Gut microbial co-metabolite 2-methylbutyrylcarnitine exacerbates thrombosis via binding to and activating integrin α2ß1.

Thrombosis represents the leading cause of death and disability upon major adverse cardiovascular events (MACEs). Numerous pathological conditions such as COVID-19 and metabolic disorders can lead to a heightened thrombotic risk; however, the underlying mechanisms remain poorly understood. Our study illustrates that 2-methylbutyrylcarnitine (2MBC), a branched-chain acylcarnitine, is accumulated in patients with COVID-19 and in patients with MACEs. 2MBC enhances platelet hyperreactivity and thrombus formation in mice. Mechanistically, 2MBC binds to integrin α2ß1 in platelets, potentiating cytosolic phospholipase A2 (cPLA2) activation and platelet hyperresponsiveness. Genetic depletion or pharmacological inhibition of integrin α2ß1 largely reverses the pro-thrombotic effects of 2MBC. Notably, 2MBC can be generated in a gut-microbiota-dependent manner, whereas the accumulation of plasma 2MBC and its thrombosis-aggravating effect are largely ameliorated following antibiotic-induced microbial depletion. Our study implicates 2MBC as a metabolite that links gut microbiota dysbiosis to elevated thrombotic risk, providing mechanistic insight and a potential therapeutic strategy for thrombosis.

COVID-19 induces new-onset insulin resistance and lipid metabolic dysregulation via regulation of secreted metabolic factors.

Abnormal glucose and lipid metabolism in COVID-19 patients were recently reported with unclear mechanism. In this study, we retrospectively investigated a cohort of COVID-19 patients without pre-existing metabolic-related diseases, and found new-onset insulin resistance, hyperglycemia, and decreased HDL-C in these patients. Mechanistically, SARS-CoV-2 infection increased the expression of RE1-silencing transcription factor (REST), which modulated the expression of secreted metabolic factors including myeloperoxidase, apelin, and myostatin at the transcriptional level, resulting in the perturbation of glucose and lipid metabolism. Furthermore, several lipids, including (±)5-HETE, (±)12-HETE, propionic acid, and isobutyric acid were identified as the potential biomarkers of COVID-19-induced metabolic dysregulation, especially in insulin resistance. Taken together, our study revealed insulin resistance as the direct cause of hyperglycemia upon COVID-19, and further illustrated the underlying mechanisms, providing potential therapeutic targets for COVID-19-induced metabolic complications.

Identification of Diagnostic Signatures and Immune Cell Infiltration Characteristics in Rheumatoid Arthritis by Integrating Bioinformatic Analysis and Machine-Learning Strategies.

Background: Rheumatoid arthritis (RA) refers to an autoimmune rheumatic disease that imposes a huge burden on patients and society. Early RA diagnosis is critical to preventing disease progression and selecting optimal therapeutic strategies more effectively. In the present study, the aim was at examining RA's diagnostic signatures and the effect of immune cell infiltration in this pathology. Methods: Gene Expression Omnibus (GEO) database provided three datasets of gene expressions. Firstly, this study adopted R software for identifying differentially expressed genes (DEGs) and conducting functional correlation analyses. Subsequently, we integrated bioinformatic analysis and machine-learning strategies for screening and determining RA's diagnostic signatures and further verify by qRT-PCR. The diagnostic values were assessed through receiver operating characteristic (ROC) curves. Moreover, this study employed cell-type identification by estimating relative subsets of RNA transcript (CIBERSORT) website for assessing the inflammatory state of RA, and an investigation was conducted on the relationship of diagnostic signatures and infiltrating immune cells. Results: On the whole, 54 robust DEGs received the recognition. Lymphocyte-specific protein 1 (LSP1), Granulysin (GNLY), and Mesenchymal homobox 2 (MEOX2) (AUC = 0.955) were regarded as RA's diagnostic markers and showed their statistically significant difference by qRT-PCR. As indicated from the immune cell infiltration analysis, resting NK cells, neutrophils, activated NK cells, T cells CD8, memory B cells, and M0 macrophages may be involved in the development of RA. Additionally, all diagnostic signatures might be different degrees of correlation with immune cells. Conclusions: In conclusion, LSP1, GNLY, and MEOX2 are likely to be available in terms of diagnosing and treating RA, and the infiltration of immune cells mentioned above may critically impact RA development and occurrence.

ARG2, MAP4K5 and TSTA3 as Diagnostic Markers of Steroid-Induced Osteonecrosis of the Femoral Head and Their Correlation With Immune Infiltration.

BACKGROUND: The diagnosis for steroid-induced osteonecrosis of the femoral head (SONFH) is hard to achieve at the early stage, which results in patients receiving ineffective treatment options and a poor prognosis for most cases. The present study aimed to find potential diagnostic markers of SONFH and analyze the effect exerted by infiltration of immune cells in this pathology. MATERIALS AND METHODS: R software was adopted for identifying differentially expressed genes (DEGs) and conducting functional investigation based on the microarray dataset. Then we combined SVM-RFE, WGCNA, LASSO logistic regression, and random forest (RF) algorithms for screening the diagnostic markers of SONFH and further verification by qRT-PCR. The diagnostic values were assessed through receiver operating characteristic (ROC) curves. CIBERSORT was then adopted for assessing the infiltration of immune cells and the relationship of infiltration-related immune cells and diagnostic markers. RESULTS: We identified 383 DEGs overall. This study found ARG2, MAP4K5, and TSTA3 (AUC = 0.980) to be diagnostic markers of SONFH. The results of qRT-PCR showed a statistically significant difference in all markers. Analysis of infiltration of immune cells indicated that neutrophils, activated dendritic cells and memory B cells were likely to show the relationship with SONFH occurrence and progress. Additionally, all diagnostic markers had different degrees of correlation with T cell follicular helper, neutrophils, memory B cells, and activated dendritic cells. CONCLUSION: ARG2, MAP4K5, and TSTA3 are potential diagnostic genes for SONFH, and infiltration of immune cells may critically impact SONFH occurrence and progression.

Text Mining-Based Drug Discovery in Osteoarthritis.

Background: Osteoarthritis (OA) is a chronic and degenerative joint disease, which causes stiffness, pain, and decreased function. At the early stage of OA, nonsteroidal anti-inflammatory drugs (NSAIDs) are considered the first-line treatment. However, the efficacy and utility of available drug therapies are limited. We aim to use bioinformatics to identify potential genes and drugs associated with OA. Methods: The genes related to OA and NSAIDs therapy were determined by text mining. Then, the common genes were performed for GO, KEGG pathway analysis, and protein-protein interaction (PPI) network analysis. Using the MCODE plugin-obtained hub genes, the expression levels of hub genes were verified using quantitative real-time polymerase chain reaction (qRT-PCR). The confirmed genes were queried in the Drug Gene Interaction Database to determine potential genes and drugs. Results: The qRT-PCR result showed that the expression level of 15 genes was significantly increased in OA samples. Finally, eight potential genes were targetable to a total of 53 drugs, twenty-one of which have been employed to treat OA and 32 drugs have not yet been used in OA. Conclusions: The 15 genes (including PTGS2, NLRP3, MMP9, IL1RN, CCL2, TNF, IL10, CD40, IL6, NGF, TP53, RELA, BCL2L1, VEGFA, and NOTCH1) and 32 drugs, which have not been used in OA but approved by the FDA for other diseases, could be potential genes and drugs, respectively, to improve OA treatment. Additionally, those methods provided tremendous opportunities to facilitate drug repositioning efforts and study novel target pharmacology in the pharmaceutical industry.

The role of perioperative intravenous low-dose dexamethasone in rapid recovery after total knee arthroplasty: a meta-analysis.

PURPOSE: The purpose of this meta-analysis was to evaluate the overall safety and effectiveness of perioperative intravenous dexamethasone to facilitate postoperative rehabilitation in patients after total knee arthroplasty (TKA). METHODS: A comprehensive literature search was performed using the Embase, PubMed, Cochrane Library, and China National Knowledge Infrastructure (CNKI) databases for relevant randomized controlled trials (RCTs) from inception to 2020. Methodological quality of the trials was assessed using the Cochrane Risk of Bias Tool, and the relevant data were extracted using a predefined data extraction form. RESULTS: Ten RCTs with 1100 knees were included. Our study showed a significant reduction in pain using a postoperative pain visual analog scale (VAS) at 24 hours and 48 hours, total opioid consumption at 24 hours and 48 hours, postoperative nausea and vomiting (PONV), active range of motion (ROM) limitation, and passive ROM limitation at 72 hours in dexamethasone-treated groups compared with controls. CONCLUSION: Intravenous low-dose dexamethasone is potentially useful in the perioperative setting for reducing postsurgical immediate ROM limitations, pain, opioid consumption, and PONV. There are no data that directly attribute an increase in postoperative complications to intravenous dexamethasone. More high-quality studies are necessary to draw these conclusions.

L-3-n-Butylphthalide Effectively Improves the Glymphatic Clearance and Reduce Amyloid-ß Deposition in Alzheimer's Transgenic Mice.

Amyloid-ß (Aß) deposit in the parenchyma is a major characteristic in Alzheimer's disease (AD), and the impaired glymphatic clearance contributes to the Aß accumulation. It was reported that L-3-n-butylphthalide (NBP) showed the potential neuroprotective effect in the rodent models of AD. The effects of NBP on the glymphatic system were explored in this study. In the wild-type mice, both CSF tracer influx and perivascular drainage increased after NBP treatment compared with vehicle treatment. Moreover, NBP promoted the perivascular drainage of Aß via increased cerebral pulsation, which could be inhibited by propranolol. Then, we studied the potential of 3-month NBP treatment on Aß deposits in 8-month-old APP/PS1 transgenic mice. NBP daily treatments remarkably improved cognitive behavior in Morris water maze. Furthermore, NBP could reduce Aß deposition and decrease parenchymal Aß levels. In addition, NBP markedly improved the perivascular AQP4 localization. Our results indicated that NBP could enhance the glymphatic clearance and reduce parenchymal Aß deposit in the APP/PS1 mice, suggesting that it may have potential in the treatment of AD.

Continuous adductor canal block provides better performance after total knee arthroplasty compared with the single-shot adductor canal block?: An updated meta-analysis of randomized controlled trials.

BACKGROUND: Adductor canal block (ACB) has emerged as an attractive alternative for femoral nerve blocks (FNB) as the peripheral nerve block of choice for total knee arthroplasty (TKA), preserving quadriceps motor function while providing analgesia comparable to FNB. However, its optimal application for TKA remains controversial. The objective of this meta-analysis was to compare continuous-injection ACB (CACB) vs single-injection ACB (SACB) for postoperative pain control in patients undergoing TKA. METHODS: This study attempts to identify the available and relevant randomized controlled trials (RCTs) regarding the analgesic effects of CACB compared to SACB in patients undergoing TKA according to electronic databases, including PubMed, Medline, Web of Science, EMbase, and the Cochrane Library, up to September 2019. Primary outcomes in this regard included the use of a visual analogue scale (VAS) pain score with rest or activity, while secondary outcomes were cumulative opioid consumption, length of hospital stay (LOS), complications of vomiting and nausea, and rescue analgesia. The corresponding data were analyzed using RevMan v5.3. ETHICAL REVIEW: Because all of the data used in this systematic review and meta-analysis has been published, the ethical approval was not necessary RESULTS:: This research included 9 studies comprised of 739 patients. The analyzed outcomes demonstrated that patients who received CACB had a better at rest-VAS scores at 4 hours (P = .007), 8 hors (P < .0001), 12 hours (P < .0001), 24 hours (P = .02), mobilization-VAS score at 48 hours (P < .0001), and rescue analgesia (P = .03) than those who underwent SACB. Nevertheless, no significant differences were present between the 2 strategies in terms of pain VAS scores 48 hours at rest (P = .23) and 24 hours at mobilization (P = .10), complications of vomiting and nausea (P = .42), and length of hospital stay (P = .09). CONCLUSION: This meta-analysis indicated that CACB is superior to SACB in regard to analgesic effect following TKA. However, due to the variation of the included studies, no firm conclusions can be drawn. Further investigations into RCT are required for verification.

The effect of musical interventions in improving short-term pain outcomes following total knee replacement: a meta-analysis and systematic review.

BACKGROUND: A growing number of patients continue to receive total knee replacement (TKR) surgery. Nevertheless, such surgeries result in moderate to severe postoperative pain and difficulty in managing it. Musical interventions are regarded as a type of multimodal analgesia, achieving beneficial results in other clinical treatments. This study aims to evaluate the effect of musical interventions in improving short-term pain outcomes following TKR in order to determine a more reasonable and standard way of delivering musical intervention. METHODS: A systematic search was conducted to identify available and relevant randomized controlled trials (RCTs) regarding musical interventions compared against non-musical interventions in patients treated with TKR in Embase, MEDLINE, Cochrane Library, Web of Science, CNKI, and Wanfang Med Online up to 8 January 2020. The authors independently assessed study eligibility and risk of bias and collected the outcomes of interest to analyze. The statistical analysis was conducted using the Review Manager (RevMan) version 5.30 software. RESULTS: Eight RCTs comprised of 555 patients satisfied the inclusion criteria and were enrolled in the present study. The results showed no significant difference between the music and control groups in pain of the visual analog scale (VAS), during postoperative recovery room, back to the ward after surgery; anxiety degree of VAS; heart rate; respiratory rate; oxygen saturation; blood pressure, systolic blood pressure, and diastolic blood pressure. Nevertheless, significant differences were observed between the two groups in average increase in continuous passive motion (CPM) angles and LF/HF ratio (one kind index of heart rate variability). CONCLUSIONS: Musical interventions fail to demonstrate an obvious effect in improving short-term pain outcomes following TKR. A reasonable standardization of musical interventions, including musical type, outcome measures used, outcomes measured, duration, timing and headphones or players, may improve pain outcomes with certain advantages and should be further explored after TKR.