RESUMEN
High blood pressure (BP) and dyslipidemia are major risk factors for cardiovascular disease mortality. The systemic immune-inflammation index (SII) has been suggested as a predictive tool to identify those at risk for chronic diseases, however, its use for predicting high BP and dyslipidemia has not been thoroughly investigated. This study aimed to examine the association between SII and high BP as well as lipid markers. Retrospective hospital data from a large cohort (nâ =â 3895) of Saudi adults agedâ ≥18 years were analyzed. Lipid markers (cholesterol, high-density lipoprotein, low-density lipoprotein [LDL]), systolic BP, and diastolic BP measures were extracted. When the sample was divided into quartiles of SII, cholesterol, triglycerides, and LDL were higher in those with a higher SII than in those with a lower SII (Pâ <â .01). After adjusting for potential confounders, higher SII was significantly associated with higher odds of hypertension (odds ratio: 1.12, 95% confidence interval: 1.04-1.21) and elevated LDL (odds ratio: 1.07, 95% CI: 1.02-1.14), but not with elevated cholesterol. Across quartiles of SII, there was a significant trend between higher SII and the odds of hypertension in people with diabetes and those agedâ ≥65 years. The SII could be an economical predictive measure for identifying individuals at risk of hypertension and some aspects of dyslipidemia. Longitudinal studies are needed to confirm this relationship.
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Presión Sanguínea , Dislipidemias , Hipertensión , Inflamación , Humanos , Estudios Retrospectivos , Masculino , Dislipidemias/sangre , Dislipidemias/epidemiología , Dislipidemias/inmunología , Femenino , Persona de Mediana Edad , Hipertensión/epidemiología , Hipertensión/sangre , Hipertensión/inmunología , Adulto , Inflamación/sangre , Inflamación/inmunología , Anciano , Presión Sanguínea/fisiología , Arabia Saudita/epidemiología , Factores de Riesgo , Biomarcadores/sangre , Triglicéridos/sangreRESUMEN
Antiretroviral therapies (ART) have reduced human immunodeficiency virus (HIV) infection-associated morbidity and mortality improving the life of people with HIV (PWH). However, ART lead to residual HIV production, which in conjunction with microbial translocation and immune dysfunction contributes to chronic inflammation and immune activation. PWH on ART remain at an increased risk for cardiovascular diseases (CVDs) including myocardial infarction and stroke; which in part is explained by chronic inflammation and immune activation. Lifestyle factors and certain ART are associated with dyslipidemia characterized by an increase of low-density lipoprotein (LDL), which further contributes in the increased risk for CVDs. Lipid-lowering agents like statins are emerging as immune modulators in decreasing inflammation in a variety of conditions including HIV. The international randomized clinical trial REPRIEVE has shed light on the reduction of CVDs with statin therapy among PWH. Such reports indicate a more than expected benefit of statins beyond their lipid-lowering effects. Bempedoic acid, a first-in-class non-statin LDL-lowering drug with immune modulatory effects, may further aid PWH in combination with statins. Herein, we critically reviewed studies aimed at lipid-lowering and immune-modulating roles of statins that may benefit aging PWH.
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Infecciones por VIH , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Humanos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Infecciones por VIH/complicaciones , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hipolipemiantes/uso terapéutico , Dislipidemias/tratamiento farmacológico , Dislipidemias/inmunología , Enfermedades Cardiovasculares/etiología , Fármacos Anti-VIH/uso terapéutico , Fármacos Anti-VIH/efectos adversosRESUMEN
Hyperglycemia is critical for initiation of diabetic vascular complications. We systemically addressed the role of hyperglycemia in the regulation of TLRs in primary human macrophages. Expression of TLRs (1-9) was examined in monocyte-derived M(NC), M(IFNγ), and M(IL4) differentiated in normoglycemic and hyperglycemic conditions. Hyperglycemia increased expression of TLR1 and TLR8 in M(NC), TLR2 and TLR6 in M(IFNγ), and TLR4 and TLR5 in M(IL4). The strongest effect of hyperglycemia in M(IL4) was the upregulation of the TLR4 gene and protein expression. Hyperglycemia amplified TLR4-mediated response of M(IL4) to lipopolysaccharide by significantly enhancing IL1ß and modestly suppressing IL10 production. In M(IL4), hyperglycemia in combination with synthetic triacylated lipopeptide (TLR1/TLR2 ligand) amplified expression of TLR4 and production of IL1ß. In summary, hyperglycemia enhanced the inflammatory potential of homeostatic, inflammatory, and healing macrophages by increasing specific profiles of TLRs. In combination with dyslipidemic ligands, hyperglycemia can stimulate a low-grade inflammatory program in healing macrophages supporting vascular diabetic complications.
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Hiperglucemia , Macrófagos , Receptores Toll-Like , Humanos , Hiperglucemia/metabolismo , Hiperglucemia/inmunología , Macrófagos/metabolismo , Macrófagos/inmunología , Macrófagos/efectos de los fármacos , Receptores Toll-Like/metabolismo , Ligandos , Dislipidemias/metabolismo , Dislipidemias/inmunología , Inflamación/metabolismo , Inflamación/inmunología , Lipopolisacáridos/farmacología , Células Cultivadas , Interleucina-1beta/metabolismo , Receptor Toll-Like 4/metabolismoRESUMEN
Suppressing inflammation has been the primary focus of therapies in autoimmune rheumatic diseases (AIRDs), including rheumatoid arthritis and systemic lupus erythematosus. However, conventional therapies with low target specificity can have effects on cell metabolism that are less predictable. A key example is lipid metabolism; current therapies can improve or exacerbate dyslipidemia. Many conventional drugs also require in vivo metabolism for their conversion into therapeutically beneficial products; however, drug metabolism often involves the additional formation of toxic by-products, and rates of drug metabolism can be heterogeneous between patients. New therapeutic technologies and research have highlighted alternative metabolic pathways that can be more specifically targeted to reduce inflammation but also to prevent undesirable off-target metabolic consequences of conventional antiinflammatory therapies. This Review highlights the role of lipid metabolism in inflammation and in the mechanisms of action of AIRD therapeutics. Opportunities for cotherapies targeting lipid metabolism that could reduce immunometabolic complications and potential increased cardiovascular disease risk in patients with AIRDs are discussed.
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Enfermedades Autoinmunes/inmunología , Enfermedades Cardiovasculares/inmunología , Dislipidemias/inmunología , Metabolismo de los Lípidos/inmunología , Enfermedades Reumáticas/inmunología , Enfermedades Autoinmunes/terapia , Enfermedades Cardiovasculares/terapia , Dislipidemias/terapia , Humanos , Inflamación/inmunología , Inflamación/terapia , Enfermedades Reumáticas/terapiaRESUMEN
Dyslipidemia is a risk factor for cardiovascular disease (CVD), a major cause of death worldwide. Angiopoietin-like protein 3 (ANGPTL3), recognized as a new therapeutic target for dyslipidemia, regulates the metabolism of low-density lipoprotein-cholesterol (LDL-C) and triglycerides. Here, we design 3 epitopes (E1-E3) for use in development of a peptide vaccine targeting ANGPTL3 and estimate effects of each on obesity-associated dyslipidemia in B6.Cg-Lepob /J (ob/ob) mice. Vaccination with the E3 (32EPKSRFAMLD41) peptide significantly reduces circulating levels of triglycerides, LDL-C, and small dense (sd)-LDL-C in ob/ob mice and decreases obese-induced fatty liver. Moreover, E3 vaccination does not induce cytotoxicity in ob/ob mice. Interestingly, the effect of E3 vaccination on dyslipidemia attenuates development of atherosclerosis in B6.KOR/StmSlc-Apoeshl mice fed a high-cholesterol diet, which represent a model of severe familial hypercholesterolemia (FH) caused by ApoE loss of function. Taken together, ANGPTL3 vaccination could be an effective therapeutic strategy against dyslipidemia and associated diseases.
Asunto(s)
Proteína 3 Similar a la Angiopoyetina/metabolismo , Dislipidemias/inmunología , Hiperlipoproteinemia Tipo II/inmunología , Obesidad/inmunología , Vacunas/inmunología , Proteína 8 Similar a la Angiopoyetina/metabolismo , Animales , Antígenos/inmunología , Aterosclerosis/complicaciones , Autoinmunidad , Muerte Celular , Modelos Animales de Enfermedad , Dislipidemias/sangre , Dislipidemias/complicaciones , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/complicaciones , Metabolismo de los Lípidos , Hígado/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Obesos , Obesidad/sangre , Obesidad/complicaciones , Triglicéridos/sangre , VacunaciónRESUMEN
BACKGROUND: Data on the burden of dyslipidaemia among people with HIV undergoing antiretroviral therapy (ART) in sub-Saharan Africa are limited and little is known about the factors contributing for poor lipid profiles. The aim of this study was to determine the prevalence of dyslipidaemia and factors associated with lipid levels among HIV-infected patients receiving first-line combination ART in North Shewa, Ethiopia. METHODS: A cross-sectional study was conducted between April and December 2018 among 392 HIV-infected adults receiving first-line ART for at least six months at the ART clinic of Mehal Meda Hospital in North Shewa, Ethiopia. Blood samples were collected for determination of total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), and CD4 counts. Logistic regression analysis was used to determine factors associated with lipid abnormalities. RESULTS: The prevalence of dyslipidaemia was 59.9% (95% CI 55.0-64.7%). High TC, high TG, low HDL-c, and high LDL-c were obtained in 47.3%, 30.9%, 19.4% and 29.6%, respectively. Fifty-four participants (13.8%) had high ratio of TC/HDL-c (TC/HDL-c ratio ≥ 5). Older age was independently associated with high TC (AOR = 2.51, 95% CI 1.64-3.84), high TG (AOR = 2.95, 95% CI 1.85-4.71), low HDL-c (AOR = 2.02, 95% CI 1.17-3.50), and high LDL-c (AOR = 3.37, 95% CI 2.08-5.47). Living in an urban area (AOR = 2.61, 95% CI 1.16-6.14) and smoking (AOR = 3.61, 95% CI 1.06-12.34) were associated with low HDL-c. Participants with longer duration of ART use were more likely to have high TG (AOR = 1.86, 95% CI: 1.13-3.07), low HDL-c (AOR = 3.47, 95% CI: 1.75-6.80), and high LDL-c (AOR = 2.20, 95% CI 1.30-3.71). High BMI was independently associated with higher TC (AOR = 2.43, 95% CI 1.19-4.97), high TG (AOR = 4.17, 95% CI 2.01-8.67) and high LDL-c (AOR = 6.53, 95% CI 3.05-13.98). CONCLUSIONS: We found a high prevalence of dyslipidaemia among HIV-infected patients receiving first-line ART in North Shewa, Ethiopia. There is a need for monitoring of blood lipid levels in patients with HIV on long term first-line ART with a special attention to be focused on older age, urban residents, longer duration of ART use, high BMI and smokers.
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Fármacos Anti-VIH/uso terapéutico , Dislipidemias/epidemiología , Infecciones por VIH/epidemiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Terapia Antirretroviral Altamente Activa/métodos , Recuento de Linfocito CD4 , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/virología , HDL-Colesterol/sangre , HDL-Colesterol/inmunología , LDL-Colesterol/sangre , LDL-Colesterol/inmunología , Estudios Transversales , Dislipidemias/tratamiento farmacológico , Dislipidemias/inmunología , Dislipidemias/virología , Etiopía/epidemiología , Femenino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Prevalencia , Población Rural , Triglicéridos/sangre , Triglicéridos/inmunología , Población UrbanaRESUMEN
Background: The significance of cTfh cells and their subsets in atherosclerosis is not well understood. We measured the frequency of cTfh subsets in patients with different degrees of stenosis using flow-cytometry. Methods: Participants included high (≥50%; n = 12) and low (<50%; n = 12) stenosis groups, as well as healthy controls (n = 6). Results: The frequency of CCR7loPD-1hiefficient-cTfh was significantly higher in patients with high stenosis compared to healthy controls (p = 0.003) and correlated with low-density lipoprotein (LDL; p = 0.043), cholesterol (p = 0.043), triglyceride (p = 0.019), neutrophil count (p = 0.032), platelet count (p = 0.024), neutrophil/lymphocyte ratio (NLR; p = 0.046), and platelet/lymphocyte ratio (PLR; p = 0.025) in high stenosis group. The frequency of CCR7hiPD-1lo quiescent-cTfh was higher in healthy controls compared to the high-stenosis group (p = 0.001) and positively correlated with high-density lipoprotein (p = 0.046). The frequency of efficient-cTfh cells was correlated with platelet count (p = 0.043), NLR (p = 0.036), and PLR (p P = 0.035) in low-stenosis group, while that of quiescent-cTfh cells was negatively correlated with LDL (p = 0.034), cholesterol (p = 0.047), platelet count (p = 0.032), and PLR (p = 0.041). Conclusion: High percentages of cTfh and efficient-cTfh cells in patients with advanced atherosclerosis and their correlation with dyslipidemia and white blood cell counts suggest an ongoing cTfh subset deviation, towards efficient phenotype in the milieu of inflammation and altered lipid profile. Efficient cTfh cells have an effector phenotype and could in turn contribute to atherosclerosis progression.
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Aterosclerosis/sangre , Aterosclerosis/inmunología , Movimiento Celular , Dislipidemias/sangre , Dislipidemias/inmunología , Células T Auxiliares Foliculares/inmunología , Aterosclerosis/complicaciones , Dislipidemias/complicaciones , Femenino , Humanos , Recuento de Leucocitos , Masculino , Persona de Mediana EdadRESUMEN
AIMS: Small-interfering RNA (siRNA)-based targeting of proprotein convertase subtilisin/kexin type 9 (PCSK9) represents a novel therapeutic approach that may provide a convenient, infrequent, and safe dosing schedule to robustly lower low-density lipoprotein cholesterol (LDL-C). Given the long duration of action, however, establishing safety in particular with respect to immunogenicity is of paramount importance. In earlier clinical studies of other RNA-targeted treatment approaches (antisense oligonucleotide therapy) immunological and haematological adverse effects, in particular thrombocytopenia and pro-inflammatory effects, have been reported. Here, we present the pre-specified safety analysis from ORION-1 evaluating platelets, immune cells, immunological markers, antidrug antibodies, and clinical immunogenicity adverse events (AEs) under PCSK9 siRNA treatment with inclisiran. METHODS AND RESULTS: The pre-specified safety analysis from ORION-1 was performed in six different inclisiran dosing regimens in patients at high risk of cardiovascular disease with elevated LDL-C levels. Patients received either a single dose (SD: 200 mg, n = 60; 300 mg, n = 62 or 500 mg, n = 66) or double-dose starting regimen (DD: 100 mg, n = 62; 200 mg, n = 63; or 300 mg, n = 61 on days 1 and 90) of inclisiran or placebo (SD: n = 65; DD: n = 62). The effects of inclisiran on haematological parameters including platelet counts, lymphocytes, and monocytes as well as on the immune markers interleukin 6 (IL-6) and tumour necrosis factor-α (TNF-α) were examined after 180 days. Immunogenicity was further evaluated by analysis of anti-drug-antibodies (ADAs) towards inclisiran in 6068 study samples and by careful analysis of immunogenicity AEs as part of the pharmacovigilance strategy. At day 180, no significant alterations of platelet counts were observed in any of the dosing groups (change from baseline, SD: 200 mg: 0.8%; 300 mg: -0.5%; 500 mg: -1.8%; DD: 100 mg: 1.3%; 200 mg: -0.5%; 300 mg: 1.0%; no significant difference for any group as compared with placebo). No significant effects on other immune cells, including leucocytes, monocytes, or neutrophils were detected. Notably, no significant increase of inflammatory biomarkers (IL-6 or TNF-α) with either the SD or DD regimen became evident. There was no evidence for immunogenicity based on ADA level analysis and careful review of clinical immunogenicity AEs in none of the treatment regimens. CONCLUSION: In this pre-specified safety analysis of ORION-1 for the siRNA therapeutic inclisiran, no adverse effects on measures of inflammation or immune activation nor adverse effects on platelets or clinical immunogenicity AEs were observed over at least 6-month treatment. These safety findings in the largest analysis of an RNAi study in humans to date provide strong reassurance about the safety of inclisiran and the potential of cardiovascular RNA-targeted therapies.
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Plaquetas/efectos de los fármacos , LDL-Colesterol/sangre , Dislipidemias/terapia , Leucocitos/efectos de los fármacos , Proproteína Convertasa 9/metabolismo , ARN Interferente Pequeño/uso terapéutico , Tratamiento con ARN de Interferencia , Anticuerpos/sangre , Biomarcadores/sangre , Plaquetas/metabolismo , Método Doble Ciego , Regulación hacia Abajo , Dislipidemias/sangre , Dislipidemias/genética , Dislipidemias/inmunología , Humanos , Interleucina-6/sangre , Leucocitos/inmunología , Proproteína Convertasa 9/genética , ARN Interferente Pequeño/efectos adversos , ARN Interferente Pequeño/inmunología , Tratamiento con ARN de Interferencia/efectos adversos , Factores de Tiempo , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/sangreRESUMEN
AIMS: A hallmark of advanced atherosclerosis is inadequate immunosuppression by regulatory T (Treg) cells inside atherosclerotic lesions. Dyslipidemia has been suggested to alter Treg cell migration by affecting the expression of specific membrane proteins, thereby decreasing Treg cell migration towards atherosclerotic lesions. Besides membrane proteins, cellular metabolism has been shown to be a crucial factor in Treg cell migration. We aimed to determine whether dyslipidemia contributes to altered migration of Treg cells, in part, by affecting cellular metabolism. METHODS AND RESULTS: Dyslipidemia was induced by feeding Ldlr-/- mice a western-type diet for 16-20 weeks and intrinsic changes in Treg cells affecting their migration and metabolism were examined. Dyslipidemia was associated with altered mTORC2 signalling in Treg cells, decreased expression of membrane proteins involved in migration, including CD62L, CCR7, and S1Pr1, and decreased Treg cell migration towards lymph nodes. Furthermore, we discovered that diet-induced dyslipidemia inhibited mTORC1 signalling, induced PPARδ activation and increased fatty acid (FA) oxidation in Treg cells. Moreover, mass-spectrometry analysis of serum from Ldlr-/- mice with normolipidemia or dyslipidemia showed increases in multiple PPARδ ligands during dyslipidemia. Treatment with a synthetic PPARδ agonist increased the migratory capacity of Treg cells in vitro and in vivo in an FA oxidation-dependent manner. Furthermore, diet-induced dyslipidemia actually enhanced Treg cell migration into the inflamed peritoneum and into atherosclerotic lesions in vitro. CONCLUSION: Altogether, our findings implicate that dyslipidemia does not contribute to atherosclerosis by impairing Treg cell migration as dyslipidemia associated with an effector-like migratory phenotype in Treg cells.
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Aterosclerosis/metabolismo , Movimiento Celular , Dieta Alta en Grasa , Dislipidemias/metabolismo , Metabolismo Energético , Inflamación/metabolismo , Linfocitos T Reguladores/metabolismo , Animales , Aterosclerosis/genética , Aterosclerosis/inmunología , Aterosclerosis/patología , Movimiento Celular/efectos de los fármacos , Células Cultivadas , Técnicas de Cocultivo , Modelos Animales de Enfermedad , Dislipidemias/genética , Dislipidemias/inmunología , Metabolismo Energético/efectos de los fármacos , Ácidos Grasos/metabolismo , Inflamación/genética , Inflamación/inmunología , Inflamación/patología , Mediadores de Inflamación/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Diana Mecanicista del Complejo 2 de la Rapamicina/metabolismo , Ratones Noqueados para ApoE , Oxidación-Reducción , PPAR gamma/agonistas , PPAR gamma/metabolismo , Fenotipo , Placa Aterosclerótica , Receptores de LDL/genética , Receptores de LDL/metabolismo , Transducción de Señal , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Tiazoles/farmacologíaRESUMEN
Immune dysfunction contributes to the higher risk of communicable and non-communicable diseases among diabetics. HLA-DR expression is a robust marker of immune competence in mononuclear cells, including antigen presentation to CD4 lymphocytes. Given the high prevalence of obesity among diabetics, we evaluated the independent association between hyperglycemia and dyslipidemias with respect to HLA-DR expression in blood monocytes from type 2 diabetes patients. The monocytes from individuals with (n = 16) or without diabetes (n = 25) were phenotyped by flow cytometry to assess the differential expression of HLA-DR on their three subpopulations (classical, intermediate and non-classical monocytes). Diabetes was independently associated with lower HLA-DR expression across all monocyte subpopulations (p < 0.05). Blood triglycerides were associated with further HLA-DR depression (interaction p < 0.002). Cholesterols counterbalanced the reductive effect, with CD36, a receptor for oxidized cholesterol, correlating with HLA-DR (rho = 0.373; p = 0.016). Future studies are warranted to elucidate the complex interactions between hyperglycemia and dyslipidemias on antigen presentation in diabetic monocytes.
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Diabetes Mellitus Tipo 2/complicaciones , Dislipidemias/inmunología , Antígenos HLA-DR/metabolismo , Hiperglucemia/inmunología , Monocitos/inmunología , Adulto , Glucemia/análisis , Estudios de Casos y Controles , Colesterol/sangre , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/inmunología , Dislipidemias/sangre , Dislipidemias/diagnóstico , Femenino , Hispánicos o Latinos , Humanos , Hiperglucemia/sangre , Hiperglucemia/diagnóstico , Masculino , Persona de Mediana Edad , Monocitos/metabolismo , Triglicéridos/sangreRESUMEN
Dyslipidemia refers to the abnormality of lipid metabolism. The aberrant lipid profiles are usually characterized by elevated plasma levels of low-density lipoprotein cholesterol (LDL-c), total cholesterol (TC), triglycerides (TGs), apoprotein B (ApoB), and decreased level of high-density lipoprotein cholesterol (HDL-c). Dyslipidemia occurs frequently in autoimmune diseases (ADs), such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), type-1 diabetes mellitus (T1DM), psoriasis, and inflammatory bowel disease (IBD), and many other diseases. An imbalance in lipid metabolism contributes to accelerated inflammatory responses in addition to promoting the formation of atherosclerosis. Although there have been many studies and reports on the relationship between abnormal lipid metabolism and ADs, it remains uncertain as to whether dyslipidemia has a unique role in promoting the occurrence and development of ADs. Here, we discuss the mechanisms of how dyslipidemia accelerates inflammatory response, autoimmunity, and atherosclerosis at epidemiological, molecular, and cellular levels, and the discussion is mainly conducted with SLE as an example.
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Aterosclerosis/inmunología , Autoinmunidad , Dislipidemias/complicaciones , Metabolismo de los Lípidos/inmunología , Lupus Eritematoso Sistémico/inmunología , Aterosclerosis/sangre , Aterosclerosis/metabolismo , Dislipidemias/sangre , Dislipidemias/inmunología , Dislipidemias/metabolismo , Humanos , Inflamación/sangre , Inflamación/inmunología , Inflamación/metabolismo , Lípidos/sangre , Lupus Eritematoso Sistémico/sangre , Lupus Eritematoso Sistémico/metabolismoAsunto(s)
Atorvastatina/efectos adversos , Dislipidemias/tratamiento farmacológico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Miotoxicidad/inmunología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/inmunología , Quimioterapia Combinada , Dislipidemias/complicaciones , Dislipidemias/inmunología , Femenino , Gliclazida/administración & dosificación , Humanos , Hipoglucemiantes/administración & dosificación , Persona de Mediana Edad , Vildagliptina/administración & dosificaciónRESUMEN
Background: Chronic kidney diseases (CKD) are usually associated with dyslipidemia. Statin therapy has been primarily recommended for the prevention of cardiovascular risk in patients with CKD; however, the effects of statins on kidney disease progression remain controversial. This study aims to investigate the effects of statin treatment on renal handling of water in patients and in animals on a high-fat diet. Methods: Retrospective cohort patient data were reviewed and the protein expression levels of aquaporin-2 (AQP2) and NLRP3 inflammasome adaptor ASC were examined in kidney biopsy specimens. The effects of statins on AQP2 and NLRP3 inflammasome components were examined in nlrp3-/- mice, 5/6 nephroectomized (5/6Nx) rats with a high-fat diet (HFD), and in vitro. Results: In the retrospective cohort study, serum cholesterol was negatively correlated to eGFR and AQP2 protein expression in the kidney biopsy specimens. Statins exhibited no effect on eGFR but abolished the negative correlation between cholesterol and AQP2 expression. Whilst nlrp3+/+ mice showed an increased urine output and a decreased expression of AQP2 protein after a HFD, which was moderately attenuated in nlrp3 deletion mice with HFD. In 5/6Nx rats on a HFD, atorvastatin markedly decreased the urine output and upregulated the protein expression of AQP2. Cholesterol stimulated the protein expression of NLRP3 inflammasome components ASC, caspase-1 and IL-1ß, and decreased AQP2 protein abundance in vitro, which was markedly prevented by statins, likely through the enhancement of ASC speck degradation via autophagy. Conclusion: Serum cholesterol level has a negative correlation with AQP2 protein expression in the kidney biopsy specimens of patients. Statins can ameliorate cholesterol-induced inflammation by promoting the degradation of ASC speck, and improve the expression of aquaporin in the kidneys of animals on a HFD.
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Acuaporina 2/análisis , Dislipidemias/tratamiento farmacológico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Riñón/efectos de los fármacos , Insuficiencia Renal Crónica/tratamiento farmacológico , Adulto , Animales , Acuaporina 2/metabolismo , Biopsia , Colesterol/sangre , Colesterol/metabolismo , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Dislipidemias/sangre , Dislipidemias/complicaciones , Dislipidemias/inmunología , Femenino , Tasa de Filtración Glomerular , Humanos , Inflamasomas/antagonistas & inhibidores , Inflamasomas/inmunología , Inflamasomas/metabolismo , Riñón/inmunología , Riñón/patología , Metabolismo de los Lípidos/efectos de los fármacos , Metabolismo de los Lípidos/inmunología , Masculino , Ratones , Ratones Noqueados , Persona de Mediana Edad , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Ratas , Insuficiencia Renal Crónica/sangre , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/inmunología , Estudios RetrospectivosRESUMEN
To the best of our knowledge, there is no published study on the use of interferon ß-1a (IFN ß-1a) in the treatment of severe COVID-19. In this randomized clinical trial, the efficacy and safety of IFN ß-1a were evaluated in patients with severe COVID-19. Forty-two patients in the interferon group received IFN ß-1a in addition to the national protocol medications (hydroxychloroquine plus lopinavir-ritonavir or atazanavir-ritonavir). Each 44-µg/ml (12 million IU/ml) dose of interferon ß-1a was subcutaneously injected three times weekly for two consecutive weeks. The control group consisted of 39 patients who received only the national protocol medications. The primary outcome of the study was time to reach clinical response. Secondary outcomes were duration of hospital stay, length of intensive care unit stay, 28-day mortality, effect of early or late administration of IFN on mortality, adverse effects, and complications during the hospitalization. Between 29 February and 3 April 2020, 92 patients were recruited, and a total of 42 patients in the IFN group and 39 patients in the control group completed the study. As the primary outcome, time to the clinical response was not significantly different between the IFN and the control groups (9.7 ± 5.8 versus 8.3 ± 4.9 days, respectively, P = 0.95). On day 14, 66.7% versus 43.6% of patients in the IFN group and the control group, respectively, were discharged (odds ratio [OR], 2.5; 95% confidence interval [CI], 1.05 to 6.37). The 28-day overall mortality was significantly lower in the IFN than the control group (19% versus 43.6%, respectively, P = 0.015). Early administration significantly reduced mortality (OR, 13.5; 95% CI, 1.5 to 118). Although IFN did not change the time to reach the clinical response, adding it to the national protocol significantly increased discharge rate on day 14 and decreased 28-day mortality. (This study is in the Iranian Registry of Clinical Trials under identifier IRCT20100228003449N28.).
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Antivirales/uso terapéutico , Sulfato de Atazanavir/uso terapéutico , Betacoronavirus/efectos de los fármacos , Infecciones por Coronavirus/tratamiento farmacológico , Interferón beta-1a/uso terapéutico , Lopinavir/uso terapéutico , Neumonía Viral/tratamiento farmacológico , Ritonavir/uso terapéutico , Adulto , Anciano , Betacoronavirus/inmunología , Betacoronavirus/patogenicidad , COVID-19 , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/inmunología , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/virología , Comorbilidad , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/mortalidad , Infecciones por Coronavirus/virología , Diabetes Mellitus/tratamiento farmacológico , Diabetes Mellitus/inmunología , Diabetes Mellitus/mortalidad , Diabetes Mellitus/virología , Esquema de Medicación , Combinación de Medicamentos , Quimioterapia Combinada , Dislipidemias/tratamiento farmacológico , Dislipidemias/inmunología , Dislipidemias/mortalidad , Dislipidemias/virología , Femenino , Humanos , Hidroxicloroquina/uso terapéutico , Unidades de Cuidados Intensivos , Tiempo de Internación , Masculino , Persona de Mediana Edad , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Neoplasias/mortalidad , Neoplasias/virología , Pandemias , Seguridad del Paciente , Neumonía Viral/inmunología , Neumonía Viral/mortalidad , Neumonía Viral/virología , SARS-CoV-2 , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Evidence to support the use of steroids in coronavirus disease 2019 (COVID-19) pneumonia is lacking. We aim to determine the impact of steroid use for COVID-19 pneumonia on hospital mortality. We performed a single-center retrospective cohort study in a university hospital in Madrid, Spain, during March of 2020. To determine the role of steroids in in-hospital mortality, patients admitted with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia and treated with steroids were compared to patients not treated with steroids, and we adjusted with a propensity score for patients on steroid treatment. Survival times were compared using the log rank test. Different steroid regimens were compared and adjusted with a second propensity score. During the study period, 463 out of 848 hospitalized patients with COVID-19 pneumonia fulfilled inclusion criteria. Among them, 396 (46.7%) patients were treated with steroids and 67 patients were not. Global mortality was 15.1%. The median time to steroid treatment from symptom onset was 10 days (interquartile range [IQR], 8 to 13 days). In-hospital mortality was lower in patients treated with steroids than in controls (13.9% [55/396] versus 23.9% [16/67]; hazard ratio [HR], 0.51 [95% confidence interval, 0.27 to 0.96]; P = 0.044). Steroid treatment reduced mortality by 41.8% relative to the mortality with no steroid treatment (relative risk reduction, 0.42 [95% confidence interval, 0.048 to 0.65]). Initial treatment with 1 mg/kg of body weight/day of methylprednisolone versus steroid pulses was not associated with in-hospital mortality (13.5% [42/310] versus 15.1% [13/86]; odds ratio [OR], 0.880 [95% confidence interval, 0.449 to 1.726]; P = 0.710). Our results show that the survival of patients with SARS-CoV-2 pneumonia is higher in patients treated with glucocorticoids than in those not treated. Rates of in-hospital mortality were not different between initial regimens of 1 mg/kg/day of methylprednisolone and glucocorticoid pulses.
Asunto(s)
Antivirales/uso terapéutico , Azitromicina/uso terapéutico , Betacoronavirus/efectos de los fármacos , Infecciones por Coronavirus/tratamiento farmacológico , Hidroxicloroquina/uso terapéutico , Interferones/uso terapéutico , Lopinavir/uso terapéutico , Metilprednisolona/uso terapéutico , Neumonía Viral/tratamiento farmacológico , Ritonavir/uso terapéutico , Anciano , Betacoronavirus/inmunología , Betacoronavirus/patogenicidad , COVID-19 , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/inmunología , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/virología , Comorbilidad , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/mortalidad , Infecciones por Coronavirus/virología , Diabetes Mellitus/tratamiento farmacológico , Diabetes Mellitus/inmunología , Diabetes Mellitus/mortalidad , Diabetes Mellitus/virología , Esquema de Medicación , Combinación de Medicamentos , Quimioterapia Combinada , Dislipidemias/tratamiento farmacológico , Dislipidemias/inmunología , Dislipidemias/mortalidad , Dislipidemias/virología , Femenino , Hospitales Universitarios , Humanos , Unidades de Cuidados Intensivos , Tiempo de Internación/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Neoplasias/mortalidad , Neoplasias/virología , Pandemias , Neumonía Viral/inmunología , Neumonía Viral/mortalidad , Neumonía Viral/virología , Estudios Retrospectivos , SARS-CoV-2 , Análisis de SupervivenciaRESUMEN
Patients with systemic lupus erythematosus (SLE) present a high incidence of atherosclerosis, which contributes significantly to morbidity and mortality in this autoimmune disease. An impaired balance between regulatory (Treg) and follicular helper (Tfh) CD4+ T cells is shared by both diseases. However, whether there are common mechanisms of CD4+ T cell dysregulation between SLE and atherosclerosis remains unclear. Pre-B cell leukemia transcription factor 1 isoform d (Pbx1d) is a lupus susceptibility gene that regulates Tfh cell expansion and Treg cell homeostasis. Here, we investigated the role of T cells overexpressing Pbx1d in low-density lipoprotein receptor-deficient (Ldlr-/-) mice fed with a high-fat diet, an experimental model for atherosclerosis. Pbx1d-transgenic T cells exacerbated some phenotypes of atherosclerosis, which were associated with higher autoantibody production, increased Tfh cell frequency, and impaired Treg cell regulation, in Ldlr-/- mice as compared with control T cells. In addition, we showed that dyslipidemia and Pbx1d-transgenic expression independently impaired the differentiation and function of Treg cells in vitro, suggesting a gene/environment additive effect. Thus, our results suggest that the combination of Pbx1d expression in T cells and dyslipidemia exacerbates both atherosclerosis and autoimmunity, at least in part through a dysregulation of Treg cell homeostasis.
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Alelos , Aterosclerosis , Dislipidemias , Regulación de la Expresión Génica/inmunología , Factor de Transcripción 1 de la Leucemia de Células Pre-B/inmunología , Linfocitos T Reguladores , Animales , Aterosclerosis/genética , Aterosclerosis/inmunología , Aterosclerosis/patología , Dislipidemias/genética , Dislipidemias/inmunología , Dislipidemias/patología , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/inmunología , Ratones , Ratones Noqueados , Factor de Transcripción 1 de la Leucemia de Células Pre-B/genética , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/patologíaRESUMEN
HMG-CoA reductase inhibitors, or statins, are potent plasma LDL-cholesterol (LDL-c) lowering agents. Since the introduction of the first statin, lovastatin, in 1987, accumulating evidence showed that non-cholesterol lowering effects play an important role in their efficacy to reduce atherosclerotic cardiovascular disease (ASCVD). Thus, these non-LDL-c lowering properties could benefit patients with immune-mediated diseases. Statins and their associated immune-modulating roles have recently received much attention. Different statins have been administered in various experimental and clinical studies focused on autoimmunity. The results indicate that statins can modulate immune responses through mevalonate pathway-dependent and -independent mechanisms. The anti-inflammatory and immune-modulating effects include cell adhesion, migration of antigen presenting cells, and differentiation, as well as activation, of T-cells. In various autoimmune diseases (e.g. rheumatoid arthritis, lupus, and multiple sclerosis), promising results have been obtained to date.
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Antiinflamatorios/uso terapéutico , Anticolesterolemiantes/uso terapéutico , Enfermedades Autoinmunes/tratamiento farmacológico , Autoinmunidad/efectos de los fármacos , Dislipidemias/tratamiento farmacológico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Sistema Inmunológico/efectos de los fármacos , Animales , Antiinflamatorios/efectos adversos , Anticolesterolemiantes/efectos adversos , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/metabolismo , Biomarcadores/sangre , LDL-Colesterol/sangre , Dislipidemias/sangre , Dislipidemias/inmunología , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Sistema Inmunológico/inmunología , Sistema Inmunológico/metabolismoRESUMEN
Diabetic peripheral neuropathy (DPN) is one of the most widespread and disabling neurological conditions, accounting for half of all neuropathy cases worldwide. Despite its high prevalence, no approved disease modifying therapies exist. There is now a growing body of evidence that DPN secondary to type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) represents different disease processes, with T2DM DPN best understood within the context of metabolic syndrome rather than hyperglycemia. In this review, we highlight currently understood mechanisms of DPN, along with their corresponding potential therapeutic targets. We frame this discussion within a practical overview of how the field evolved from initial human observations to murine pathomechanistic and therapeutic models into ongoing and human clinical trials, with particular emphasis on T2DM DPN and metabolic syndrome.
Asunto(s)
Neuropatías Diabéticas , Dislipidemias , Metabolismo Energético , Inflamación , Síndrome Metabólico , Animales , Neuropatías Diabéticas/tratamiento farmacológico , Neuropatías Diabéticas/inmunología , Neuropatías Diabéticas/metabolismo , Dislipidemias/tratamiento farmacológico , Dislipidemias/inmunología , Dislipidemias/metabolismo , Metabolismo Energético/efectos de los fármacos , Metabolismo Energético/inmunología , Humanos , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Inflamación/metabolismo , Síndrome Metabólico/tratamiento farmacológico , Síndrome Metabólico/inmunología , Síndrome Metabólico/metabolismo , RatonesRESUMEN
BACKGROUND: The pathological basis of coronary artery disease (CAD) is atherosclerosis which is associated with inflammation and dyslipidemia. However, the involvement of hypersensitive C-reactive protein (hs-CRP) in lipid metabolism and how it affects the pathogenesis of CAD is uncertain. OBJECTIVE: To explore whether the relationship between dyslipidemia and CAD is partly mediated by hs-CRP levels. METHODS: Three hundred fifteen pairs of randomly sexand age-matched CAD and non-CAD subjects collected from Zhongda Hospital Affiliated to Southeast University were involved in the final analysis. We gathered information about each subjects clinical history as well as their results of detected hs-CRP and lipid levels. Linear regression analysis was used to determine the association between dyslipidemia and hs-CRP levels in which univariate and multivariate logistic regression analyzes were performed to determine the relationship between hs-CRP levels and CAD as well as dyslipidemia and CAD. Mediation analysis was used to evaluate whether hs-CRP levels act as a mediator of the relationship between dyslipidemia and CAD. RESULTS: Dyslipidemia and hs-CRP levels were significantly associated with an increased risk of CAD, with ß = 0.594 (P = 0.001) and ß = 0.016 (P = 0.024), respectively, and there was a correlation between dyslipidemia and hs-CRP levels (ß = 3.273, P = 0.004). Mediation analysis results revealed that the correlation between dyslipidemia and CAD was 8.27% mediated by hs-CRP levels with a direct effect of 0.621 and an indirect effect of 0.056. CONCLUSION: Hs-CRP levels played a partial mediation role in the association between dyslipidemia and CAD.
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Proteína C-Reactiva , Enfermedad de la Arteria Coronaria , Dislipidemias , Inflamación , Proteína C-Reactiva/inmunología , Proteína C-Reactiva/metabolismo , Estudios de Casos y Controles , China/epidemiología , Angiografía Coronaria/métodos , Enfermedad de la Arteria Coronaria/diagnóstico , Enfermedad de la Arteria Coronaria/epidemiología , Enfermedad de la Arteria Coronaria/inmunología , Enfermedad de la Arteria Coronaria/metabolismo , Correlación de Datos , Dislipidemias/sangre , Dislipidemias/diagnóstico , Dislipidemias/inmunología , Femenino , Factores de Riesgo de Enfermedad Cardiaca , Humanos , Inflamación/sangre , Inflamación/metabolismo , Metabolismo de los Lípidos/inmunología , Masculino , Análisis de Mediación , Persona de Mediana EdadRESUMEN
BACKGROUND: Psoriasis is associated with elevated risk of heart attack and increased accumulation of subclinical noncalcified coronary burden by coronary computed tomography angiography (CCTA). Machine learning algorithms have been shown to effectively analyze well-characterized data sets. OBJECTIVE: In this study, we used machine learning algorithms to determine the top predictors of noncalcified coronary burden by CCTA in psoriasis. METHODS: The analysis included 263 consecutive patients with 63 available variables from the Psoriasis Atherosclerosis Cardiometabolic Initiative. The random forest algorithm was used to determine the top predictors of noncalcified coronary burden by CCTA. We evaluated our results using linear regression models. RESULTS: Using the random forest algorithm, we found that the top 10 predictors of noncalcified coronary burden were body mass index, visceral adiposity, total adiposity, apolipoprotein A1, high-density lipoprotein, erythrocyte sedimentation rate, subcutaneous adiposity, small low-density lipoprotein particle, cholesterol efflux capacity and the absolute granulocyte count. Linear regression of noncalcified coronary burden yielded results consistent with our machine learning output. LIMITATION: We were unable to provide external validation and did not study cardiovascular events. CONCLUSION: Machine learning methods identified the top predictors of noncalcified coronary burden in psoriasis. These factors were related to obesity, dyslipidemia, and inflammation, showing that these are important targets when treating comorbidities in psoriasis.