular endothelial growth factor (VEGF) was more effective at inhibiting apoptosis and preventing injury progression than other factors. A new strategy for improving the bioavailability of vascular growth factors was developed by loading VEGF with chitosan nanoparticles. The VEGF-chitosan nanoparticles showed a protective effect on vascular endothelial cells, improved the local microcirculation, and delayed the development of radioactive skin damage.

Proteins associated with pancreatic cancer survival in patients with resectable pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with a dismal prognosis. However, while most patients die within the first year of diagnosis, very rarely, a few patients can survive for >10 years. Better understanding the molecular characteristics of the pancreatic adenocarcinomas from these very-long-term survivors (VLTS) may provide clues for personalized medicine and improve current pancreatic cancer treatment. To extend our previous investigation, we examined the proteomes of individual pancreas tumor tissues from a group of VLTS patients (survival ≥10 years) and short-term survival patients (STS, survival <14 months). With a given analytical sensitivity, the protein profile of each pancreatic tumor tissue was compared to reveal the proteome alterations that may be associated with pancreatic cancer survival. Pathway analysis of the differential proteins identified suggested that MYC, IGF1R and p53 were the top three upstream regulators for the STS-associated proteins, and VEGFA, APOE and TGFß-1 were the top three upstream regulators for the VLTS-associated proteins. Immunohistochemistry analysis using an independent cohort of 145 PDAC confirmed that the higher abundance of ribosomal protein S8 (RPS8) and prolargin (PRELP) were correlated with STS and VLTS, respectively. Multivariate Cox analysis indicated that 'High-RPS8 and Low-PRELP' was significantly associated with shorter survival time (HR=2.69, 95% CI 1.46-4.92, P=0.001). In addition, galectin-1, a previously identified protein with its abundance aversely associated with pancreatic cancer survival, was further evaluated for its significance in cancer-associated fibroblasts. Knockdown of galectin-1 in pancreatic cancer-associated fibroblasts dramatically reduced cell migration and invasion. The results from our study suggested that PRELP, LGALS1 and RPS8 might be significant prognostic factors, and RPS8 and LGALS1 could be potential therapeutic targets to improve pancreatic cancer survival if further validated.

PGE2 Elevates IL-23 Production in Human Dendritic Cells via a cAMP Dependent Pathway.

PGE2 elevates IL-23 production in mouse dendritic cells while inhibits IL-23 production in isolated human monocytes. Whether this differential effect of PGE2 on IL-23 production is cell-type- or species-specific has not been investigated in detail. The present study was designed to investigate the effect of PGE2 on IL-23 production in human DCs and the possible underlying mechanisms. Human monocytes derived dendritic cells (Mo-DCs) were pretreated with or without PGE2. Then the cells were incubated with zymosan. Our results demonstrated that PGE2 promoted zymosan-induced IL-23 production in a concentration dependent manner. In addition, it was found that PGE2 is also able to elevate MyD88-mediated IL-23 p19 promoter activity. More importantly, ELISA data demonstrated that db-cAMP, a cAMP analog, and forskolin, an adenylate cyclase activator, can mimic the effect of PGE2 on zymosan-induced IL-23 production, and rp-cAMP, a protein kinase A (PKA) inhibitor, can block the effect of PGE2. Moreover, PGE2 can increase zymosan-induced expression of the mRNA levels of both p19 and p40 subunits, which was mimicked by db-cAMP and forskolin. Our data suggest that PGE2 elevates the production of IL-23 in human Mo-DCs via a cAMP dependent pathway.

Patella rings for treatment of patellar fracture.

To evaluate a new fixation technique for patellar fracture using patella rings. A total of 75 patients (average age of 51.3 years) with comminuted or transverse patellar fractures were treated by fixation with patella rings. The Böstman scores at the time of bone union and at 12 months postoperatively were recorded, as was the degree of pain on a visual analogue scale (VAS), the range of motion of the knee at 12 months postoperatively, and any signs of postoperative complications. The average Böstman scores for patients in the transverse fracture group were 25.2 and 29.4 at 3 and 12 months postoperatively, respectively, while the scores for patients in the comminuted fracture group were 27.6 and 28.7, at the same time points. Böstman scores were graded as excellent and good in more than 90 % for patients with either a transverse or comminuted fracture. At the time of 12 months after surgery, the VAS score for patients with comminuted fractures was 0.38, whereas the score for patients in the transverse fracture group was 0.35. No statistically significant difference was found in the range of motion between the affected and uninjured knee at 12 months after surgery for patients in both groups (P > 0.05). This new fixation technique using a patella ring resulted in good outcomes for both transverse fracture and comminuted fracture and is beneficial for patients wishing to commence early functional activity.

Effect of perioperative parecoxib on postoperative pain and local inflammation factors PGE2 and IL-6 for total knee arthroplasty: a randomized, double-blind, placebo-controlled study.

To assess the efficacy of postoperative pain management and the concentration change of PGE-2 and IL-6 of joint fluid with parecoxib after postoperative total knee arthroplasty. In the study, 100 patients experiencing primary TKA were randomly divided into study group, receiving parecoxib sodium (40 mg) intravenously (IV) at the completion of surgery and once every 12 h for totally 6 times postoperatively, and placebo group, receiving normal saline 2 mL IV at the same time points. Efficacy was assessed by total amount of morphine consumed, pain intensity, range of motion (ROM), the concentration change of PGE-2 and IL-6 of joint fluid, and postoperative nausea and vomiting (PONV) postoperatively. Patients in study group consumed significantly less morphine, experienced significant less pain scores, and obtained significantly more ROM (P < 0.01) compared with that in placebo group during 3 days postoperatively. The concentration of PGE-2 and IL-6 of joint fluid in study group are significantly lower than that in placebo group (P < 0.01) during 24 h postoperatively. The overall incidence of PONV was low and was not significantly different between the two groups. The present study demonstrated that the perioperative administration of parecoxib after primary TKA resulted in significantly improved postoperative analgesic management as defined by reduction in opioid requirement, lower pain scores and ROM, and significantly lowered local inflammation factors PGE2 and IL-6.

Systematic review and meta-analysis of single-stage versus two-stage revision for periprosthetic joint infection after knee arthroplasty: a call for a randomised trial.

Purpose: Knee arthroplasty is an effective treatment for severe knee degeneration; however, periprosthetic joint infection (PJI) is one of its serious complications. Single- and two-stage revision are common treatments, but few studies have compared single- and two-stage revision for PJI after knee arthroplasty. This study aimed to compare the reinfection and reoperation rates of single- and two-stage revision through meta-analysis. Methods: The review process was conducted according to the PRISMA guidelines. We searched the PubMed, Medline, Embase and Cochrane Central Register of Controlled Trials databases for trials comparing single- and two-stage revision for PJI after knee arthroplasty from the respective inception dates to April 2023. Two researchers individually screened the studies, performed the literature quality evaluation and data extraction and used Stata 17 software for data analysis. Results: The meta-analysis showed that the reinfection rate was significantly lower in the single-stage revision group than in the two-stage revision group. While the reoperation rates demonstrated no statistically significant difference between the two groups. We presented descriptive results because the discrepancies in the knee function scores and data reported in the studies meant that these data could not be combined in the meta-analysis. Conclusion: Based on the available research, single-stage revision is a reliable option for PJI after knee arthroplasty. However, when developing the best treatment strategy, it is still necessary to consider the individual circumstances and needs of the patient, as well as the risks of postoperative rehabilitation and complications.

The active components and potential mechanisms of Wuji Wan in the treatment of ethanol-induced gastric ulcer: An integrated metabolomics, network pharmacology and experimental validation.

ETHNOPHARMACOLOGICAL RELEVANCE: Wuji Wan (WJW) is a traditional Chinese medicine formula that can be found in the "Prescriptions of Taiping Benevolent Dispensary" that has been employed in treating gastric discomfort, burning epigastric pain, and gastric reflux for hundreds of years and has shown promise for treating gastric ulcers (GUs). However, the active components and mechanism of action against GUs remain unclear. AIM OF THE STUDY: The aim of this study was to explore the active components of WJW and elucidate the underlying mechanism involved in treating GUs. MATERIALS AND METHODS: Initially, cell viability was measured by a cell counting kit 8 (CCK-8) assay to evaluate the efficacy of WJW-containing serum in vitro. The gastric ulcer index, ulcer inhibition rate, hematoxylin and staining (H&E), and periodic acid-Schiff (PAS) staining were used to evaluate the therapeutic effect of WJW in vivo. Subsequently, the levels of inflammatory factors and oxidative stress factors were determined using an enzyme-linked immunosorbent assays (ELISA) on in vitro and in vivo samples. Additionally, UPLC-Q Exactive Plus Orbitrap HRMS was used to analyze the components that were absorbed into the blood of WJW and its metabolites. Network pharmacology and metabolomics were subsequently used to identify the targets and pathways. Real-time quantitative PCR (RT‒qPCR) and Western blotting were used to verify the mRNA and protein levels of the key targets and pathways. Finally, the active components were identified by molecular docking to verify the binding stability of the components and key targets. RESULTS: WJW-containing serum ameliorated ethanol-induced damage in GES-1 cells and promoted cell healing. WJW-containing serum reduced IL-6, TNF-α, MDA, and LDH levels while increasing IL-10, SOD, and T-AOC levels in the cells. Moreover, WJW treatment resulted in decreased IL-6, TNF-α, and MDA levels and increased IL-10, SOD, PGE2, and NO levels in GUs rats. In addition, eight components of WJW were absorbed into the blood. The network pharmacology results revealed 192 common targets for blood entry components and GUs, and KEGG analysis revealed that apoptosis signaling pathways were the main pathways involved in WJW activity against GUs. Metabolomic screening was used to identify 13 differential metabolites. There were 23 common targets for blood entry components, GUs, and differential metabolites, with the key targets TNF (TNF-α), AKT1, PTGS2 (COX2) and MAPK1. WJW significantly inhibited the expression of Bax, Caspase-9, Caspase-3, cleaved Caspase-9, cleaved Caspase-3, TNF-α, COX2, and p-p44/42 MAPK while promoting the expression of Bcl-2 and p-AKT1. Molecular docking revealed that the active components of WJW for the treatment of GUs are berberine, palmatine, coptisine, evodiamine, rutaecarpine, evocarpine, and paeoniflorin. CONCLUSIONS: WJW treatment reduces inflammation and oxidative stress injury and inhibits apoptosis signaling pathways. The main active components are berberine, palmatine, coptisine, evodiamine, rutaecarpine, evocarpine, and paeoniflorin. In this paper, we provide a new strategy for exploring the active components of traditional Chinese medicine formulas for the treatment of diseases based on target mechanisms.

Gut bacteria-driven homovanillic acid alleviates depression by modulating synaptic integrity.

The gut-brain axis is implicated in depression development, yet its underlying mechanism remains unclear. We observed depleted gut bacterial species, including Bifidobacterium longum and Roseburia intestinalis, and the neurotransmitter homovanillic acid (HVA) in individuals with depression and mouse depression models. Although R. intestinalis does not directly produce HVA, it enhances B. longum abundance, leading to HVA generation. This highlights a synergistic interaction among gut microbiota in regulating intestinal neurotransmitter production. Administering HVA, B. longum, or R. intestinalis to mouse models with chronic unpredictable mild stress (CUMS) and corticosterone (CORT)-induced depression significantly improved depressive symptoms. Mechanistically, HVA inhibited synaptic autophagic death by preventing excessive degradation of microtubule-associated protein 1 light chain 3 (LC3) and SQSTM1/p62 proteins, protecting hippocampal neurons' presynaptic membrane. These findings underscore the role of the gut microbial metabolism in modulating synaptic integrity and provide insights into potential novel treatment strategies for depression.