Search

• Macrophages are key immune cells in inflammatory bowel disease. • Alcohol is a widely used solvent in pharmaceutical formulations. • Alcohol consumption is associated with an increased risk and severity of colitis. • Alcohol promotes macrophage M2b polarization through the TRPV1-MAPK/NF-κB pathways. Macrophages exhibit different phenotypes in inflammatory bowel disease (IBD) and promote inflammation or tissue repair depending on their polarization state. Alcohol is a widely used solvent in pharmaceutical formulations, and its consumption is associated with an increased risk of colitis; however, its effects on macrophages in IBD remain poorly understood. This study aimed to investigate the effect of alcohol on macrophages in dextran sodium sulfate (DSS)-induced colitis and understand the underlying mechanisms. DSS-treated C57BL/6 mice were exposed to varying concentrations of alcohol, transient receptor potential vanilloid 1 (TRPV1) antagonist, and 5-aminosalicylic acid. The distal colon was resected, fixed, stained, and histologically analyzed, through hematoxylin and eosin (H&E) staining and immunofluorescence staining. Ratio [Ca2+]i measurements, western blotting, quantitative polymerase chain reaction, cytokine measurements, and RNA sequencing analyses were also performed. Peritoneal macrophages and RAW264.7 cells were used for in vitro experiments, and various assays were performed to evaluate cellular responses, gene expression, and signaling pathways. Alcohol exacerbated DSS-treated mice colitis and promoted the secretion of various inflammatory cytokines from colonic macrophages. Alcohol enhances the calcium ion influx induced by lipopolysaccharide (LPS) in peritoneal macrophages, while the TRPV1 antagonist capsazepine (CPZ) inhibits LPS- and/or alcohol- induced calcium influx in macrophages. Alcohol and LPS activate the MAPK/P38, MAPK/ERK, and NF-κB signaling pathways and induce the macrophage M2b polarization, resulting in the increased expression level of inflammatory cytokines such as Tnf, Il1b, and Il10. Additionally, CPZ can inhibit the facilitatory effects of alcohol or LPS on the abovementioned pathways and inflammatory factors, reversing macrophage M2b polarization and promoting alcohol-induced colitis. The inhibition of nucleotide binding oligomerization domain containing 2 (NOD2) partially suppressed the alcohol and LPS effects on macrophages. Alcohol exacerbates experimental colitis and induces M2b polarization of macrophage via TRPV1-MAPK/NF-κB. Our study provides new insights into the potential therapeutic targets for IBD treatment by elucidating the role of TRPV1 in alcohol-exacerbated colitis, using CPZ as a potential therapeutic option. The identification of transient receptor potential ankyrin subtype 1 (TRPA1) as a therapeutic target expands the scope of future research. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Previous studies indicate that the levels of d-dimer and blood lipids at admission affect the prognosis of patients with acute ischemic stroke (AIS), however, whether there is a dose-response effect of d-dimer on prognosis, or a combined effect of d-dimer with blood lipids on prognosis, remains unclear.Methods: In this prospective cohort study, 1485 AIS patients were recruited. All participants received medical care within 24 h from the onset of stroke, the level of d-dimer and related indices were measured at admission. Then, National Institutes of Health Stroke Scale (NIHSS) scores were obtained at the time of admission and discharge. Afterwards, 3-, 6- and 12- month follow-up was conducted to obtain Modified Rankin Scale (mRS) scores after discharge.Results: A high level of d-dimer at admission was associated with clinical outcome of AIS, after adjusting other relevant factors, with an OR (95%CI) of 2.934(1.914-4.500), 3.052(1.912-4.872), 3.306(1.873-5.835) and 2.828(1.447-5.527) at discharge, at 3-, 6-, and 12-month follow-up respectively, a dose-response effect was observed during follow-up (p = 0.00001). When d-dimer was combined with total cholesterol (TC), after adjusting other relevant factors, OR (95%CI) was 2.799 (1.708-4.587), 2.473 (1.475-4.147), 2.381 (1.333-4.255), and 2.619 (1.320-5.193), at each follow-up period respectively. When combined with low-density lipoprotein (LDL), OR (95%CI) was 3.105 (1.729-5.577), 3.280 (1.762-6.104), 2.744 (1.344-5.604), and 4.400 (1.883-10.282), respectively.Conclusions: D-dimer levels at admission may predict the prognosis of AIS patients in a dose-response pattern. Moreover, d-dimer combined with TC or LDL predict prognosis of AIS. [ABSTRACT FROM AUTHOR]

D-dimer level and platelet count (PC) have been reported separately as significant independent predictors of Acute Ischemic Stroke (AIS). Here, we aimed to investigate the combined prognostic value of abnormal D-dimer level and PC as defined for specific in-hospital and long-term outcomes in AIS patients. A total of 1468 patients admitted for ischemic stroke within 24 h of symptom onset from April 1, 2016 to November 31, 2019 at the Department of Neurology, the First Affiliated Hospital of Harbin Medical University were included in the final analysis. Eligible subjects were divided into four groups in terms of their levels of D-dimer and PC: DD−PC− (normal D-dimer level and normal PC), DD−PC+ (normal D-dimer level and abnormal PC), DD+PC− (higher D-dimer level and normal PC), and DD+PC+ (higher D-dimer level and abnormal PC). Logistic regression model and multinomial logit model were used to estimate the combined effect of D-dimer level and PC on in-hospital outcomes including discharge outcome and early neurological changes, and poor outcomes at 3, 6 and 12 months. DD+PC+ was found to be associated with the risk of in-hospital mortality (adjusted odds ratio [OR], 6.904; 95% confidence interval [CI], 2.781–17.144) and 3-month mortality (adjusted OR, 5.455; 95% CI, 2.019–14.743) compared with DD−PC−. Combination of the two indicators significantly improved the independent predictive value for functional outcomes, including early neurological deterioration (END) (OR, 3.622; 95% CI, 1.732–7.573) with threshold of at least 4-point increase on NIHSS, discharge outcome (OR, 2.713; 95% CI, 1.421–5.177); mRS of 0–1 point (OR, 0.409; 95% CI, 0.211–0.792), mRS of 0–2 points (OR, 0.234; 95% CI, 0.118, 0.461), and higher mRS-shift (OR, 2.379; 95% CI, 1.237–4.576) at 3 months; unfavorable outcome at 3 months (OR, 4.280; 95% CI, 2.169–8.446), 6 months (OR, 3.297; 95% CI, 1.452–7.488) and 12 months (OR, 4.157; 95% CI, 1.598–10.816). While comparatively weaker statistical significance was shown in DD+PC− and no correlation was found between adverse outcomes and DD−PC+. Similarly, patients with abnormal D-dimer level and PC were less likely to reach the status of stable or improving. Combination of D-dimer level and PC may have more significant prognostic value on END, in-hospital mortality, discharge outcome, and long-term outcomes than either index of D-dimer level or PC alone in AIS patients. • D-dimer and platelet are biomarkers in acute ischemic stroke. • Co-existing abnormal D-dimer level and platelet count indicates significantly higher risk. • Outcomes include functional dependence, a modified Rankin Scale shift and mortality. • The prediction of early neurological deterioration, or the status of stable or improving. [ABSTRACT FROM AUTHOR]