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1.
EMBO Rep ; 24(12): e57238, 2023 Dec 06.
Artículo en Inglés | MEDLINE | ID: mdl-37929625

RESUMEN

Interferons (IFN) are crucial antiviral and immunomodulatory cytokines that exert their function through the regulation of a myriad of genes, many of which are not yet characterized. Here, we reveal that lipin-2, a phosphatidic acid phosphatase whose mutations produce an autoinflammatory syndrome known as Majeed syndrome in humans, is regulated by IFN in a STAT-1-dependent manner. Lipin-2 inhibits viral replication both in vitro and in vivo. Moreover, lipin-2 also acts as a regulator of inflammation in a viral context by reducing the signaling through TLR3 and the generation of ROS and release of mtDNA that ultimately activate the NLRP3 inflammasome. Inhibitors of mtDNA release from mitochondria restrict IL-1ß production in lipin-2-deficient animals in a model of viral infection. Finally, analyses of databases from COVID-19 patients show that LPIN2 expression levels negatively correlate with the severity of the disease. Overall, these results uncover novel regulatory mechanisms of the IFN response driven by lipin-2 and open new perspectives for the future management of patients with LPIN2 mutations.


Asunto(s)
ADN Mitocondrial , Interferones , Animales , Humanos , Fosfatidato Fosfatasa/genética , Fosfatidato Fosfatasa/metabolismo
3.
Med Clin (Barc) ; 162(9): 409-416, 2024 05 17.
Artículo en Inglés, Español | MEDLINE | ID: mdl-38423940

RESUMEN

BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) has been reported to increase the risk of early atherosclerosis even in young patients. Moreover, metabolic dysfunction-associated steatotic liver disease (MASLD), which has been linked to IBD, is a well-recognized but underdiagnosis entity related to cardiovascular risk. We analyze the impact of MASLD in IBD patients' cardiovascular risk through both advanced lipoprotein profile sorted by nuclear magnetic resonance spectroscopy, and carotid artery intima-media thickness (CIMT). METHODS: Cross-sectional cohort study which involves 941 IBD adult outpatients. Of them, 50 patients with IBD who met criteria for MASLD and 50 with IBD without MASLD, matched by sex and age were included. Alterations in CIMT were evaluated considering abnormal measures above the 75th percentile adjusted for sex and age. Specific advanced lipoprotein profile was also carried out. RESULTS: Most of the patients had an abnormal CIMT (58%). MASLD (OR=5.05, CI 95%=1.71-14.92) and female sex (OR=3.32, CI 95%=1.03-10) were significantly associated with CIMT alterations. Dense LDL particles (with high cholesterol composition in general cohort (OR=3.62, 95% CI=1.07-12.19) and high triglycerides density in young subgroup (OR=6.25, 95% CI=1.04-50) but not total LDL cholesterol were associated with CIMT alterations. CONCLUSIONS: MASLD and female sex are associated with early atherosclerosis in IBD patients. Dense LDL particle in combination with vascular imaging findings should be evaluated as non-invasive tools in the management of cardiovascular risk in IBD patients.


Asunto(s)
Grosor Intima-Media Carotídeo , Enfermedades Inflamatorias del Intestino , Humanos , Masculino , Femenino , Estudios Transversales , Adulto , Enfermedades Inflamatorias del Intestino/complicaciones , Persona de Mediana Edad , Medición de Riesgo , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/epidemiología , Factores de Riesgo de Enfermedad Cardiaca , Hígado Graso/complicaciones , Hígado Graso/diagnóstico , Hígado Graso/diagnóstico por imagen , Espectroscopía de Resonancia Magnética
4.
Eur J Intern Med ; 120: 99-106, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37872034

RESUMEN

BACKGROUND AND AIMS: Controversial data have been reported regarding the prevalence of Non-Alcoholic Fatty Liver Disease (NAFLD) in Inflammatory Bowel Disease (IBD) population and IBD-related risk factors. The aim of the study was to assess the prevalence and risk factors associated with NAFLD and liver fibrosis in IBD participants compared with non-IBD controls. METHODS: Cross-sectional, case-control study including 741 IBD cases and 170 non-IBD controls, matched by sex and age. All participants underwent liver ultrasound, transient elastography and laboratory tests. A logistic regression multivariable analysis was performed adjusting for classic metabolic risk factors and history of systemic steroid use. RESULTS: The prevalence of NAFLD and significant liver fibrosis was 45 % and 10 % in IBD group, and 40 % and 2.9 % in non-IBD group (p = 0.255 and 0.062, respectively). Longer IBD duration (aOR 1.02 95% CI (1.001-1.04)) and older age at IBD diagnosis (aOR 1.02 95 % CI (1.001-1.04)) were independent risk factors for NAFLD in IBD group. Crohn´s Disease was an independent risk factor for significant liver fibrosis in participants with IBD and NAFLD (aOR 3.97 95 % CI (1.78-8.96)). NAFLD occurred at lower BMI levels in IBD group with NAFLD compared to non-IBD group with NAFLD (aOR 0.92 95 % CI (0.87-0.98)). CONCLUSIONS: Although we found no differences in the prevalence of NAFLD and liver fibrosis between IBD group and non-IBD group, our findings suggest that liver fibrosis progression should be closely monitored in patients with concomitant CD and NAFLD, more in particular in those with long standing active disease.


Asunto(s)
Enfermedad de Crohn , Enfermedades Inflamatorias del Intestino , Enfermedad del Hígado Graso no Alcohólico , Humanos , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Enfermedad de Crohn/complicaciones , Enfermedad de Crohn/epidemiología , Estudios de Casos y Controles , Estudios Transversales , Factores de Riesgo , Enfermedades Inflamatorias del Intestino/complicaciones , Cirrosis Hepática/complicaciones , Prevalencia
5.
Sci Rep ; 13(1): 23061, 2023 12 27.
Artículo en Inglés | MEDLINE | ID: mdl-38155275

RESUMEN

Suboptimal vaccine response is a significant concern in patients with Inflammatory Bowel Disease (IBD) receiving biologic drugs. This single-center observational study involved 754 patients with IBD. In Phase I (October 2020-April 2021), 754 IBD participants who had not previously received the SARS-CoV-2 vaccine, underwent blood extraction to assess the seroprevalence of SARS-CoV-2 infection and IBD-related factors. Phase II (May 2021-October 2021) included a subgroup of 52 IBD participants with confirmed previous SARS-CoV-2 infection, who were studied for humoral and cellular response to the SARS-CoV-2 vaccine. In Phase I, treatment with anti-TNF was associated with lower rates of seroconversion (aOR 0.25 95% CI [0.10-0.61]). In Phase II, a significant increase in post-vaccination IgG levels was observed regardless of biologic treatment. However, patients treated with anti-TNF exhibited significantly lower IgG levels compared to those without IBD therapy (5.32 ± 2.47 vs. 7.99 ± 2.59 U/ml, p = 0.042). Following vaccination, a lymphocyte, monocyte, and NK cell activation pattern was observed, with no significant differences between patients receiving biologic drugs and those without IBD treatment. Despite lower seroprevalence and humoral response to the SARS-CoV-2 vaccine in patients treated with anti-TNF, the cellular response to the vaccine did not differ significantly from that patients without IBD therapy.


Asunto(s)
COVID-19 , Enfermedades Inflamatorias del Intestino , Humanos , Vacunas contra la COVID-19 , Estudios Seroepidemiológicos , Inhibidores del Factor de Necrosis Tumoral , SARS-CoV-2 , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Vacunación , Inmunoglobulina G
6.
Biomedicines ; 10(6)2022 May 26.
Artículo en Inglés | MEDLINE | ID: mdl-35740260

RESUMEN

Cholestatic diseases can be caused by the dysfunction of transporters involved in hepatobiliary circulation. Although pharmacological treatments constitute the current standard of care for these diseases, none are curative, with liver transplantation being the only long-term solution for severe cholestasis, albeit with many disadvantages. Liver-directed gene therapy has shown promising results in clinical trials for genetic diseases, and it could constitute a potential new therapeutic approach for cholestatic diseases. Many preclinical gene therapy studies have shown positive results in animal models of both acquired and genetic cholestasis. The delivery of genes that reduce apoptosis or fibrosis or improve bile flow has shown therapeutic effects in rodents in which cholestasis was induced by drugs or bile duct ligation. Most studies targeting inherited cholestasis, such as progressive familial intrahepatic cholestasis (PFIC), have focused on supplementing a correct version of a mutated gene to the liver using viral or non-viral vectors in order to achieve expression of the therapeutic protein. These strategies have generated promising results in treating PFIC3 in mouse models of the disease. However, important challenges remain in translating this therapy to the clinic, as well as in developing gene therapy strategies for other types of acquired and genetic cholestasis.

7.
Cell Biosci ; 12(1): 79, 2022 May 31.
Artículo en Inglés | MEDLINE | ID: mdl-35641984

RESUMEN

BACKGROUND: Bile acid (BA) homeostasis is mainly regulated by bile salt excretory pump (BSEP), a hepatocyte transporter that transfers BAs to the bile. BSEP expression is regulated by BA levels through activation of farnesoid X receptor transcription factor, which binds to the inverted repeat (IR-1) element in the BSEP promoter. Gene therapy of cholestatic diseases could benefit from using vectors carrying endogenous promoters physiologically regulated by BAs, however their large size limits this approach, especially when using adeno-associated viral vector (AAV) vectors. RESULTS: We evaluated the functionality and BA-mediated regulation of minimal versions of human and mouse BSEP promoters containing IR-1 using AAV vectors expressing luciferase. Unexpectedly, a minimal mouse BSEP promoter (imPr) showed higher BA-mediated expression and inducibility than a minimal human promoter (ihPr) or than full-length BSEP promoters in human hepatic cells. In addition, in mice receiving an AAV8 vector carrying imPr promoter-driven luciferase expression was efficiently regulated by administration of a BA-enriched diet. Interestingly, this vector also expressed significantly higher luciferase levels in Abcb4-/- mice, which have high levels of BAs, compared to wild type mice, or to mice receiving a vector containing the luciferase gene downstream of the constitutive alpha-1 antitrypsin promoter. In contrast, the AAV vector containing ihPr showed very low luciferase expression with no inducibility. Finally, we optimized imPr by adding three IR-1 repeats at its 5' end. This new promoter provided higher levels of luciferase than imPr both in vitro and in vivo. CONCLUSIONS: The imPr could represent a useful tool for gene therapy approaches in which physiological BA regulation is desired.

8.
Mol Ther Oncolytics ; 26: 246-264, 2022 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-35949950

RESUMEN

The outcomes of metastatic and nonresponder pediatric osteosarcoma patients are very poor and have not improved in the last 30 years. These tumors harbor a highly immunosuppressive environment, making existing immunotherapies ineffective. Here, we evaluated the use of Semliki Forest virus (SFV) vectors expressing galectin-3 (Gal3) inhibitors as therapeutic tools, since both the inhibition of Gal3, which is involved in immunosuppression and metastasis, and virotherapy based on SFV have been demonstrated to reduce tumor progression in different tumor models. In vitro, inhibitors based on the Gal3 amino-terminal domain alone (Gal3-N) or fused to a Gal3 peptide inhibitor (Gal3-N-C12) were able to block the binding of Gal3 to the surface of activated T cells. In vivo, SFV expressing Gal3-N-C12 induced strong antitumor responses in orthotopic K7M2 and MOS-J osteosarcoma tumors, leading to complete regressions in 47% and 30% of mice, respectively. Pulmonary metastases were also reduced in K7M2 tumor-bearing mice after treatment with SFV-Gal3-N-C12. Both the antitumor and antimetastatic responses were dependent on modulation of the immune system, primarily including an increase in tumor-infiltrating lymphocytes and a reduction in the immunosuppressive environment inside tumors. Our results demonstrated that SFV-Gal3-N-C12 could constitute a potential therapeutic agent for osteosarcoma patients expressing Gal3.

9.
Ther Adv Infect Dis ; 9: 20499361221130212, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36382138

RESUMEN

Introduction: International guidelines recommend hospital care for patients with severe Coronavirus disease (COVID-19), but fragile health care systems struggle to cope with high number of admissions, placing patients at risk of receiving substandard care. We describe an outpatient ambulatory surveillance and treatment strategy (OPAT) for health care workers (HCWs) with severe COVID-19 during low hospital bed availability periods in Mexico City. Methods: In this observational, descriptive, retrospective study, we included HCWs with severe disease for whom there were no hospital beds available at the time of evaluation. We provided daily assessments by infectious disease specialists, daily ambulatory steroid, oral thromboprophylaxis and domiciliary low-dose oxygen. We recorded the number of patients who recovered, were hospitalized or died on follow-up. Results: From 18 March 2020 to 16 July 2021, 1739 HCWs attended our service. A total of 540 were diagnosed with COVID-19. Seventy-four had severe COVID-19 and needed hospitalization. Immediate hospitalization was not possible in 56 patients who were sent to the OPAT and included in our study. Twenty-four patients subsequently required hospitalization and 32 recovered as outpatients. Conclusions: We describe a feasible and safe outpatient management strategy for HCWs with severe COVID-19 in a low-resource setting.

10.
Nat Commun ; 10(1): 5694, 2019 12 13.
Artículo en Inglés | MEDLINE | ID: mdl-31836711

RESUMEN

Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a rare monogenic disease caused by mutations in the ABCB4 gene, resulting in a reduction in biliary phosphatidylcholine. Reduced biliary phosphatidylcholine cannot counteract the detergent effects of bile salts, leading to cholestasis, cholangitis, cirrhosis and ultimately liver failure. Here, we report results from treating two- or five-week-old Abcb4-/- mice with an AAV vector expressing human ABCB4, resulting in significant decreases of PFIC3 disease biomarkers. All male mice achieved a sustained therapeutic effect up through 12 weeks, but the effect was achieved in only 50% of females. However, two-week-old females receiving a second inoculation three weeks later maintained the therapeutic effect. Upon sacrifice, markers of PFIC3 disease such as, hepatosplenomegaly, biliary phosphatidylcholine and liver histology were significantly improved. Thus, AAV-mediated gene therapy successfully prevented PFIC3 symptoms in a clinically relevant mouse model, representing a step forward in improving potential therapy options for PFIC3 patients.


Asunto(s)
Subfamilia B de Transportador de Casetes de Unión a ATP/deficiencia , Colestasis Intrahepática/terapia , Terapia Genética/métodos , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Animales , Línea Celular Tumoral , Colestasis Intrahepática/genética , Dependovirus/genética , Modelos Animales de Enfermedad , Femenino , Vectores Genéticos/administración & dosificación , Vectores Genéticos/genética , Células HEK293 , Humanos , Masculino , Ratones , Ratones Noqueados , Proteínas Recombinantes/genética , Factores Sexuales , Resultado del Tratamiento
11.
Front Pediatr ; 5: 117, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28589115

RESUMEN

The immune system's correct functioning requires a sophisticated balance between responses to continuous microbial challenges and tolerance to harmless antigens, such as self-antigens, food antigens, commensal microbes, allergens, etc. When this equilibrium is altered, it can lead to inflammatory pathologies, tumor growth, autoimmune disorders, and allergy/asthma. The objective of this review is to show the existing data on the importance of regulatory T cells (Tregs) on this balance and to underline how intrauterine and postnatal environmental exposures influence the maturation of the immune system in humans. Genetic and environmental factors during embryo development and/or early life will result in a proper or, conversely, inadequate immune maturation with either beneficial or deleterious effects on health. We have focused herein on Tregs as a reflection of the maturity of the immune system. We explain the types, origins, and the mechanisms of action of these cells, discussing their role in allergy and asthma predisposition. Understanding the importance of Tregs in counteracting dysregulated immunity would provide approaches to diminish asthma and other related diseases in infants.

12.
Int J Ophthalmol ; 10(5): 796-802, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28546940

RESUMEN

AIM: To assess the proportion of refractive errors in the Mexican population that visited primary care optometry clinics in fourteen states of Mexico. METHODS: Refractive data from 676 856 patients aged 6 to 90y were collected from optometry clinics in fourteen states of Mexico between 2014 and 2015. The refractive errors were classified by the spherical equivalent (SE), as follows: sphere+½ cylinder. Myopia (SE>-0.50 D), hyperopia (SE>+0.50 D), emmetropia (-0.50≤SE≤+0.50), and astigmatism alone (cylinder≥-0.25 D). A negative cylinder was selected as a notation. RESULTS: The proportion (95% confidence interval) among all of the subjects was hyperopia 21.0% (20.9-21.0), emmetropia 40.7% (40.5-40.8), myopia 24.8% (24.7-24.9) and astigmatism alone 13.5% (13.4-13.5). Myopia was the most common refractive error and frequency seemed to increase among the young population (10 to 29 years old), however, hyperopia increased among the aging population (40 to 79 years old), and astigmatism alone showed a decreasing trend with age (6 to 90y; from 19.7% to 10.8%). There was a relationship between age and all refractive errors (approximately 60%, aged 50 and older). The proportion of any clinically important refractive error was higher in males (61.2%) than in females (58.3%; P<0.0001). From fourteen states that collected information, the proportion of refractive error showed variability in different geographical areas of Mexico. CONCLUSION: Myopia is the most common refractive error in the population studied. This study provides the first data on refractive error in Mexico. Further programs and studies must be developed to address the refractive errors needs of the Mexican population.

13.
J Infect Dev Ctries ; 8(3): 331-8, 2014 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-24619265

RESUMEN

INTRODUCTION: The influenza A virus is responsible for high morbidity and mortality in children and adults worldwide. Thus, a rapid, sensitive, and specific diagnosis tool is required. METHODOLOGY: An immunofluorescence assay (DFA) and a lateral-flow immunochromatographic assay were compared with RT-PCR for detection of the influenza A virus in 113 nasopharyngeal wash samples obtained from pediatric patients. Samples were collected between July and December 2009, during the pandemic outbreak of influenza A H1N1/09. RESULTS: The sensitivity, specificity, and positive and negative predictive values obtained for the DFA were 68.97%, 76.63%, 75.47%, and 70%, respectively, while the values obtained for the immunochromatographic assay were 58.62%, 81.82%, 77.27%, and 65.22%, respectively. The frequency of the influenza A virus was 51.33%, and a total of 27 samples were positive for the pandemic influenza A H1N1/09. CONCLUSIONS: DFA and the immunochromatographic assay can be important tools for patient care during influenza season and in outbreaks as they usually provide results within 45 minutes. Furthermore, positive results in conjunction with the patient's symptoms could provide a correct diagnosis, thus facilitating appropriate patient management. Nonetheless, the results of these assays still require confirmation by RT-PCR.


Asunto(s)
Cromatografía de Afinidad/métodos , Pruebas Diagnósticas de Rutina/métodos , Virus de la Influenza A/aislamiento & purificación , Gripe Humana/diagnóstico , Gripe Humana/virología , Sistemas de Atención de Punto , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Adolescente , Niño , Preescolar , Femenino , Técnica del Anticuerpo Fluorescente/métodos , Humanos , Lactante , Masculino , Nasofaringe/virología , Valor Predictivo de las Pruebas , Sensibilidad y Especificidad
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