Prostaglandins & other lipid mediators最新文献

This mini-review addresses lipoxygenases and receptors for leukotrienes in hematological malignancies. Potential novel biomarkers and drug targets in leukemia and B-cell lymphoma are discussed.

Dysregulation of energy balance leading to obesity is a significant risk factor for cardiometabolic diseases such as diabetes, non-alcoholic fatty liver disease and atherosclerosis. In rodents and several other vertebrates, feeding has been shown to induce a rapid rise in the intestinal levels of N-acyl-ethanolamines (NAEs) and the chronic consumption of a high fat diet abolishes this rise. Administering NAEs to rodents consuming a high fat diet reduces their adiposity, in part by reducing food intake and enhancing fat oxidation, so that feeding-induced intestinal NAE biosynthesis appears to be critical to appropriate regulation of energy balance. However, the contribution of feeding-induced intestinal NAE biosynthesis to appropriate energy balance remains poorly understood in part because there are multiple enzymes that can contribute to NAE biosynthesis and the specific enzyme(s) that are responsible for feeding-induced intestinal NAE biosynthesis have not been identified. The rate-limiting step in the intestinal biosynthesis of NAEs is formation of their immediate precursors, the N-acyl-phosphatidylethanolamines (NAPEs), by phosphatidylethanolamine N-acyltransferases (NATs). At least six NATs are found in humans and multiple homologs of these NATs are found in most vertebrate species. In recent years, the fecundity and small size of zebrafish (Danio rerio), as well as their similarities in feeding behavior and energy balance regulation with mammals, have led to their use to model key features of cardiometabolic disease. We therefore searched the Danio rerio genome to identify all NAT homologs and found two additional NAT homologs besides the previously reported plaat1, rarres3, and rarres3l, and used CRISPR/cas9 to delete these two NAT homologs (plaat1l1 and plaat1l2). While wild-type fish markedly increased their intestinal NAPE levels in response to a meal after fasting, this response was completely ablated in plaat1l1^-/- fish. Furthermore, plaat1l1^-/- fish fed a standard flake diet had increased weight gain and glucose intolerance compared to wild-type fish. The results support a critical role for feeding-induced NAPE and NAE biosynthesis in regulating energy balance and suggest that restoring this response in obese animals could potentially be used to treat obesity and cardiometabolic disease.

Several studies reported the benefits of flaxseed on inflammatory biomarkers, while others reported conflicting findings. Thus, the aim of this meta-analysis was to assess the impacts of flaxseed on inflammatory biomarkers in adults. Databases including Embase, PubMed, Scopus, and Web of Sciences were searched till February 2024. The 54 RCTs were included in the final analysis, which involved 3000 individuals from 12 countries. Overall, the flaxseed supplementation had a significant reduction in C-reactive protein (CRP) (SMD = −0.46; 95 % CI: −0.70, −0.23, P < 0.001; I² = 82.9 %, P < 0.001), and interleukin 6 (IL-6) (SMD = −0.64, 95 % CI: −1.13, −0.16, P = 0.010; I² = 92.7, P < 0.001). Furthermore, flaxseed did not significantly change the concentration of tumor necrosis factor α (TNF-α) (SMD = −0.17; 95 % CI: −0.63, 0.29, P = 0.467; I² = 92, P < 0.001). Flaxseed supplementation significantly decreased serum concentrations of CRP and IL-6, but not TNF-a. Thus, this meta-analysis suggests that the current evidence supports the potential benefits of flaxseed in managing inflammatory conditions.

Introduction

Inflammation is a fundamental response to various insults, including microbial invasion and tissue injury. While aspirin (ASA) has been widely used for its anti-inflammatory properties, its adverse effects and limitations highlight the need for novel therapeutic alternatives. Recently, a novel salicylic acid derivative, 2-((3-(chloromethyl)benzoyl)oxy)benzoic acid (3-CH₂Cl), has emerged as a potential substitute for ASA, offering a simpler, environmentally friendly synthesis and a promising safety profile.

Aim of the study

This research aims to evaluate the anti-inflammatory mechanism of 3-CH₂Cl in a lipopolysaccharide (LPS)-induced mouse model, focusing on its effects on prostaglandin E-2 (PGE-2) concentration, NOX2 and NFkB expression, ROS production, and COX-2 expression.

Material and methods

Utilizing BALB/C mice subjected to LPS-induced inflammation, we investigated the therapeutic potential of 3-CH₂Cl. The study included synthesis and tablet preparation, experimental design, peripheral blood plasma PGE-2 measurement, splenocyte isolation and COX-2 expression analysis, nitric oxide and ROS measurement, and immunohistochemical analysis of NOX2 and NFkB expression.

Results

3-CH₂Cl significantly reduced PGE-2 levels (p = 0.005), NO concentration in liver homogenates (p = 0.005) and plasma (p = 0.0011), and expression of NOX2 and NFkB in liver (p < 0.0001) and splenocytes (p = 0.0036), demonstrating superior anti-inflammatory activity compared to ASA. Additionally, it showed potential in decreasing COX-2 expression in splenocytes.

Conclusion

3-CH₂Cl exhibits potent anti-inflammatory properties, outperforming ASA in several key inflammatory markers in an LPS-induced inflammation model. The reduction of COX-2 expression, alongside the reduction of pro-inflammatory cytokines and oxidative stress markers, suggest it as a promising therapeutic agent for various inflammatory conditions.

The vasculature of the retina is exposed to systemic and local factors that have the capacity to induce several retinal vascular diseases, each of which may lead to vision loss. Prostaglandin signaling has arisen as a potential therapeutic target for several of these diseases due to the diverse manners in which these lipid mediators may affect retinal blood vessel function. Previous reports and clinical practices have investigated cyclooxygenase (COX) inhibition by nonsteroidal anti-inflammatory drugs (NSAIDs) to address retinal diseases with varying degrees of success; however, targeting individual prostanoids or their distinct receptors affords more signaling specificity and poses strong potential for therapeutic development. This review offers a comprehensive view of prostanoid signaling involved in five key retinal vascular diseases: retinopathy of prematurity, diabetic retinopathy, age-related macular degeneration, retinal occlusive diseases, and uveitis. Mechanistic and clinical studies of these lipid mediators provide an outlook for therapeutic development with the potential to reduce vision loss in each of these conditions.

Pneumonia, an acute inflammatory lesion of the lung, is the leading cause of death in children aged < 5 years. We aimed to study the function and mechanism of Golgi phosphoprotein 3 (GOLPH3) in infantile pneumonia. Lipopolysaccharide (LPS)-induced acute lung injury (ALI) mice and injury of MLE-12 cells were used as the pneumonia model in vitro. After GOLPH3 was knocked down, the histopathological changes of lung tissues were assessed by hematoxylin-eosin (H&E) staining. The Wet/Dry ratio of lung tissues was calculated. The enzyme-linked immunosorbent assay (ELISA) method was used to detecte the contents of inflammatory factors in bronchoalveolar lavage fluid (BALF). The damaged DNA in apoptotic cells in lung tissues was tested by Terminal deoxynucleotidyl transferase-mediated dUTP Nick end labeling (TUNEL) staining. Immunofluorescence staining analyzed LC3II and Golgi matrix protein 130 (GM130) expression in lung tissues and MLE-12 cells. The apoptosis of MLE-12 cells was measured by flow cytometry analysis. Additionally, the expression of proteins related to apoptosis, autophagy and Golgi stress was examined with immunoblotting. Results indicated that GOLPH3 knockdown alleviated lung tissue pathological changes in LPS-triggered ALI mice. LPS-induced inflammation and apoptosis in lung tissues and MLE-12 cells were remarkably alleviated by GOLPH3 deficiency. Besides, GOLPH3 depletion suppressed autophagy and Golgi stress in lung tissues and MLE-12 cells challenged with LPS. Moreover, Rapamycin (Rap), an autophagy inhibitor, counteracted inflammation and apoptosis inhibited by GOLPH3 silencing in LPS-induced MLE-12 cells. Furthermore, brefeldin A (BFA) pretreatment apparently abrogated the inhibitory effect of GOLPH3 knockdown on autophagy in MLE-12 cells exposed to LPS. To be concluded, GOLPH3 knockdown exerted lung protective effect against LPS-triggered inflammation and apoptosis by inhibiting Golgi stress mediated autophagy.

Numerous interventional studies have revealed the beneficial impact of curcumin supplementation on inflammation, oxidative stress, and endothelial function biomarkers, but the findings are still inconsistent. Thus, this study was conducted to investigate the effects of curcumin supplementation on inflammation, oxidative stress, and endothelial function biomarkers. A meta-analyses of randomized clinical trials was performed by searching PubMed, Embase, Scopus, and Web of Science up to March 31, 2024. Pooled estimates of 21 meta-analyses revealed that curcumin significantly reduced CRP (weighted mean difference (WMD) = −0.87; 95 % CI: - 1.14, - 0.59, P< 0.001), tumor-necrosis factor-alpha (TNF-α) (WMD = −2.72; 95 % CI: −4.05, −1.38; P< 0.001), interleukin-6 (IL-6) (WMD = −0.97, 95 % CI: −1.40, −0.54; P< 0.001), malondialdehyde (MDA) (Effect size (ES) = −0.81; 95 % CI: −1.39, −0.23, P = 0.006) and pulse wave velocity (PWV) (WMD = −45.60; 95 % CI: −88.16, −3.04, P = 0.036), and increased flow-mediated dilation (FMD) (WMD = 1.64, 95 % CI: 1.06, 2.22, P < 0.001), catalase (CAT) (WMD = 10.26; 95 % CI: 0.92, 19.61, P= 0.03), glutathione peroxidase (GPx) (WMD = 8.90; 95 % CI: 6.62, 11.19, P <0.001), and superoxide dismutase (SOD) levels (WMD = 20.51; 95 % CI: 7.35, 33.67, P= 0.002 and SMD = 0.82; 95 % CI: 0.27, 1.38, P= 0.004). However, curcumin did not significantly change total antioxidant capacity (TAC) (ES = 0.29; 95 % CI: −0.09, 0.66, P= 0.059). These results suggest that curcumin has a beneficial effect on CRP, IL-6, TNF-α, SOD, GPx, CAT, MDA, PWV, and FMD levels and may be an effective adjunctive therapy for improving inflammation, oxidative stress, and endothelial function. Registration number: PROSPERO, CRD42024539018.

Myocardial ischemia/reperfusion (MI/R) injury is a detrimental disease with high mortality worldwide. We aimed to explore the role of G protein-coupled receptor 4 (GPR4) and lysophosphatidic acid receptor 1 (LPAR1) in MI/R injury in vitro. H9c2 cells were exposed to oxygen-glucose deprivation/reoxygenation (OGD/R) conditions to simulate the MI/R injury and GPR4 expression was detected. Then, GPR4 was knocked down and cell viability was examined with a CCK-8 assay. The activities of LDH, CK and CK-MB were detected to evaluate the damage of OGD/R-induced H9c2 cells. ELISA kits and TUNEL staining were used to examine the inflammation and apoptosis of H9c2 cells exposed to OGD/R conditions. Western blot was employed to detect the expression of proteins related to apoptosis and NLRP3 inflammasome signaling. Additionally, Co-IP analyzed the binding between GPR4 and LPAR1. Finally, LPAR1 was overexpressed to conduct the rescue experiments. Results revealed that GPR4 was upregulated in OGD/R-treated H9c2 cells and GPR4 knockdown attenuated the damage of H9c2 cells. OGD/R induced inflammation and apoptosis were markedly inhibited by GPR4 silencing, as evidenced by the decreased TNF-α, IL-6 and IL-8 levels as well as the elevated Bcl-2 expression and reduced Bax and cleaved caspase3 expression. Moreover, GPR4 bound to LPAR1 and upregulated LPAR1 expression. Interference with GPR4 inactivated the NLRP3 inflammasome signaling. Besides, LPAR1 overexpression abrogated the effects of GPR4 silencing on the damage, inflammation and apoptosis of H9c2 cells induced by OGD/R. Particularly, LPAR1 upregulation promoted the activation of NLRP3 inflammasome signaling in GPR4-silenced H9c2 cells induced by OGD/R. To be concluded, GPR4 deficiency inactivates NLRP3 inflammasome signaling by inhibiting LPAR1 expression to ameliorate OGD/R -induced inflammation and apoptosis of cardiomyocytes.

Atherosclerosis is a chronic inflammatory disease forming plaques in medium and large-sized arteries. ADAMTS-4 (a disintegrin and metalloproteinase with thrombospondin motifs-4) is an extracellular-matrix remodelling enzyme involved in the degradation of versican in the arterial wall. Recent reports indicated that increased expression of ADAMTS-4 is associated with plaque progression and vulnerability. Bioactive components of dietary oil, like sesame oil, are reported to have anti-inflammatory and antioxidant properties. Here, we studied the effect of sesame oil on regulating ADAMTS-4 in high-fat diet-induced atherosclerosis rat model. Our results indicated that sesame oil supplementation improved the anti-inflammatory and anti-oxidative status of the body. It also reduced atherosclerotic plaque formation in high-fat diet-fed rats. Our results showed that the sesame oil supplementation significantly down-regulated the expression of ADAMTS-4 in serum and aortic samples. The versican, the large proteoglycan substrate of ADAMTS-4 in the aorta, was downregulated to normal control level on sesame oil supplementation. This study, for the first time, reveals that sesame oil could down-regulate the expression of ADAMTS-4 in high-fat diet-induced atherosclerosis, imparting a new therapeutic potential for sesame oil in the management of atherosclerosis.

The endocannabinoid 2-arachidonoylglycerol (2-AG) has been reported to exhibit anticancer effects, including against colorectal cancer (CRC); however, the detailed mechanisms have not been clarified. Herein, we demonstrated that 2-AG suppressed cyclooxygenase-2 (COX-2) expression induced by prostaglandin E₂ in human colon cancer HCA-7 cells. The suppression of COX-2 expression by 2-AG was through the acceleration of processing body (P-body) formation followed by COX-2 mRNA degradation. These effects were restored by TAK-715, a specific inhibitor of p38 MAPK. Therefore, the effect of 2-AG on COX-2 may be distinct from conventional non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs inhibit the function of COX-2, whereas 2-AG suppresses the protein expression of COX-2. Recently, the cardiovascular risks of NSAIDs were reported by the Food and Drug Administration in the United States. Therefore, elucidation of the effect of 2-AG is expected to contribute to the development of an alternative and novel therapeutic option that would have no or fewer risks regarding cardiovascular events.