Meta-analyses of the relationship between five CXCL8 gene polymorphisms and overall cancer risk, and a case-control study of oral cancer.

BACKGROUND: C-X-C motif chemokine ligand (CXCL8), also known as interleukin-8, is a prototypical CXC family chemokine bearing a glutamic acid-leucine-arginine (ELR) motif that plays key roles in the onset and progression of a range of cancers in humans. Many prior studies have focused on exploring the relationship between CXCL8 gene polymorphisms and the risk of cancer. However, the statistical power of many of these reports was limited, yielding ambiguous or conflicting results in many cases. METHODS: Accordingly, the PubMed, Wanfang, Scopus and Web of Science databases were searched for articles published until July 20, 2023 using the keywords 'IL-8' or 'interleukin-8' or 'CXCL8', 'polymorphism' and 'cancer' or 'tumor'. Odds ratios (ORs) and 95% confidence intervals (CIs) were utilized to examine the association. The CXCL8 +781 polymorphism genotypes were assessed with a TaqMan assay. RESULTS: About 29 related publications was conducted in an effort to better understand the association between these polymorphisms and disease risk. The CXCL8 -353A/T polymorphism was associated with an increased overall cancer risk [A vs. T, odds ratio (OR) = 1.255, 95% confidence interval (CI) (1.079-1.459), Pheterogeneity = 0.449, P = 0.003]. The CXCL8 +781 T/C allele was similarly associated with a higher risk of cancer among Caucasians [TT vs. TC + CC, OR = 1.320, 95%CI (1.046-1.666), Pheterogeneity = 0.375, P = 0.019]. Furthermore, oral cancer patients carrying the CXCL8 +781 TT + TC genotypes exhibited pronounced increases in serum levels of CXCL8 as compared to the CC genotype (P < 0.01), and also shown similar trend as compared to genotype-matched normal controls (P < 0.01). Finally, several limitations, such as the potential for publication bias or heterogeneity among the included studies should be paid attention. CONCLUSION: Current study suggested that the CXCL8 -353 and +781 polymorphisms may be associated with a greater risk of cancer, which might impact cancer prevention, diagnosis, or treatment through the different expression of CXCL8. At the same time, the +781 polymorphism may further offer value as a biomarker that can aid in the early identification and prognostic evaluation of oral cancer.

Cortistatin protects against septic cardiomyopathy by inhibiting cardiomyocyte pyroptosis through the SSTR2-AMPK-NLRP3 pathway.

BACKGROUND: Although the pathophysiological mechanism of septic cardiomyopathy has been continuously discovered, it is still a lack of effective treatment method. Cortistatin (CST), a neuroendocrine polypeptide of the somatostatin family, has emerged as a novel cardiovascular-protective peptide, but the specific mechanism has not been elucidated. PURPOSE: The aim of our study is to explore the role of CST in cardiomyocytes pyroptosis and myocardial injury in sepsis and whether CST inhibits cardiomyocytes pyroptosis through specific binding with somastatin receptor 2 (SSTR2) and activating AMPK/Drp1 signaling pathway. METHODS AND RESULTS: In this study, plasma CST levels were significantly high and were negatively correlated with N-terminal pro-B type natriuretic peptide (NT-proBNP), a biomarker for cardiac dysfunction, in patients with sepsis. Exogenous administration of CST significantly improved survival rate and cardiac function in mouse models of sepsis by inhibiting the activation of the NLRP3 inflammasome and pyroptosis of cardiomyocytes (decreased cleavage of caspase-1, IL-1ß and gasdermin D). Pharmacological inhibition and genetic ablation revealed that CST exerted anti-pyroptosis effects by specifically binding to somatostatin receptor subtype 2 (SSTR2), thus activating AMPK and inactivating Drp1 to inhibit mitochondrial fission in cardiomyocytes. CONCLUSIONS: This study is the first to report that CST attenuates septic cardiomyopathy by inhibiting cardiomyocyte pyroptosis through the SSTR2-AMPK-Drp1-NLRP3 pathway. Importantly, CST specifically binds to SSTR2, which promotes AMPK phosphorylation, inhibits Drp1-mediated mitochondrial fission, and reduces ROS levels, thereby inhibiting NLRP3 inflammasome activation-mediated pyroptosis and alleviating sepsis-induced myocardial injury.

HHcy Induces Pyroptosis and Atherosclerosis via the Lipid Raft-Mediated NOX-ROS-NLRP3 Inflammasome Pathway in apoE-/- Mice.

Lipid rafts play important roles in signal transduction, particularly in responses to inflammatory processes. The current study aimed to identify whether lipid raft-mediated inflammation contributes to hyperhomocysteinemia (HHcy)-accelerated atherosclerosis (AS), and to investigate the underlying mechanisms. THP-1-derived macrophages were used for in vitro experiments. ApoE-/- mice were fed a high-fat diet for 12 weeks to establish an AS model, and a high-fat plus high-methionine diet was used to induce HHcy. We found that homocysteine (Hcy) increased the expression of p22phox and p67phox and promoted their recruitment into lipid rafts (indicating the assembly of the NOX complex), thereby increasing ROS generation and NOX activity, NLRP3 inflammasome activation, and pyroptosis. Mechanistically, Hcy activated the NOX-ROS-NLRP3 inflammasome pathway and induced pyroptosis by increasing the expression of acid sphingomyelinase (ASM) to promote the formation of lipid raft clustering. Importantly, lipid raft-mediated pyroptosis was confirmed in HHcy mice, and HHcy-promoted macrophage recruitment in atherosclerotic lesions and HHcy-aggravated AS were blocked by the lipid raft disruptor methyl-ß-cyclodextrin. The study findings indicate that Hcy promotes lipid raft clustering via the upregulation of ASM, which mediates the assembly of the NOX complex, causing an increase in ROS generation, NLRP3 inflammasome activation, and pyroptosis, and contributes to HHcy-induced AS.