Our results provide evidence for a complex mechanism and new approach by which PAR4 mediates the macrophage response triggered by LPS through counter-regulating the phagocytic activity of macrophages and innate response mechanisms implicated in the killing of invading pathogens.Glomeruli and renal tubule injury in chronic kidney disease (CKD) is reported to involve induction of macrophage activation through the CCL2/CCR2 axis. The effects of inhibitors of the CCL2/CCR2 axis, such as anti-CCL2 antibody and CCR2 antagonist, on kidney function in animal models or humans with kidney dysfunction have been demonstrated. The N-terminal glutamine on immature CCL2 is replaced with pyroglutamate (pE) by glutaminyl cyclase (QC) and isoQC. pE-CCL2 is stable and resistant to peptidases. We hypothesized that inhibiting QC/isoQC activity would lead to the degradation of CCL2, thereby ameliorating CKD and reducing kidney inflammation. To test this hypothesis, we investigated the renoprotective properties of the QC/isoQC inhibitor PQ529 in anti-glomerular basement membrane (GBM) antibody-induced glomerulonephritis Wistar Kyoto (WKY) rats. Three-week repeated administration of PQ529 (30 and 100 mg/kg, twice daily) significantly reduced the serum and urine CCL2 and urinary protein excretion in a dose-dependent manner. Correlations between the urinary protein level and serum or urinary CCL2 levels were confirmed in tested animals. Repeated administration of PQ529 significantly reduced the expression of CD68, a macrophage marker, in the kidney cortex and mononuclear infiltration into the tubulointerstitium. Eprenetapopt In addition, decreased levels of urinary KIM-1, β2 microglobulin, and clusterin were detected, suggesting the inhibition of inflammation in both the proximal and distal tubules. These results suggest that PQ529 suppresses the progression of inflammation-induced renal dysfunction by inhibiting the CCL2/CCR2 axis. Inhibition of QC/isoQC may thus be a viable alternative therapeutic approach for treating glomerulonephritis and CKD patients.
To produce national and regional estimates and trends for gabapentinoid-opioid co-prescribing rates in patients with OA, both in absolute terms and relative to matched controls without OA.
Using the UK Clinical Practice Research Datalink database we first constructed age-sex-practice-date 11 matched cohorts of patients aged ≥40 years with and without a new diagnosis of OA between 1995-2017 and estimated the relative incidence of a first gabapentinoid prescription. Incident gabapentinoid users in both cohorts were followed to estimate and compare the event rate of gabapentinoid-opioid co-prescription (prescription from both classes within the same 28-day window).
The incidence of first gabapentinoid prescription was 3-fold higher in patients with OA than in matched controls [n = 215357; incidence rate ratio (IRR) 2.93; 95% CI 2.87, 3.00]. Among incident gabapentinoid users with OA (n = 27374, median follow-up 3.9 years) the event rate of gabapentinoid-opioid co-prescription was 4.03 (4.02-4.05) per persoid co-prescription, and improved access to, and uptake of, effective non-pharmacological and surgical alternatives for OA are required.
To identify endotypes of osteoarthritis (OA) by a metabolomics analysis.
Study participants included hip/knee OA patients and controls. Fasting plasma samples were metabolomically profiled. Common factor analysis and K-means clustering were applied to the metabolomics data to identify the endotypes of OA patients. Logistic regression was utilized to identify the most significant metabolites contributing to the endotypes. Clinical and epidemiological factors were examined in relation to the identified OA endotypes.
Six hundred and fifteen primary OA patients and 237 controls were included. Among the 186 metabolites measured, 162 passed the quality control analysis. The 615 OA patients were classified in three clusters (A, 66; B, 200; and C, 349). Patients in cluster A had a significantly higher concentration of butyrylcarnitine (C4) than other clusters and controls (all P < 0.0002). Elevated C4 is thought to be related to muscle weakness and wasting. Patients in cluster B had a significantly lower arginine concentration than other clusters and controls (all P < 7.98 × 10-11). Cluster C patients had a significantly lower concentration of lysophosphatidylcholine (with palmitic acid), which is a pro-inflammatory bioactive compound, than other clusters and controls (P < 3.79 × 10-6). Further, cluster A had a higher BMI and prevalence of diabetes than other clusters (all P ≤ 0.0009), and also a higher prevalence of coronary heart disease than cluster C (P = 0.04). Cluster B had a higher prevalence of coronary heart disease than cluster C (P = 0.003) whereas cluster C had a higher prevalence of osteoporosis (P = 0.009).
Our data suggest three possible clinically actionable endotypes in primary OA muscle weakness, arginine deficit and low inflammatory OA.
Our data suggest three possible clinically actionable endotypes in primary OA muscle weakness, arginine deficit and low inflammatory OA.
Despite classic analgesic or effective treatments in rheumatic diseases, such as synthetic DMARDs in RA, patients remain in pain and often turn to non-prescribed pharmacological alternatives, such as cannabis self-therapeutic use. However, this medical use of cannabis has not been thoroughly studied.
We performed a systematic literature review up to June 2020. The incidence of cannabis consumption was calculated by metaproportion. Differences between cannabis users and non-users were expressed as standardized mean differences using the inverse-variance method. We also assessed the effects of cannabis on pain.
A total of 2900 patients reported cannabis consumption in a sample of 10873 patients [incidence 40.4% (95% confidence interval (CI) 0.28, 0.54)], and 15.3% (95% CI 0.07, 0.27) specified that they were currently taking cannabis. Cannabis use was higher in the four fibromyalgia studies [68.2% (95% CI 0.41, 0.90), n = 611] compared with seven articles concerning RA or lupus [26.0% (95% CI 0.14, 0.41), n = 8168].Eprenetapopt
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