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1.
Microorganisms ; 12(2)2024 Jan 24.
Artículo en Inglés | MEDLINE | ID: mdl-38399646

RESUMEN

Orally administered compounds represent the great majority of all pharmaceutical compounds produced for human use and are the most popular among patients since they are practical and easy to self-administer. Following ingestion, orally administered drugs begin a "perilous" journey down the gastrointestinal tract and their bioavailability is modulated by numerous factors. The gastrointestinal (GI) tract anatomy can modulate drug bioavailability and accounts for interpatient drug response heterogeneity. Furthermore, host genetics is a contributor to drug bioavailability modulation. Importantly, a component of the GI tract that has been gaining notoriety with regard to drug treatment interactions is the gut microbiota, which shares a two-way interaction with pharmaceutical compounds in that they can be influenced by and are able to influence administered drugs. Overall, orally administered drugs are a patient-friendly treatment option. However, during their journey down the GI tract, there are numerous host factors that can modulate drug bioavailability in a patient-specific manner.

2.
PLoS One ; 16(7): e0248792, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34288921

RESUMEN

Whole genome sequencing of viral specimens following molecular diagnosis is a powerful analytical tool of molecular epidemiology that can critically assist in resolving chains of transmission, identifying of new variants or assessing pathogen evolution and allows a real-time view into the dynamics of a pandemic. In Cyprus, the first two cases of COVID-19 were identified on March 9, 2020 and since then 33,567 confirmed cases and 230 deaths were documented. In this study, viral whole genome sequencing was performed on 133 SARS-CoV-2 positive samples collected between March 2020 and January 2021. Phylogenetic analysis was conducted to evaluate the genomic diversity of circulating SARS-CoV-2 lineages in Cyprus. 15 different lineages were identified that clustered into three groups associated with the spring, summer and autumn/winter wave of SARS-CoV-2 incidence in Cyprus, respectively. The majority of the Cypriot samples belonged to the B.1.258 lineage first detected in September that spread rapidly and largely dominated the autumn/winter wave with a peak prevalence of 86% during the months of November and December. The B.1.1.7 UK variant (VOC-202012/01) was identified for the first time at the end of December and spread rapidly reaching 37% prevalence within one month. Overall, we describe the changing pattern of circulating SARS-CoV-2 lineages in Cyprus since the beginning of the pandemic until the end of January 2021. These findings highlight the role of importation of new variants through travel towards the emergence of successive waves of incidence in Cyprus and demonstrate the importance of genomic surveillance in determining viral genetic diversity and the timely identification of new variants for guiding public health intervention measures.


Asunto(s)
COVID-19/epidemiología , SARS-CoV-2/genética , Chipre/epidemiología , Humanos , Epidemiología Molecular , Filogenia , SARS-CoV-2/fisiología
3.
Microorganisms ; 10(1)2021 Dec 31.
Artículo en Inglés | MEDLINE | ID: mdl-35056533

RESUMEN

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has hit its second year and continues to damage lives and livelihoods across the globe. There continues to be a global effort to present serological data on SARS-CoV-2 antibodies in different individuals. As such, this study aimed to characterize the seroprevalence of SARS-CoV-2 antibodies in the Cypriot population for the first time since the pandemic started. Our results show that a majority of people infected with SARS-CoV-2 developed IgG antibodies against the virus, whether anti-NP, anti-S1RBD, or both, at least 20 days after their infection. Additionally, the percentage of people with at least one antibody against SARS-CoV-2 in the group of volunteers deemed SARS-CoV-2 negative via RT-PCR or who remain untested/undetermined (14.43%) is comparable to other reported percentages worldwide, ranging anywhere from 0.2% to 24%. We postulate that these percentages reflect the underreporting of true infections in the population, and also show the steady increase of herd immunity. Additionally, we showed a significantly marked decrease in anti-NP IgG antibodies in contrast to relatively stable levels of anti-S1RBD IgG antibodies in previously infected individuals across time.

4.
Cell ; 182(6): 1441-1459.e21, 2020 09 17.
Artículo en Inglés | MEDLINE | ID: mdl-32888430

RESUMEN

Throughout a 24-h period, the small intestine (SI) is exposed to diurnally varying food- and microbiome-derived antigenic burdens but maintains a strict immune homeostasis, which when perturbed in genetically susceptible individuals, may lead to Crohn disease. Herein, we demonstrate that dietary content and rhythmicity regulate the diurnally shifting SI epithelial cell (SIEC) transcriptional landscape through modulation of the SI microbiome. We exemplify this concept with SIEC major histocompatibility complex (MHC) class II, which is diurnally modulated by distinct mucosal-adherent SI commensals, while supporting downstream diurnal activity of intra-epithelial IL-10+ lymphocytes regulating the SI barrier function. Disruption of this diurnally regulated diet-microbiome-MHC class II-IL-10-epithelial barrier axis by circadian clock disarrangement, alterations in feeding time or content, or epithelial-specific MHC class II depletion leads to an extensive microbial product influx, driving Crohn-like enteritis. Collectively, we highlight nutritional features that modulate SI microbiome, immunity, and barrier function and identify dietary, epithelial, and immune checkpoints along this axis to be potentially exploitable in future Crohn disease interventions.


Asunto(s)
Enfermedad de Crohn/microbiología , Células Epiteliales/metabolismo , Microbioma Gastrointestinal , Antígenos de Histocompatibilidad Clase II/metabolismo , Intestino Delgado/inmunología , Intestino Delgado/microbiología , Transcriptoma/genética , Animales , Antibacterianos/farmacología , Relojes Circadianos/fisiología , Enfermedad de Crohn/inmunología , Enfermedad de Crohn/metabolismo , Dieta , Células Epiteliales/citología , Células Epiteliales/inmunología , Citometría de Flujo , Microbioma Gastrointestinal/efectos de los fármacos , Microbioma Gastrointestinal/genética , Perfilación de la Expresión Génica , Antígenos de Histocompatibilidad Clase II/genética , Homeostasis , Hibridación Fluorescente in Situ , Interleucina-10/metabolismo , Interleucina-10/farmacología , Intestino Delgado/fisiología , Linfocitos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Periodicidad , Linfocitos T/inmunología , Transcriptoma/fisiología
5.
J Pediatr Gastroenterol Nutr ; 69(6): 633-638, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31765333

RESUMEN

The human genome has been proposed to contribute to interpersonal variability in the way we respond to nutritional intake. However, personalized diets solely based on gene-nutrient interactions have not lived up to their expectations to date. Advances in microbiome research have indicated that a science-based generation of a personalized diet based on a combination of clinical and microbial features may constitute a promising new approach enabling accurate prediction of dietary responses. In addition, scientific advances in our understanding of defined dietary components and their effects on human physiology led to the incorporation and testing of defined diets as preventive and treatment approaches for diseases, such as epilepsy, ulcerative colitis, Crohn disease, and type 1 diabetes mellitus. Additionally, exciting new studies show that tailored diet regiments have the potential to modulate pharmaceutical treatment efficacy in cancer treatment. Overall, the true therapeutic potential of nutritional interventions is coming to light but is also facing substantial challenges in understanding mechanisms of activity, optimization of dietary interventions for specific human subpopulations, and elucidation of adverse effects potentially stemming from some dietary components in a number of individuals.


Asunto(s)
Microbiota , Nutrigenómica/métodos , Medicina de Precisión/métodos , Diabetes Mellitus Tipo 1/dietoterapia , Diabetes Mellitus Tipo 1/microbiología , Epilepsia/dietoterapia , Epilepsia/microbiología , Humanos , Enfermedades Inflamatorias del Intestino/dietoterapia , Enfermedades Inflamatorias del Intestino/microbiología , Neoplasias/dietoterapia , Neoplasias/microbiología , Terapia Nutricional/métodos , Obesidad Infantil/dietoterapia , Obesidad Infantil/microbiología
6.
Nature ; 572(7770): 474-480, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31330533

RESUMEN

Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disorder, in which the clinical manifestations may be influenced by genetic and unknown environmental factors. Here we show that ALS-prone Sod1 transgenic (Sod1-Tg) mice have a pre-symptomatic, vivarium-dependent dysbiosis and altered metabolite configuration, coupled with an exacerbated disease under germ-free conditions or after treatment with broad-spectrum antibiotics. We correlate eleven distinct commensal bacteria at our vivarium with the severity of ALS in mice, and by their individual supplementation into antibiotic-treated Sod1-Tg mice we demonstrate that Akkermansia muciniphila (AM) ameliorates whereas Ruminococcus torques and Parabacteroides distasonis exacerbate the symptoms of ALS. Furthermore, Sod1-Tg mice that are administered AM are found to accumulate AM-associated nicotinamide in the central nervous system, and systemic supplementation of nicotinamide improves motor symptoms and gene expression patterns in the spinal cord of Sod1-Tg mice. In humans, we identify distinct microbiome and metabolite configurations-including reduced levels of nicotinamide systemically and in the cerebrospinal fluid-in a small preliminary study that compares patients with ALS with household controls. We suggest that environmentally driven microbiome-brain interactions may modulate ALS in mice, and we call for similar investigations in the human form of the disease.


Asunto(s)
Esclerosis Amiotrófica Lateral/microbiología , Esclerosis Amiotrófica Lateral/fisiopatología , Microbioma Gastrointestinal/fisiología , Niacinamida/metabolismo , Akkermansia , Esclerosis Amiotrófica Lateral/metabolismo , Esclerosis Amiotrófica Lateral/patología , Animales , Antibacterianos/farmacología , Modelos Animales de Enfermedad , Disbiosis , Femenino , Microbioma Gastrointestinal/efectos de los fármacos , Vida Libre de Gérmenes , Humanos , Longevidad , Masculino , Ratones , Ratones Transgénicos , Niacinamida/biosíntesis , Superóxido Dismutasa-1/genética , Superóxido Dismutasa-1/metabolismo , Tasa de Supervivencia , Simbiosis/efectos de los fármacos , Verrucomicrobia/metabolismo , Verrucomicrobia/fisiología
7.
Cell ; 174(6): 1388-1405.e21, 2018 09 06.
Artículo en Inglés | MEDLINE | ID: mdl-30193112

RESUMEN

Empiric probiotics are commonly consumed by healthy individuals as means of life quality improvement and disease prevention. However, evidence of probiotic gut mucosal colonization efficacy remains sparse and controversial. We metagenomically characterized the murine and human mucosal-associated gastrointestinal microbiome and found it to only partially correlate with stool microbiome. A sequential invasive multi-omics measurement at baseline and during consumption of an 11-strain probiotic combination or placebo demonstrated that probiotics remain viable upon gastrointestinal passage. In colonized, but not germ-free mice, probiotics encountered a marked mucosal colonization resistance. In contrast, humans featured person-, region- and strain-specific mucosal colonization patterns, hallmarked by predictive baseline host and microbiome features, but indistinguishable by probiotics presence in stool. Consequently, probiotics induced a transient, individualized impact on mucosal community structure and gut transcriptome. Collectively, empiric probiotics supplementation may be limited in universally and persistently impacting the gut mucosa, meriting development of new personalized probiotic approaches.


Asunto(s)
Microbioma Gastrointestinal , Probióticos/administración & dosificación , Adolescente , Adulto , Anciano , Animales , Bacterias/genética , Bacterias/aislamiento & purificación , Heces/microbiología , Femenino , Mucosa Gástrica/microbiología , Humanos , Mucosa Intestinal/microbiología , Masculino , Metagenómica , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Efecto Placebo , Análisis de Componente Principal , ARN Ribosómico 16S/genética , ARN Ribosómico 16S/metabolismo , Transcriptoma , Adulto Joven
8.
Cell ; 174(6): 1406-1423.e16, 2018 09 06.
Artículo en Inglés | MEDLINE | ID: mdl-30193113

RESUMEN

Probiotics are widely prescribed for prevention of antibiotics-associated dysbiosis and related adverse effects. However, probiotic impact on post-antibiotic reconstitution of the gut mucosal host-microbiome niche remains elusive. We invasively examined the effects of multi-strain probiotics or autologous fecal microbiome transplantation (aFMT) on post-antibiotic reconstitution of the murine and human mucosal microbiome niche. Contrary to homeostasis, antibiotic perturbation enhanced probiotics colonization in the human mucosa but only mildly improved colonization in mice. Compared to spontaneous post-antibiotic recovery, probiotics induced a markedly delayed and persistently incomplete indigenous stool/mucosal microbiome reconstitution and host transcriptome recovery toward homeostatic configuration, while aFMT induced a rapid and near-complete recovery within days of administration. In vitro, Lactobacillus-secreted soluble factors contributed to probiotics-induced microbiome inhibition. Collectively, potential post-antibiotic probiotic benefits may be offset by a compromised gut mucosal recovery, highlighting a need of developing aFMT or personalized probiotic approaches achieving mucosal protection without compromising microbiome recolonization in the antibiotics-perturbed host.


Asunto(s)
Antibacterianos/farmacología , Microbioma Gastrointestinal/efectos de los fármacos , Probióticos/administración & dosificación , Adolescente , Adulto , Anciano , Animales , Trasplante de Microbiota Fecal , Heces/microbiología , Femenino , Humanos , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/microbiología , Lactobacillus/efectos de los fármacos , Lactobacillus/genética , Lactobacillus/aislamiento & purificación , Lactococcus/genética , Lactococcus/aislamiento & purificación , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , ARN Ribosómico 16S/análisis , ARN Ribosómico 16S/genética , ARN Ribosómico 16S/metabolismo , Adulto Joven
9.
Curr Opin Biotechnol ; 51: 57-63, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29223004

RESUMEN

Generalized dietary and lifestyle guidelines have been formulated and published for decades now from a variety of relevant agencies in an attempt to guide people towards healthy choices. As the pandemic rise in metabolic diseases continues to increase, it has become clear that the one-fit-for-all diet approach does not work and that there is a significant variation in inter-individual responses to diet and lifestyle interventions. Recent technological advances have given an unprecedented insight into the sources of this variation, pointing towards our genome and microbiome as potentially and previously under-explored culprits contributing to individually unique dietary responses. Variations in our genome influence the bioavailability and metabolism of nutrients between individuals, while inter-individual compositional variation of commensal gut microbiota leads to different microbe functional potential, metabolite production and metabolism modulation. Quantifying and incorporating these factors into a comprehensive personalized nutrition approach may enable practitioners to rationally incorporate individual nutritional recommendations in combating the metabolic syndrome pandemic.


Asunto(s)
Microbioma Gastrointestinal/genética , Genoma Humano , Síndrome Metabólico/prevención & control , Microbiota , Terapia Nutricional , Medicina de Precisión , Dieta , Humanos , Estilo de Vida , Nutrigenómica
10.
Semin Immunol ; 32: 74-81, 2017 08.
Artículo en Inglés | MEDLINE | ID: mdl-28431920

RESUMEN

The commensal microbiome constitutes an important modulator of host physiology and risk of disease, including cancer development and progression. Lately, the microbiome has been suggested to modulate the efficacy of anti-cancer treatment. Examples include chemotherapy and total body irradiation-induced barrier function disruption, leading to microbial efflux that drives activation of anti-tumorigenic T cells; Microbiome-driven release of reactive oxygen species contributing to the efficacy of platinum salts; and microbiome-induced immune priming promoting the anti-tumor effects of alkylating chemotherapy and immune checkpoint inhibitors. Furthermore, selected commensals are able to colonize solid tumors. This 'tumor microbiome' may further impact local tumor responses to treatment and potentially be harnessed for tumor-specific targeting and therapeutic delivery. In this review, we present recent advances in understanding of the intricate role of microbiome in modulating efficacy of a number of anti-cancer treatments, and discuss how anti-cancer treatment approaches utilizing the tumor microbiome may enhance oncological treatment efficacy.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos Alquilantes/uso terapéutico , Inmunomodulación , Inmunoterapia/métodos , Microbiota/inmunología , Neoplasias/microbiología , Neoplasias/terapia , Animales , Carcinogénesis , Receptores Coestimuladores e Inhibidores de Linfocitos T/inmunología , Humanos , Neoplasias/inmunología , Simbiosis , Resultado del Tratamiento
11.
Cell Metab ; 25(3): 506-521, 2017 03 07.
Artículo en Inglés | MEDLINE | ID: mdl-28273474

RESUMEN

In addition to the immune system's traditional roles of conferring anti-infectious and anti-neoplastic protection, it has been recently implicated in the regulation of systemic metabolic homeostasis. This cross-talk between the immune and the metabolic systems is pivotal in promoting "metabolic health" throughout the life of an organism and plays fundamental roles in its adaptation to ever-changing environmental makeups and nutritional availability. Perturbations in this intricate immune-metabolic cross-talk contribute to the tendency to develop altered metabolic states that may culminate in metabolic disorders such as malnutrition, obesity, type 2 diabetes mellitus (T2DM), and other features of the metabolic syndrome. Regulators of immune-metabolic interactions include host genetics, nutritional status, and the intestinal microbiome. In this Perspective, we highlight current understanding of immune-metabolism interactions, illustrate differences among individuals and between populations in this respect, and point toward future avenues of research possibly enabling immune harnessing as means of personalized treatment for common metabolic disorders.


Asunto(s)
Salud , Enfermedades Metabólicas/inmunología , Envejecimiento/fisiología , Animales , Humanos , Enfermedades Metabólicas/genética , Microbiota , Modelos Biológicos , Investigación Biomédica Traslacional
12.
Mol Metab ; 5(9): 782-94, 2016 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-27617201

RESUMEN

BACKGROUND: Non-alcoholic fatty liver (NAFLD) is a common, multi-factorial, and poorly understood liver disease whose incidence is globally rising. NAFLD is generally asymptomatic and associated with other manifestations of the metabolic syndrome. Yet, up to 25% of NAFLD patients develop a progressive inflammatory liver disease termed non-alcoholic steatohepatitis (NASH) that may progress towards cirrhosis, hepatocellular carcinoma, and the need for liver transplantation. In recent years, several lines of evidence suggest that the gut microbiome represents a significant environmental factor contributing to NAFLD development and its progression into NASH. Suggested microbiome-associated mechanisms contributing to NAFLD and NASH include dysbiosis-induced deregulation of the gut endothelial barrier function, which facilitates systemic bacterial translocation, and intestinal and hepatic inflammation. Furthermore, increased microbiome-modulated metabolites such as lipopolysaccharides, short chain fatty acids (SCFAs), bile acids, and ethanol, may affect liver pathology through multiple direct and indirect mechanisms. SCOPE OF REVIEW: Herein, we discuss the associations, mechanisms, and clinical implications of the microbiome's contribution to NAFLD and NASH. Understanding these contributions to the development of fatty liver pathogenesis and its clinical course may serve as a basis for development of therapeutic microbiome-targeting approaches for treatment and prevention of NAFLD and NASH. MAJOR CONCLUSIONS: Intestinal host-microbiome interactions play diverse roles in the pathogenesis and progression of NAFLD and NASH. Elucidation of the mechanisms driving these microbial effects on the pathogenesis of NAFLD and NASH may enable to identify new diagnostic and therapeutic targets of these common metabolic liver diseases. This article is part of a special issue on microbiota.

13.
BMC Med ; 14(1): 83, 2016 06 03.
Artículo en Inglés | MEDLINE | ID: mdl-27256449

RESUMEN

HIV/AIDS causes severe dysfunction of the immune system through CD4+ T cell depletion, leading to dysregulation of both the adaptive and innate immune arms. A primary target for viral infection is the gastrointestinal tract, which is a reservoir of CD4+ T cells. In addition to being a major immune hub, the human gastrointestinal tract harbors trillions of commensal microorganisms, the microbiota, which have recently been shown to play critical roles in health. Alterations in the composition and function of microbiota have been implicated in a variety of 'multi-factorial' disorders, including infectious, autoimmune, metabolic, and neoplastic disorders. It is widely accepted that, in addition to its direct role in altering the gastrointestinal CD4+ T cell compartment, HIV infection is characterized by gut microbiota compositional and functional changes. Herein, we review such alterations and discuss their potential local and systemic effects on the HIV-positive host, as well as potential roles of novel microbiota-targeting treatments in modulating HIV progression and associated adverse systemic manifestations.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Microbioma Gastrointestinal/inmunología , Infecciones por VIH/microbiología , Linfocitos T CD4-Positivos/microbiología , Infecciones por VIH/virología , Humanos
14.
Bioinform Biol Insights ; 10: 19-25, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27127406

RESUMEN

The human intestinal microbiome is a microbial ecosystem that expresses as many as 100 times more genes than the human host, thereby constituting an important component of the human holobiome, which contributes to multiple health and disease processes. As most commensal species are difficult or impossible to culture, genomic characterization of microbiome composition and function, under various environmental conditions, comprises a central tool in understanding its roles in health and disease. The first decade of microbiome research was mainly characterized by usage of DNA sequencing-based 16S rDNA and shotgun metagenome sequencing, allowing for the elucidation of microbial composition and genome structure. Technological advances in RNA-seq have recently provided us with an ability to gain insight into the genes that are actively expressed in complex bacterial communities, enabling the elucidation of the functional changes that dictate the microbiome functions at given contexts, its interactions with the host, and functional alterations that accompany the conversion of a healthy microbiome toward a disease-driving configuration. Here, we highlight some of the key metatranscriptomics strategies that are implemented to determine microbiota gene expression and its regulation and discuss the advantages and potential challenges associated with these approaches.

15.
Proc Natl Acad Sci U S A ; 113(17): E2421-9, 2016 Apr 26.
Artículo en Inglés | MEDLINE | ID: mdl-27035961

RESUMEN

Inherited demyelinating peripheral neuropathies are progressive incurable diseases without effective treatment. To develop a gene therapy approach targeting myelinating Schwann cells that can be translatable, we delivered a lentiviral vector using a single lumbar intrathecal injection and a myelin-specific promoter. The human gene of interest, GJB1, which is mutated in X-linked Charcot-Marie-Tooth Disease (CMT1X), was delivered intrathecally into adult Gjb1-null mice, a genetically authentic model of CMT1X that develops a demyelinating peripheral neuropathy. We obtained widespread, stable, and cell-specific expression of connexin32 in up to 50% of Schwann cells in multiple lumbar spinal roots and peripheral nerves. Behavioral and electrophysiological analysis revealed significantly improved motor performance, quadriceps muscle contractility, and sciatic nerve conduction velocities. Furthermore, treated mice exhibited reduced numbers of demyelinated and remyelinated fibers and fewer inflammatory cells in lumbar motor roots, as well as in the femoral motor and sciatic nerves. This study demonstrates that a single intrathecal lentiviral gene delivery can lead to Schwann cell-specific expression in spinal roots extending to multiple peripheral nerves. This clinically relevant approach improves the phenotype of an inherited neuropathy mouse model and provides proof of principle for treating inherited demyelinating neuropathies.


Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Enfermedades Desmielinizantes/genética , Animales , Terapia Genética , Humanos , Vaina de Mielina/metabolismo , Células de Schwann/metabolismo
16.
Cell Metab ; 23(3): 393-4, 2016 Mar 08.
Artículo en Inglés | MEDLINE | ID: mdl-26959178

RESUMEN

Malnutrition is a global health burden affecting the development of millions of children worldwide, but the effects of current treatment strategies are modest. Charbonneau et al. (2016) identify sialylated oligosaccharides in breast milk as microbiota-dependent growth-promoting metabolites, paving the way for a new rational treatment of severe infant stunting.


Asunto(s)
Desarrollo Infantil , Desnutrición/dietoterapia , Leche Humana/química , Leche/química , Oligosacáridos/metabolismo , Animales , Humanos , Masculino
17.
Ann Neurol ; 78(2): 303-16, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-26010264

RESUMEN

OBJECTIVE: X-linked Charcot-Marie-Tooth disease (CMT1X) is a common inherited neuropathy caused by mutations in the GJB1 gene encoding the gap junction protein connexin32 (Cx32). Clinical studies and disease models indicate that neuropathy mainly results from Schwann cell autonomous, loss-of-function mechanisms; therefore, CMT1X may be treatable by gene replacement. METHODS: A lentiviral vector LV.Mpz-GJB1 carrying the GJB1 gene under the Schwann cell-specific myelin protein zero (Mpz) promoter was generated and delivered into the mouse sciatic nerve by a single injection immediately distal to the sciatic notch. Enhanced green fluorescent protein (EGFP) reporter gene expression was quantified and Cx32 expression was examined on a Cx32 knockout (KO) background. A gene therapy trial was performed in a Cx32 KO model of CMT1X. RESULTS: EGFP was expressed throughout the length of the sciatic nerve in up to 50% of Schwann cells starting 2 weeks after injection and remaining stable for up to 16 weeks. Following LV.Mpz-GJB1 injection into Cx32 KO nerves, we detected Cx32 expression and correct localization in non-compact myelin areas where gap junctions are normally formed. Gene therapy trial by intraneural injection in groups of 2-month-old Cx32 KO mice, before demyelination onset, significantly reduced the ratio of abnormally myelinated fibers (p = 0.00148) and secondary inflammation (p = 0.0178) at 6 months of age compared to mock-treated animals. INTERPRETATION: Gene delivery using a lentiviral vector leads to efficient gene expression specifically in Schwann cells. Restoration of Cx32 expression ameliorates nerve pathology in a disease model and provides a promising approach for future treatments of CMT1X and other inherited neuropathies.


Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Conexinas/genética , ARN Mensajero/metabolismo , Células de Schwann/metabolismo , Nervio Ciático/metabolismo , Animales , Enfermedad de Charcot-Marie-Tooth/metabolismo , Modelos Animales de Enfermedad , Terapia Genética , Vectores Genéticos , Lentivirus , Ratones , Ratones Noqueados , Proteína beta1 de Unión Comunicante
18.
J Gene Med ; 16(11-12): 364-73, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25394283

RESUMEN

BACKGROUND: Most leukodystrophies result from mutations in genes expressed in oligodendrocytes that may cause autonomous loss of function of cell structural proteins. Therefore, effective gene delivery to oligodendrocytes is necessary to develop future treatments. MATERIALS: To achieve this, we cloned a lentiviral vector in which the enhanced green fluorescent protein (EGFP) expression was driven by the oligodendrocyte specific 2,3-cyclic nucleotide 3-phosphodiesterase promoter. The vector was inserted into C57BL/6 neonatal mouse brain by combined intraventricular and parenchymal injections. RESULTS: Assessment of EGFP expression revealed a widespread distribution, specifically in cells of the oligodendrocyte linage, starting from postnatal day 6 (P6) in the subventricular zone and spreading through migrating oligodendrocyte precursors. By P30, it was detectable throughout the brain and persisted for at least 3 months, showing an increase both in the number of expressing cells and in intensity over time. EGFP expression was restricted to oligodendrocyte linage cells. On average, 20.3 ± 2.56% of all oligodendrocytes in different central nervous system areas were EGFP-positive, with regional variations. CONCLUSIONS: Lentiviral gene delivery using an oligodendrocyte-specific promoter may achieve widespread and long-lasting expression selectively in oligodendrocytes, offering a possibility for gene therapy in certain leukodystrophies, although the relatively low rates of oligodendrocyte transduction are a limitation that remains to be overcome.


Asunto(s)
Terapia Genética , Lentivirus/genética , Oligodendroglía/metabolismo , Animales , Encéfalo/metabolismo , Técnicas de Cocultivo , Femenino , Expresión Génica , Vectores Genéticos , Proteínas Fluorescentes Verdes/biosíntesis , Proteínas Fluorescentes Verdes/genética , Masculino , Ratones Endogámicos C57BL , Células PC12 , Ratas , Nervio Ciático/metabolismo
19.
BMC Pediatr ; 14: 6, 2014 Jan 13.
Artículo en Inglés | MEDLINE | ID: mdl-24410941

RESUMEN

BACKGROUND: Erythema infectiosum is the most common clinical manifestation of Parvovirus B19 infection although it has also been associated with rheumatologic diseases and various types of systemic vasculitides. Acute hepatitis and benign myositis however are rarely reported in association with Parvovirus B19 infection. CASE PRESENTATION: Here we report a 14-year old male, who developed acute hepatitis and benign myositis associated with erythema infectiosum following Parvovirus B19 infection. CONCLUSION: Parvovirus B19 infection has rarely been associated with acute hepatitis and exceptionally rarely with benign myositis. Parvovirus B19 should be considered in the differential diagnosis of acute non-A to E hepatitis and in the case of acute benign myositis presenting with a rash especially in children.


Asunto(s)
Eritema Infeccioso , Hepatitis/virología , Miositis/virología , Enfermedad Aguda , Adolescente , Hepatitis/complicaciones , Humanos , Masculino , Miositis/complicaciones , Parvovirus B19 Humano
20.
J Infect Dev Ctries ; 7(9): 642-50, 2013 Sep 16.
Artículo en Inglés | MEDLINE | ID: mdl-24042099

RESUMEN

INTRODUCTION: The prevalence of H. pylori varies with geographic locations. To date there are no epidemiological data on its prevalence in Cyprus; therefore, we determined the prevalence and molecular characteristics of H. pylori infection in Cypriot patients. METHODOLOGY: DNA extracted from 103 gastric biopsies was analyzed for the presence of H. pylori by PCR using primers for ureA. H. pylori-positive biopsies were characterized by PCR using specific primers for cagA and vacA genes. The presence of clarithromycin-associated resistant mutations such as A2143G, A2142G, A2142C in 23S rRNA gene of H. pylori-positive patients was determined using a real-time PCR allelic discrimination assay. RESULTS: H. pylori was detected in 41 (39.8%) biopsies and, out of these, 17 (41.5%) tested positive for the cagA gene. The vacA alleles m1, m2, s1a, s1b, and s2 were detected in 7 (17.1%), 34 (82.9%), 12 (29.3%), 2 (4.9%), and 22 (53.7%) isolates, respectively. One (2.4%) biopsy was vacA s1a and s2-positive while one (2.4%) was positive for vacA s1a, s1b, and s2. Three (7.3%) biopsies were untypable for vacA s1, s1b, and s2. The majority (35; 85.4%) of strains were susceptible to clarithromycin while two (4.9%) had the A2143G mutation. Three (7.3%) had a mixture of an A2143G point mutant and susceptible strains while one (2.4%) had a mixture of an A2142G point mutant and susceptible strains. CONCLUSIONS: The distribution of the virulence factors cagA and vacA in the Cypriot strains resembled that of strains circulating in Middle Eastern countries geographically close to Cyprus.


Asunto(s)
Antígenos Bacterianos/genética , Proteínas Bacterianas/genética , Infecciones por Helicobacter/epidemiología , Infecciones por Helicobacter/microbiología , Helicobacter pylori/genética , Factores de Virulencia/genética , Adulto , Antibacterianos/farmacología , Biopsia , Claritromicina/farmacología , Chipre/epidemiología , ADN Bacteriano/genética , ADN Bacteriano/aislamiento & purificación , Farmacorresistencia Bacteriana , Mucosa Gástrica/microbiología , Helicobacter pylori/aislamiento & purificación , Humanos , Filogeografía , Mutación Puntual , Prevalencia , ARN Ribosómico 23S/genética , Ureasa/genética
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