RESUMEN
Interleukin-17 (IL-17), a pivotal cytokine in immune regulation, has attracted significant attention in recent years due to its roles in various physiological and pathological processes. This review explores IL-17 in immunological context, emphasizing its structure, production, and signaling pathways. Specifically, we explore its involvement in inflammatory diseases and autoimmune diseases, with a notable focus on its emerging implications in cardiovascular system. Through an array of research insights, IL-17 displays multifaceted functions yet awaiting comprehensive discovery. Highlighting therapeutic avenues, we scrutinize the efficacy and clinical application of four marketed IL-17 mAbs along other targeted therapies, emphasizing their potential in immune-mediated disease management. Additionally, we discussed the novel IL-17D-CD93 axis, elucidating recent breakthroughs in their biological function and clinical implications, inviting prospects for transformative advancements in immunology and beyond.
Asunto(s)
Enfermedades Autoinmunes , Enfermedades Cardiovasculares , Interleucina-17 , Humanos , Interleucina-17/inmunología , Animales , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/terapia , Enfermedades Cardiovasculares/inmunología , Enfermedades Cardiovasculares/terapia , Transducción de Señal , Inflamación/inmunología , Sistema Cardiovascular/inmunología , Anticuerpos Monoclonales/uso terapéuticoRESUMEN
AIMS: To determine the association between all-cause mortality and low-density lipoprotein cholesterol (LDL-C) in patients with idiopathic cardiomyopathy (iDCM). BACKGROUND: LDL-C had long been considered as a dangerous predictor of cardiovascular diseases; however, the correlation between them was not fully clarified. METHODS: A total of 1058 patients who met the World Health Organization criteria for iDCM in West China Hospital (2009-2016) were enrolled in this retrospective study. Baseline demographic characteristics and correlations between variables were calculated and analyzed, and potential predictors were explored using univariate and multivariate regressions. Cox proportional hazards models were used to determine correlation on a continuous scale. RESULTS: LDL-C is an independent prognostic factor and higher LDL-C levels are associated with better prognosis in iDCM patients according to cox regression analysis. Compared with individuals which LDL > 2.28 mmol/L (75th-100th percentile), the multivariable-adjusted hazard ratio for all-cause mortality was 1.52 (95%CI: 1.03-2.26) in patients with LDL-C < 1.78 mmol/L (0-25th percentile). In patients with New York Heart Association function III and IV, LDL-C levels have a hazard ratio of 0.83 (confidence interval 0.73-0.95). CONCLUSIONS: In patients with iDCM, lower LDL-C level was associated with an increased risk of all-cause mortality. The correlation between mortality and LDL-C level was stronger in patients with worse heart function. LDL-C levels have a potential predictive value in iDCM patients.
Asunto(s)
Cardiomiopatía Dilatada , Humanos , LDL-Colesterol , Estudios Retrospectivos , Cardiomiopatía Dilatada/diagnóstico , Factores de Riesgo , Pronóstico , Modelos de Riesgos ProporcionalesRESUMEN
The residue located at 15 positions before the most conserved residue in TM7 (7.35 of Ballesteros-Weinstein number) plays important roles in ligand binding and the receptor activity for class A GPCRs. Nevertheless, its regulation mechanism has not been clearly clarified in experiments, and some controversies also exist for its impact on µ-opioid receptors (µOR) bound by agonists. Thus, we chose the µ-opioid receptor (µOR) of class A GPCRs as a representative and utilized a microsecond accelerated molecular dynamics simulation (aMD) coupled with a protein structure network (PSN) to explore the effect of W3187.35 on its functional activity induced by the agonist endomorphin2 mainly by a comparison of the wild system and its W7.35A mutant. When endomorphin2 binds to the wild-type µOR, TM6 in µOR moves outward to form an open intracellular conformation that is beneficial to accommodating the ß-arrestin transducer, rather than the G-protein transducer due to the clash with the α5 helix of G-protein, thus acting as a ß-arrestin biased agonist. However, the W318A mutation induces the intracellular part of µOR to form a closed state, which disfavors coupling with either G-protein or ß-arrestin. The allosteric pathway analysis further reveals that the binding of endomorphin2 to the wild-type µOR transmits more activation signals to the ß-arrestin binding site while the W318A mutation induces more structural signals to transmit to common binding residues of the G protein and ß-arrestin. More interestingly, the residue at the 7.35 position regulates the shortest allosteric pathway in indirect ways by influencing the interactions between other ligand-binding residues and endomorphin2. W2936.48 and F2896.44 are important for regulating the different activities of µOR induced either by the agonist or by the mutation. Y3367.53, F3438.50, and D3408.47 play crucial roles in activating the ß-arrestin biased signal induced by the agonist endomorphin2, while L1583.43 and V2866.41 devote important contributions to the change in the activity of endomorphin2 from the ß-arrestin biased agonist to the antagonist upon the W318A mutation.