Decreased Serum Maresin 1 Concentration Is Associated With Postmenopausal Osteoporosis: A Cross-Sectional Study

Background: Maresin 1 plays a role in the regulation of inflammation and metabolic diseases in vivo. An increasing number of studies have reported that postmenopausal osteoporosis (PMOP) is associated with inflammation. However, the potential relationship between the serum Maresin 1 content and PMOP is unclear.Aims: 1) To evaluate the Maresin 1 content in postmenopausal women with osteopenia, osteoporosis, or without these conditions (normal group) and 2) to analyze the correlations between Maresin 1 concentrations and bone mineral density (BMD) and bone turnover markers.Methods: In this cross-sectional study, we measured serum Maresin 1 concentrations, serum biochemical parameters, markers of bone metabolism, and BMD of the femoral neck, lumbar spine, and hip in 141 postmenopausal women.Results: We found that serum Maresin 1 in the osteopenia (140.09 ± 30.54 pg/ml) and PMOP (124.68 ± 31.35 pg/ml) groups were significantly lower than those in the normal group (167.38 ± 24.85 pg/ml) (P < 0.05 and P < 0.001). Serum Maresin 1 levels were positively correlated with femoral neck, lumbar spine, and hip BMD (P < 0.001). Meanwhile, Maresin 1 concentrations were positively associated with 25-hydroxyvitamin D [25(OH)D] levels (P < 0.001), but negatively correlated with β-CrossLaps of type 1 collagen containing cross-linked C-telopeptide (β-CTX) (P = 0.002), procollagen type I amino-terminal propeptide (PINP) (P = 0.004), tartrate-resistant acid phosphatase 5b (TRAP-5b) (P = 0.005), and osteocalcin (OC) levels (P = 0.001). Multivariate logistic regression analysis showed that a decrease in Maresin 1 concentration was still associated with osteopenia (P = 0.035) or PMOP (P = 0.016). Maresin 1 levels had a maximum area under curve of 0.820 for osteopenia and 0.746 for PMOP (P < 0.001). Our results showed that the serum Maresin 1 levels were reduced in osteopenia and PMOP patients compared with that in normal subjects, and were the lowest in the PMOP subjects. The results suggest that Maresin 1 may serve as a new non-invasive diagnostic biomarker for PMOP.

Maresin 1 Attenuates Lipopolysaccharide-Induced Acute Kidney Injury via Inhibiting NOX4/ROS/NF-κB Pathway

Sepsis-associated acute kidney injury (S-AKI) is a common complication in hospitalized and critically ill patients, which increases the risk of multiple comorbidities and is associated with extremely high mortality. Maresin 1 (MaR1), a lipid mediator derived from the omega-3 fatty acid docosahexaenoic acid has been reported to protect against inflammation and promote the regression of acute inflammation. This study proposed to systematically investigate the renoprotective effects and potential molecular mechanism of MaR1 in septic acute kidney injury. We established a S-AKI animal model by a single intraperitoneal injection of lipopolysaccharide (LPS), 10 mg/kg, on male C57BL/6J mice. LPS-stimulated (100 μg/ml) mouse kidney tubular epithelium cells (TCMK-1) were used to simulate septic AKI in vitro. The results showed that pretreatment with MaR1 significantly reduced serum creatinine and blood urea nitrogen levels as well as tubular damage scores and injury marker neutrophil gelatinase-associated lipocalin in septic AKI mice. Meanwhile, MaR1 administration obviously diminished pro-inflammatory cytokines (TNF-α, IL-6, IL-1β, and MCP-1), downregulated BAX and cleaved caspase-3 expression, and upregulated BCL-2 expression in the injured kidney tissues and TCMK-1 cells. In addition, MaR1 reduced malondialdehyde production and improved the superoxide dismutase activity of renal tissues while inhibiting reactive oxygen species (ROS) production and protecting the mitochondria. Mechanistically, LPS stimulated the expression of the NOX4/ROS/NF-κB p65 signaling pathway in S-AKI kidneys, while MaR1 effectively suppressed the activation of the corresponding pathway. In conclusion, MaR1 attenuated kidney inflammation, apoptosis, oxidative stress, and mitochondrial dysfunction to protect against LPS-induced septic AKI via inhibiting the NOX4/ROS/NF-κB p65 signaling pathway.

Maresin-1 Prevents Liver Fibrosis by Targeting Nrf2 and NF-κB, Reducing Oxidative Stress and Inflammation

Liver fibrosis is a complex process characterized by the excessive accumulation of extracellular matrix (ECM) and an alteration in liver architecture, as a result of most types of chronic liver diseases such as cirrhosis, hepatocellular carcinoma (HCC) and liver failure. Maresin-1 (MaR1) is derivative of ω-3 docosahexaenoic acid (DHA), which has been shown to have pro-resolutive and anti-inflammatory effects. We tested the hypothesis that the application of MaR1 could prevent the development of fibrosis in an animal model of chronic hepatic damage. Sprague-Dawley rats were induced with liver fibrosis by injections of diethylnitrosamine (DEN) and treated with or without MaR1 for four weeks. In the MaR1-treated animals, levels of AST and ALT were normalized in comparison with DEN alone, the hepatic architecture was improved, and inflammation and necrotic areas were reduced. Cell proliferation, assessed by the mitotic activity index and the expression of Ki-67, was increased in the MaR1-treated group. MaR1 attenuated liver fibrosis and oxidative stress was induced by DEN. Plasma levels of the pro-inflammatory mediators TNF-α and IL-1β were reduced in MaR1-treated animals, whereas the levels of IL-10, an anti-inflammatory cytokine, increased. Interestingly, MaR1 inhibited the translocation of the p65 subunit of NF-κB, while increasing the activation of Nrf2, a key regulator of the antioxidant response. Finally, MaR1 treatment reduced the levels of the pro-fibrotic mediator TGF-β and its receptor, while normalizing the hepatic levels of IGF-1, a proliferative agent. Taken together, these results suggest that MaR1 improves the parameters of DEN-induced liver fibrosis, activating hepatocyte proliferation and decreasing oxidative stress and inflammation. These results open the possibility of MaR1 as a potential therapeutic agent in fibrosis and other liver pathologies.

Low serum Maresin-1 levels are associated with non-alcoholic fatty liver disease: a cross-sectional study

Background Maresin-1 (MaR1) is an anti-inflammatory pro-resolving mediator and is considered a potential regulator of metabolic diseases. Non-alcoholic fatty liver disease (NAFLD) is a very common metabolic liver disease. However, little information is available on the relationship between MaR1 and NAFLD in humans. Therefore, the study explored the association between serum MaR1 levels and NAFLD. Methods A cross-sectional study was conducted in 240 Chinese people, including 116 non-NAFLD subjects and 124 NAFLD patients. Serum MaR1 levels were determined by enzyme-linked immunosorbent assay (ELISA). The association between MaR1 and NAFLD was assessed. Results Circulating MaR1 levels in NAFLD patients were markedly lower than those in non-NAFLD subjects (63.63 [59.87–73.93] vs 73.11 [65.12–84.50] pg/mL, P = 0.000). The percentages of patients with NAFLD gradually decreased with the increase of MaR1 quartiles (P < 0.001). Furthermore, serum MaR1 levels were positively associated with aspartate aminotransferase/alanine aminotransferase (AST/ALT), albumin, the albumin-globulin-ratio, and high-density lipoprotein cholesterol (HDL-C) (all P < 0.05) and negatively associated with body mass index (BMI), waist circumference, hip circumference, the waist-to-hip ratio, ALT, gamma-glutamyl transpeptidase (GGT), uric acid, triglyceride (TG), and fasting blood glucose (FBG) (all P < 0.05) after adjusting for sex and age. Binary logistic regression analysis revealed that serum MaR1 levels were significantly associated with NAFLD. Conclusions Circulating MaR1 levels were decreased in patients with NAFLD, and a negative correlation was identified between NAFLD and serum MaR1 concentrations. Decreased MaR1 might be involved in the development of NAFLD.

Low Serum Maresin-1 Levels Are Associated with Non-alcoholic Fatty Liver Disease: A Cross Sectional Study

Background Maresin-1 is one of anti-inflammatory pro-resolving mediators, which is considered as a potential regulator of metabolic diseases. However, little information is available on the relationship between Maresin-1 and non-alcoholic fatty liver disease (NAFLD) in humans. Therefore, this study explored the associations between serum Maresin-1 levels and NAFLD. Methods A cross-sectional study was conducted in 240 Chinese people, including 116 non-NAFLD subjects and 124 NAFLD patients. NAFLD was diagnosed by abdominal ultrasonography. Serum Maresin-1 levels were determined by ELISA. The association between Maresin-1 and NAFLD was assessed. Results Serum Maresin-1 levels in NAFLD patients were markedly lower than those in non-NAFLD subjects (63.63 [59.87–73.93] vs 73.11 [65.12–84.50] pg/mL, P = 0.000). The percentages of patients with NAFLD gradually decreased in tandem with increasing quartiles of Maresin-1 (P < 0.001). Furthermore, serum Maresin-1 levels were positively associated with AST/ALT, albumin, Albumin-globulin-ratio, and HDL-C (all P < 0.05) and negatively associated with BMI, waist circumference, hip circumference, waist-to-hip ratio, ALT, GGT, uric acid, TG, and FBG (all P < 0.05) after adjusting for sex and age. We found that serum Maresin-1 levels were significantly associated with NAFLD by binary logistic regression analysis. Conclusions Circulating Maresin-1 levels were decreased in patients with NAFLD, and there was a negative correlation between NAFLD and serum Maresin-1 concentrations. Decreased Maresin-1 might be involved in the development of NAFLD.

Maresin-1 induces cardiomyocyte hypertrophy through IGF-1 paracrine pathway

The resolution of inflammation is closely linked with tissue repair. Recent studies have revealed that macrophages suppress inflammatory reactions by producing lipid mediators, called specialized proresolving mediators (SPMs); however, the biological significance of SPMs in tissue repair remains to be fully elucidated in the heart. In this study, we focused on maresin-1 (MaR1) and examined the reparative effects of MaR1 in cardiomyocytes. The treatment with MaR1 increased cell size in cultured neonatal rat cardiomyocytes. Since the expression of fetal cardiac genes was unchanged by MaR1, physiological hypertrophy was induced by MaR1. SR3335, an inhibitor of retinoic acid-related orphan receptor α (RORα), mitigated MaR1-induced cardiomyocyte hypertrophy, consistent with the recent report that RORα is one of MaR1 receptors. Importantly, in response to MaR1, cardiomyocytes produced IGF-1 via RORα. Moreover, MaR1 activated phosphoinositide 3-kinase (PI3K) / Akt signaling pathway and wortmannin, a PI3K inhibitor, or triciribine, an Akt inhibitor, abrogated MaR1-induced cardiomyocyte hypertrophy. Finally, the blockade of IGF-1 receptor by NVP-AEW541 inhibited MaR-1-induced cardiomyocyte hypertrophy as well as the activation of PI3K/Akt pathway. These data indicate that MaR1 induces cardiomyocyte hypertrophy through RORα/IGF-1/PI3K/Akt pathway. Considering that MaR1 is a potent resolving factor, MaR1 could be a key mediator that orchestrates the resolution of inflammation with myocardial repair.