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1.
Eur Respir J ; 54(1)2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-31073086

RESUMEN

BACKGROUND: Pulmonary fibrosis is one of the leading indications for lung transplantation. The disease, which is of unknown aetiology, can be progressive, resulting in distortion of the extracellular matrix (ECM), inflammation, fibrosis and eventual death. METHODS: 13 patients born to consanguineous parents from two unrelated families presenting with interstitial lung disease were clinically investigated. Nine patients developed respiratory failure and subsequently died. Molecular genetic investigations were performed on patients' whole blood or archived tissues, and cell biological investigations were performed on patient-derived fibroblasts. RESULTS: The combination of a unique pattern of early-onset lung fibrosis (at 12-15 years old) with distinctive radiological findings, including 1) traction bronchiectasis, 2) intralobular septal thickening, 3) shrinkage of the secondary pulmonary lobules mainly around the bronchovascular bundles and 4) early type 2 respiratory failure (elevated blood carbon dioxide levels), represents a novel clinical subtype of familial pulmonary fibrosis. Molecular genetic investigation of families revealed a hypomorphic variant in S100A3 and a novel truncating mutation in S100A13, both segregating with the disease in an autosomal recessive manner. Family members that were either heterozygous carriers or wild-type normal for both variants were unaffected. Analysis of patient-derived fibroblasts demonstrated significantly reduced S100A3 and S100A13 expression. Further analysis demonstrated aberrant intracellular calcium homeostasis, mitochondrial dysregulation and differential expression of ECM components. CONCLUSION: Our data demonstrate that digenic inheritance of mutations in S100A3 and S100A13 underlie the pathophysiology of pulmonary fibrosis associated with a significant reduction of both proteins, which suggests a calcium-dependent therapeutic approach for management of the disease.


Asunto(s)
Pulmón/patología , Fibrosis Pulmonar/genética , Fibrosis Pulmonar/fisiopatología , Proteínas S100/genética , Adolescente , Niño , Salud de la Familia , Femenino , Predisposición Genética a la Enfermedad , Heterocigoto , Humanos , Masculino , Mutación , Linaje , Fibrosis Pulmonar/diagnóstico , Arabia Saudita
2.
Adv Anat Pathol ; 24(4): 226-234, 2017 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-28537941

RESUMEN

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is characterized as inflammation of small-sized to medium-sized blood vessels and encompasses several clinicopathologic entities including granulomatosis with polyangiitis, microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis, and renal-limited ANCA-associated vasculitis. Over the past several decades, significant progress has been made in understanding the pathophysiology of ANCA-associated vasculitis. Although neutrophils contain a multitude of granular proteins, clinically significant autoantibodies are only recognized against myeloperoxidase and proteinase 3, both of which are present in the azurophilic granules. The propensity to develop these antibodies depends on a variety of predisposing factors such as microbial infection, genetic factors, environmental agents, and therapeutic drugs among others. These factors are usually associated with production of proinflammatory cytokines with capacity to prime the neutrophils. As a result a high proportion of neutrophils in circulation may be primed resulting in exposure of cytoplasmic proteins including myeloperoxidase and proteinase 3 on the surface of the neutrophils. Primed neutrophils are activated by interaction with ANCA in circulation. Activated neutrophils attach to and transmigrate through endothelium and accumulate within the vessel wall. These neutrophils degranulate and produce reactive oxygen radicals and ultimately die, causing tissue injury. Endothelial injury results in leakage of serum proteins and coagulation factors causing fibrinoid necrosis. B cells produce ANCAs, as well as neutrophil abnormalities and imbalances in different T-cell subtypes with excess of Th17, which perpetuate the inflammatory process.


Asunto(s)
Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/patología , Neutrófilos/patología , Peroxidasa/metabolismo , Linfocitos T/patología , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/diagnóstico , Anticuerpos Anticitoplasma de Neutrófilos/inmunología , Humanos
3.
Clin Exp Rheumatol ; 35(2): 327-329, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28134088

RESUMEN

Lipopolysaccharide-responsive, beige-like anchor protein (LRBA) deficiency causes common variable immunodeficiency (CVID) disorders and autoimmunity. LRBA deficiency has become a clinically variable syndrome with a wide spectrum of clinical manifestations. We report a patient with LRBA deficiency associated chronic non-erosive arthritis. This report highlights the spectrum of arthritis in such patients and the potential causative role of LRBA gene in juvenile arthritis.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Artritis Juvenil/genética , Inmunodeficiencia Variable Común/genética , Mutación , Abatacept/administración & dosificación , Proteínas Adaptadoras Transductoras de Señales/deficiencia , Proteínas Adaptadoras Transductoras de Señales/inmunología , Adolescente , Artritis Juvenil/diagnóstico , Artritis Juvenil/tratamiento farmacológico , Artritis Juvenil/inmunología , Artrografía , Enfermedad Crónica , Inmunodeficiencia Variable Común/diagnóstico , Inmunodeficiencia Variable Común/tratamiento farmacológico , Inmunodeficiencia Variable Común/inmunología , Análisis Mutacional de ADN , Predisposición Genética a la Enfermedad , Humanos , Inmunosupresores/administración & dosificación , Articulación de la Rodilla/diagnóstico por imagen , Imagen por Resonancia Magnética , Masculino , Fenotipo , Resultado del Tratamiento
4.
Biochim Biophys Acta ; 1850(2): 352-64, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25450488

RESUMEN

BACKGROUND: Lipid metabolism dysfunction leading to excess fat deposits (obesity) may cause tumor (cancer) development. Both obesity and cancer are the epicenter of important medical issues. Lipid metabolism and cell death/proliferation are controlled by biochemical and molecular pathways involving many proteins, and organelles; alteration in these pathways leads to fat accumulation or tumor growth. Mammalian Krüppel-like factors, KLFs play key roles in both lipid metabolism and tumor development. SCOPE OF REVIEW: Substantial epidemiological and clinical studies have established strong association of obesity with a number of human cancers. However, we need more experimental verification to determine the exact role of this metabolic alteration in the context of tumor development. A clear understanding of molecules, pathways and the mechanisms involved in lipid metabolism and cell death/proliferation will have important implications in pathogenesis, and prevention of these diseases. MAJOR CONCLUSION: The regulatory role of KLFs, in both cell death/proliferation and lipid metabolism suggests a common regulation of both processes. This provides an excellent model for delivering a precise understanding of the mechanisms linking altered expression of KLFs to obesity and tumor development. GENERAL SIGNIFICANCE: Currently, mouse and rats are the models of choice for investigating disease mechanisms and pharmacological therapies but a genetic model is needed for a thorough examination of KLF function in vivo during the development of an organism. The worm Caenorhabditis elegans is an ideal model to study the connectivity between lipid metabolism and cell death/proliferation.


Asunto(s)
Metabolismo de los Lípidos , Neoplasias , Obesidad , Animales , Caenorhabditis elegans , Muerte Celular , Proliferación Celular , Humanos , Ratones , Neoplasias/epidemiología , Neoplasias/metabolismo , Neoplasias/patología , Neoplasias/terapia , Obesidad/epidemiología , Obesidad/metabolismo , Obesidad/patología , Obesidad/terapia , Ratas
5.
J Immunol ; 191(5): 2796-805, 2013 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-23872050

RESUMEN

Significant immunological obstacles are to be negotiated before xenotransplantation becomes a clinical reality. An initial rejection of transplanted vascularized xenograft is attributed to Galα1,3Galß1,4GlcNAc-R (Galα1,3-Gal)-dependent and -independent mechanisms. Hitherto, no receptor molecule has been identified that could account for Galα1,3-Gal-independent rejection. In this study, we identify the tetraspanin CD82 as a receptor molecule for the Galα1,3-Gal-independent mechanism. We demonstrate that, in contrast to human undifferentiated myeloid cell lines, differentiated cell lines are capable of recognizing xenogeneic porcine aortic endothelial cells in a calcium-dependent manner. Transcriptome-wide analysis to identify the differentially expressed transcripts in these cells revealed that the most likely candidate of the Galα1,3-Gal-independent recognition moiety is the tetraspanin CD82. Abs to CD82 inhibited the calcium response and the subsequent activation invoked by xenogeneic encounter. Our data identify CD82 on innate immune cells as a major "xenogenicity sensor" and open new avenues of intervention to making xenotransplantation a clinical reality.


Asunto(s)
Rechazo de Injerto/inmunología , Proteína Kangai-1/inmunología , Trasplante Heterólogo/inmunología , Animales , Western Blotting , Células Endoteliales/inmunología , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Humanos , Microscopía Confocal , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Porcinos
6.
Front Immunol ; 14: 1289769, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38162642

RESUMEN

Introduction: The evolution of adaptive immunity in Camelidae resulted in the concurrent expression of classic heterotetrameric and unconventional homodimeric heavy chain-only IgG antibodies. Heavy chain-only IgG bears a single variable domain and lacks the constant heavy (CH) γ1 domain required for pairing with the light chain. It has not been reported whether this distinctive feature of IgG is also observed in the IgA isotype. Methods: Gene-specific primers were used to generate an IgA heavy chain cDNA library derived from RNA extracted from the dromedary's third eyelid where isolated lymphoid follicles and plasma cells abound at inductive and effector sites, respectively. Results: Majority of the cDNA clones revealed hallmarks of heavy chain-only antibodies, i.e. camelid-specific amino acid substitutions in framework region 1 and 2, broad length distribution of complementarity determining region 3, and the absence of the CHα1 domain. In a few clones, however, the cDNA of the canonical IgA heavy chain was amplified which included the CHα1 domain, analogous to CHγ1 domain in IgG1 subclass. Moreover, we noticed a short, proline-rich hinge, and, at the N-terminal end of the CHα3 domain, a unique, camelid-specific pentapeptide of undetermined function, designated as the inter-α region. Immunoblots using rabbit anti-camel IgA antibodies raised against CHα2 and CHα3 domains as well as the inter-α region revealed the expression of a ~52 kDa and a ~60 kDa IgA species, corresponding to unconventional and canonical IgA heavy chain, respectively, in the third eyelid, trachea, small and large intestine. In contrast, the leporine anti-CHα1 antibody detected canonical, but not unconventional IgA heavy chain, in all the examined tissues, milk, and serum, in addition to another hitherto unexplored species of ~45 kDa in milk and serum. Immunohistology using anti-CHα domain antibodies confirmed the expression of both variants of IgA heavy chains in plasma cells in the third eyelid's lacrimal gland, conjunctiva, tracheal and intestinal mucosa. Conclusion: We found that in the dromedary, the IgA isotype has expanded the immunoglobulin repertoire by co-expressing unconventional and canonical IgA heavy chains, comparable to the IgG class, thus underscoring the crucial role of heavy chain-only antibodies not only in circulation but also at the mucosal frontiers.


Asunto(s)
Camelus , Cadenas Pesadas de Inmunoglobulina , Animales , Conejos , ADN Complementario , Inmunoglobulina G , Inmunoglobulina A
7.
Rheumatol Int ; 32(3): 791-4, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-20054691

RESUMEN

We describe a flare of Behçet's syndrome in a 42-year-old man who presented with florid mucocutaneous manifestations, headache and vomiting, but without meningeal or neurologic signs. A single, non-enhancing cortical lesion was found in the frontal lobe by computed tomography and magnetic resonance (MR) imaging studies. Diffusion-weighted analysis and MR spectroscopy were consistent with focal inflammation. The patient improved with colchicine, and after 5 months, a repeat MR scan demonstrated resolution of the inflammatory changes suggesting that involvement of the cerebral cortex may be a self-limiting phenomenon, distinct from other more frequent and destructive parenchymal manifestations of neuro-Behçet's disease.


Asunto(s)
Síndrome de Behçet/patología , Corteza Cerebral/patología , Colchicina/uso terapéutico , Meningoencefalitis/patología , Moduladores de Tubulina/uso terapéutico , Adulto , Síndrome de Behçet/complicaciones , Síndrome de Behçet/tratamiento farmacológico , Encéfalo/patología , Humanos , Imagen por Resonancia Magnética , Espectroscopía de Resonancia Magnética , Masculino , Meningoencefalitis/complicaciones , Meningoencefalitis/tratamiento farmacológico , Tomografía Computarizada por Rayos X , Resultado del Tratamiento
8.
J Biomed Mater Res B Appl Biomater ; 110(3): 691-701, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-34619017

RESUMEN

The limited availability of human donor organs suitable for transplantation has resulted in ever-increasing patient waiting lists globally. Xenotransplantation is considered a potential option, but is yet to reach clinical practice. Although remarkable progress has been made in overcoming immunological rejection, issues with functionality are still to be resolved. Bioengineering approaches have been used to create cardiac tissues with optimized functions. The use of decellularized xenogeneic cardiac tissues seeded with donor-derived cardiac cells may prove to be a viable strategy as supporting structures of the native tissue such as vasculature can be utilized. Here we used sequential perfusion to decellularize adult rat hearts. The acellular scaffolds were reseeded with human endothelial cells, human fibroblasts, human mesenchymal stem cells, and cardiac cells derived from human-induced pluripotent stem cells. The ability of the resultant recellularized rat scaffolds to activate human naïve neutrophils in vitro was investigated to measure xenogeneic recognition. Our results demonstrate that in contrast to cadaveric xenogeneic hearts, acellular and recellularized xenogeneic scaffolds did not activate human naïve neutrophils and suggest that decellularization removes the xenogeneic antigens that lead to human naïve neutrophil activation thus allowing human cells to populate the now "allogenized" xenogeneic scaffolds.


Asunto(s)
Células Madre Pluripotentes Inducidas , Animales , Células Endoteliales , Matriz Extracelular/química , Xenoinjertos , Humanos , Neutrófilos , Ratas , Ingeniería de Tejidos/métodos , Andamios del Tejido/química , Trasplante Heterólogo
9.
Ann Thorac Med ; 16(3): 294-298, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34484446

RESUMEN

Interstitial lung disease (ILD) is a well-established common manifestation of idiopathic inflammatory myopathies. Yet, till now, the pathogenetic mechanisms are still poorly understood, classification is evolving and prognosis is variable. A refractory and rapidly progressive ILD (RPILD) that is associated with dermatomyositis (DM) with minimal muscle weakness and normal creatine kinase (termed clinically amyopathic DM) is increasingly being recognized, with more incidence in Asians. However, we are not aware of reports of the Arab region. Herein, we present a 38-year-old male with this condition that ended with a fatal outcome despite aggressive therapy, with a review of recent literature.

10.
PLoS One ; 16(3): e0247758, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33647017

RESUMEN

ß2-microglobulin (ß2-m), a 11.8 kDa protein, pairs non-covalently with the α3 domain of the major histocompatibility class (MHC) I α-chain and is essential for the conformation of the MHC class I protein complex. Shed ß2-m is measurable in circulation, and various disorders are accompanied by increases in ß2-m levels, including several viral infections. Therefore, we explored whether ß2-m levels could also be elevated in Coronavirus disease 2019 (Covid-19) and whether they predict disease severity. Serum ß2-m levels were measured in a cohort of 34 patients infected with SARS-CoV-2 on admission to a tertiary care hospital in Riyadh, Saudi Arabia, as well as in an approximately age-sex matched group of 34 uninfected controls. Mean ß2-m level was 3.25±1.68 mg/l (reference range 0.8-2.2 mg/l) in patients (mean age 48.2±21.6) and 1.98±0.61 mg/l in controls (mean age 48.2±21.6). 17 patients (mean age 36.9± 18.0) with mean ß2-m levels of 2.27±0.64 mg/l had mild disease by WHO severity categorization, 12 patients (mean age 53.3±18.1) with mean ß2-m levels of 3.57±1.39 mg/l had moderate disease, and five patients (of whom 2 died; mean age 74.4±13.8) with mean ß2-m levels of 5.85±1.85 mg/l had severe disease (P < = 0.001, by ANOVA test for linear trend). In multivariate ordinal regression ß2-m levels were the only significant predictor of disease severity. Our findings suggest that higher ß2-m levels could be an early indicator of severity of disease and predict outcome of Covid-19. As the main limitations of the study are a single-center study, sample size and ethnicity, these results need confirmation in larger cohorts outside the Arabian Peninsula in order to delineate the value of ß2-m measurements. The role of ß2-m in the etiology and pathogenesis of severe Covid-19 remains to be elucidated.


Asunto(s)
COVID-19/sangre , Índice de Severidad de la Enfermedad , Microglobulina beta-2/sangre , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , COVID-19/diagnóstico , Estudios de Cohortes , Comorbilidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Arabia Saudita
11.
Chem Res Toxicol ; 23(11): 1796-805, 2010 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-20961102

RESUMEN

A novel in vitro system was developed to investigate the effects of two forms of calcined mesoporous silica particles (MCM41-cal and SBA15-cal) on cellular respiration of mouse tissues. O(2) consumption by lung, liver, kidney, spleen, and pancreatic tissues was unaffected by exposure to 200 µg/mL MCM41-cal or SBA15-cal for several hours. Normal tissue histology was confirmed by light microscopy. Intracellular accumulation of the particles in the studied tissues was evident by electron microscopy. The results show reasonable in vitro biocompatibility of the mesoporous silicas with murine tissue bioenergetics.


Asunto(s)
Dióxido de Silicio/química , Animales , Materiales Biocompatibles/química , Metabolismo Energético , Riñón/efectos de los fármacos , Riñón/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Ratones , Microscopía Electrónica de Transmisión , Consumo de Oxígeno , Páncreas/efectos de los fármacos , Páncreas/metabolismo , Tamaño de la Partícula , Porosidad , Bazo/efectos de los fármacos , Bazo/metabolismo
12.
Front Pharmacol ; 11: 585761, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33384600

RESUMEN

Rapidly progressive interstitial lung disease is typically associated with clinically amyopathic dermatomyositis and the anti-melanoma differentiation associated gene 5 antibody, a condition with high mortality and resistance to classic immunosuppression. Recent reports have described the efficacy of the Janus kinase inhibitor tofacitinib in the treatment of rapidly progressive interstitial lung disease in anti-melanoma differentiation associated gene 5 antibody-positive clinically amyopathic dermatomyositis. It is uncertain, however, whether tofacitinib alters the course of rapidly progressive interstitial lung disease in other variants of dermatomyositis that are unrelated to the anti-melanoma differentiation associated gene 5 antibody and whether the early addition of the anti-fibrotic tyrosine kinase inhibitor nintedanib interferes with the development of fibrosis. To answer these questions, we present and discuss the case of an elderly woman who presented with a flare of dermatomyositis sine myositis. Based upon the detection of anti-Jo-1 antibodies and the absence of anti-melanoma differentiation associated gene 5 antibodies, anti-synthetase syndrome was diagnosed. While the cutaneous manifestations quickly resolved with prednisone, azathioprine and tacrolimus, the respiratory function paradoxically and rapidly deteriorated, and invoked the use of tofacitinib. Markedly raised ferritin levels and a severe numerical deficiency of circulating natural killer cells paralleled the acute lung inflammation, which was reflected by 18F-fluorodeoxyglucose hypermetabolism on positron emission tomography/CT. Tofacitinib lead to a prompt clinical recovery, with a reduction in oxygen requirement, correction of hyperferritinemia, reversal of the natural killer cell deficiency, and a decrease in 18F-fluorodeoxyglucose uptake in the affected lung segments. Subsequently, nintedanib was added at a point in time when inflammation subsided. Apart from cytomegalovirus reactivation no adverse events occurred. In conclusion, tofacitinib reversed the pronounced inflammatory component of anti-Jo-1 antibody-positive, anti-melanoma differentiation associated gene 5 antibody-negative rapidly progressive interstitial lung disease, confirming that Janus kinase signaling pathways are critically involved in the pathogenesis of rapidly progressive interstitial lung disease, apparently independently of the targeted autoantigen. Although some improvement in pulmonary function was observed, it seems premature to conclusively judge on reversibility or prevention of pulmonary fibrosis by pairing both kinase inhibitors for which an extended follow-up and ideally, prospective and controlled studies are needed.

13.
Arq Bras Oftalmol ; 82(2): 155-157, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30726411

RESUMEN

Numerous studies have reported on structural vascular anomalies and ischemia associated with neurofibromatosis type 1 that are thought to stem from dysfunction of neurofibromin, the neurofibromatosis type 1 protein. Documented cases of associated antiphospholipid syndrome fulfilling the accepted diagnostic criteria are exceptionally rare, with only three cases reported in the literature. Here, we report on a patient with neurofibromatosis type 1 and a history of spontaneous abortions presenting with sudden vision loss in the right eye and swelling of the optic nerve head. Fluorescein angiography indicated anterior ischemic optic neuropathy. Brain magnetic resonance imaging revealed findings consistent with left cavernous sinus meningioma. Serologic testing demonstrated persistently elevated anti-b2-glycoprotein antibodies. Her findings suggested antiphospholipid syndrome with concomitant clinical and laboratory evidence of antiphospholipid syndrome: frequent abortions, a vaso-occlusive episode, and persistently elevated antiphospholipid syndrome antibodies. To our knowledge, this case represents the first neuro-ophthalmic manifestation of antiphospholipid syndrome associated with neurofibromatosis type 1.


Asunto(s)
Síndrome Antifosfolípido/complicaciones , Neurofibromatosis 1/complicaciones , Aborto Espontáneo/etiología , Adulto , Síndrome Antifosfolípido/diagnóstico , Femenino , Angiografía con Fluoresceína/métodos , Humanos , Neurofibromatosis 1/diagnóstico , Tomografía de Coherencia Óptica/métodos
15.
Data Brief ; 21: 2395-2397, 2018 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-30547064

RESUMEN

The data set presented here is associated with the article "Intracellular calcium and NF-kB regulate hypoxia-induced leptin, VEGF, IL-6 and adiponectin secretion in human adipocytes" (Al-Anazi et al., 2018). Data illustrate hypoxia-induced VEGF and leptin expression in human adipocytes treated with the calcium chelator BAPTA-AM (1 µM). It also shows NF-κB p65 induced expression by hypoxia. Preadipocytes were differentiated for 14 days and then subjected to 0.5-1.5% oxygen in the presence and absence of BAPTA-AM or the NF-κB inhibitor SN50 for 48 h prior to RNA isolation and PCR analysis.

16.
Life Sci ; 212: 275-284, 2018 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-30308181

RESUMEN

AIMS: Hypoxia-induced adipokine release has been attributed mainly to HIF-1α. Here we investigate the role of intracellular calcium and NF-kB in the hypoxia-dependent release of leptin, VEGF, IL-6 and the hypoxia-induced inhibition of adiponectin release in human adipocytes. MAIN METHODS: We used intracellular calcium imaging to compare calcium status in preadipocytes and in adipocytes. We subjected both cell types to hypoxic conditions and measured the release of adipokines induced by hypoxia in the presence and absence of HIF-1α inhibitor YC-1, NF-κB inhibitor SN50 and intracellular calcium chelator BAPTA-AM. KEY FINDINGS: We demonstrate reduced intracellular calcium oscillations and increased oxidative stress as the cells transitioned from preadipocytes to adipocytes. We show that differentiation of preadipocytes to adipocytes is associated with distinct morphological changes in the mitochondria. We also show that hypoxia-induced secretion of leptin, VEGF, IL-6 and hypoxia-induced inhibition of adiponectin secretion are independent of HIF-1α expression. The hypoxia-induced leptin, VEGF and IL-6 release are [Ca++]i dependent whereas adiponectin is NF-kB dependent. SIGNIFICANCE: Our work suggests a major role for [Ca++]i in preadipocyte differentiation to adipocytes and that changes in mitochondrial morphology in the adipocytes might underlie the reduced calcium oscillations observed in the adipocytes. It also demonstrates that multiple signaling pathways are associated with the hypoxia-induced adipokine secretion.


Asunto(s)
Adipocitos/metabolismo , Adiponectina/metabolismo , Calcio/farmacología , Hipoxia/fisiopatología , Interleucina-6/metabolismo , Leptina/metabolismo , FN-kappa B/farmacología , Factor A de Crecimiento Endotelial Vascular/metabolismo , Adipocitos/citología , Adipocitos/efectos de los fármacos , Diferenciación Celular , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Transducción de Señal/efectos de los fármacos
17.
Front Immunol ; 9: 1384, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29973931

RESUMEN

Growing evidence indicates a link between persistent infections and the development of autoimmune diseases. For instance, the inability to control Salmonella infection due to defective toll-like receptor (TLR)/myeloid differentiation primary response 88 (MyD88) signaling has linked the development of persistent infections to a breakdown in B cell tolerance. However, the extent of immune dysregulation in the absence of TLR-MyD88 signaling remains poorly characterized. Here, we show that MyD88-/- mice are unable to eliminate attenuated Salmonella enterica serovar Typhimurium, even when challenged with a low-dose inoculum (200 CFUs/mouse), developing a persistent and progressive infection when compared to wild-type (MyD88+/+) animals. The splenic niche of MyD88-/- mice revealed increased counts of activated, Sca-1-positive, myeloid subpopulations highly expressing BAFF during persistent Salmonella infection. Likewise, the T cell compartment of Salmonella-infected MyD88-/- mice showed increased levels of CD4+ and CD8+ T cells expressing Sca-1 and CD25 and producing elevated amounts of IL-4, IL-10, and IL-21 in response to CD3/CD28 stimulation. This was associated with increased Tfh cell differentiation and the presence of CD4+ T cells co-expressing IFN-γ/IL-4 and IFN-γ/IL-10. Noteworthy, infected MyD88-/- mice had enhanced serum titers of both anti-Salmonella antibodies as well as autoantibodies directed against double-stranded DNA, thyroglobulin, and IgG rheumatoid factor, positive nuclear staining with HEp-2 cells, and immune complex deposition in the kidneys of MyD88-/- mice infected with live but not heat-killed Salmonella. Infection with other microorganisms (Acinetobacter baumanii, Streptococcus agalactiae, or Escherichia coli) was unable to trigger the autoimmune phenomenon. Our findings suggest that dysregulation of the immune response in the absence of MyD88 is pathogen-dependent and highlight potentially important genotype-environmental factor correlations.

20.
Int J Cardiol ; 186: 77-89, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25814349

RESUMEN

BACKGROUND: The molecular mechanisms underlying the geometrical changes of the left ventricle during the progression to heart failure and recovery are not well defined. OBJECTIVE: Here we investigate the involvement of matrixins and cardiokines in an ovine model of pressure-induced left ventricular failure (LVF). METHODS: Fifteen sheep underwent supracoronary aortic banding with an inflatable cuff. A controlled and progressive increase of LV pressure was monitored echocardiographically. Endomyocardial biopsies were collected throughout the development of LVF and subsequent recovery after pressure unloading. RESULTS: Thirteen sheep developed LVF with a subsequent recovery. Peak left ventricular hypertrophy (LVH) and dilatation (LVD) occurred at 31.5 ± 1.6 weeks and 102.7 ± 2.2 weeks post-banding respectively, with an increase in LV internal diameter in diastole (LVIDd 5.11 ± 0.12 compared to the control 3.37 ± 0.07 cm, p<0.001), with preserved LV ejection fraction (LVEF). Reduced LVEF became evident 116.5 ± 2.7 weeks post-banding. Clinical and echocardiographic improvements were observed following deflation of the aortic banding cuff. By 138.1 ± 3.1 weeks cardiac performance recovered with restoration of LVEF. Significant changes in the expression of matrix metalloproteinases (MMP)-1, -2, -3, vascular endothelial cell growth factor (VEGF), fibroblast growth factor (FGF)-2, interferon (INF)-α-2 and soluble CD40 ligand (sCD40L) were observed throughout the progression to failure and recovery. CONCLUSIONS: We used an ovine model to study reversible LV remodelling without interruption and found significant changes in matrixin and cardiokine expression during LV progression to failure and recovery.


Asunto(s)
Citocinas/genética , Regulación de la Expresión Génica , Insuficiencia Cardíaca/genética , Metaloproteinasas de la Matriz/genética , ARN/genética , Recuperación de la Función/fisiología , Remodelación Ventricular , Animales , Citocinas/biosíntesis , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/fisiopatología , Immunoblotting , Metaloproteinasas de la Matriz/biosíntesis , Reacción en Cadena en Tiempo Real de la Polimerasa , Ovinos , Oveja Doméstica
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