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Structure-activity studies of 4-substituted-2,5-dimethoxyphenethylamines led to the discovery of 2,5-dimethoxy-4-thiotrifluoromethylphenethylamines, including CYB210010, a potent and long-acting serotonin 5-HT2 receptor agonist. CYB210010 exhibited high agonist potency at 5-HT2A and 5-HT2C receptors, modest selectivity over 5-HT2B, 5-HT1A, 5-HT6, and adrenergic α2A receptors, and lacked activity at monoamine transporters and over 70 other proteins. CYB210010 (0.1-3 mg/kg) elicited a head-twitch response (HTR) and could be administered subchronically at threshold doses without behavioral tolerance. CYB210010 was orally bioavailable in three species, readily and preferentially crossed into the CNS, engaged frontal cortex 5-HT2A receptors, and increased the expression of genes involved in neuroplasticity in the frontal cortex. CYB210010 represents a new tool molecule for investigating the therapeutic potential of 5-HT2 receptor activation. In addition, several other compounds with high 5-HT2A receptor potency, yet with little or no HTR activity, were discovered, providing the groundwork for the development of nonpsychedelic 5-HT2A receptor ligands.
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Fenetilaminas , Agonistas del Receptor de Serotonina 5-HT2 , Relación Estructura-Actividad , Animales , Humanos , Fenetilaminas/farmacología , Fenetilaminas/química , Fenetilaminas/síntesis química , Administración Oral , Agonistas del Receptor de Serotonina 5-HT2/farmacología , Agonistas del Receptor de Serotonina 5-HT2/química , Agonistas del Receptor de Serotonina 5-HT2/síntesis química , Masculino , Disponibilidad Biológica , Ratas , Ratones , Ratas Sprague-Dawley , Descubrimiento de Drogas , Receptores de Serotonina 5-HT2/metabolismo , Receptor de Serotonina 5-HT2A/metabolismoRESUMEN
There are no approved pharmacotherapies for fragile X syndrome (FXS), a rare neurodevelopmental disorder caused by a mutation in the FMR1 promoter region that leads to various symptoms, including intellectual disability and auditory hypersensitivity. The gene that encodes inhibitory serotonin 1A receptors (5-HT1ARs) is differentially expressed in embryonic brain tissue from individuals with FXS, and 5-HT1ARs are highly expressed in neural systems that are disordered in FXS, providing a rationale to focus on 5-HT1ARs as targets to treat symptoms of FXS. We examined agonist-labeled 5-HT1AR densities in male and female Fmr1 knockout mice and found no differences in whole-brain 5-HT1AR expression in adult control compared to Fmr1 knockout mice. However, juvenile Fmr1 knockout mice had lower whole-brain 5-HT1AR expression than age-matched controls. Consistent with these results, juvenile Fmr1 knockout mice showed reduced behavioral responses elicited by the 5-HT1AR agonist (R)-8-OH-DPAT, effects blocked by the selective 5-HT1AR antagonist, WAY-100635. Also, treatment with the selective 5-HT1AR agonist, NLX-112, dose-dependently prevented audiogenic seizures (AGS) in juvenile Fmr1 knockout mice, an effect reversed by WAY-100635. Suggestive of a potential role for 5-HT1ARs in regulating AGS, compared to males, female Fmr1 knockout mice had a lower prevalence of AGS and higher expression of antagonist-labeled 5-HT1ARs in the inferior colliculus and auditory cortex. These results provide preclinical support that 5-HT1AR agonists may be therapeutic for young individuals with FXS hypersensitive to auditory stimuli.
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Epilepsia Refleja , Síndrome del Cromosoma X Frágil , Colículos Inferiores , Animales , Femenino , Masculino , Ratones , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/metabolismo , Síndrome del Cromosoma X Frágil/tratamiento farmacológico , Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/metabolismo , Colículos Inferiores/metabolismo , Ratones Noqueados , Receptor de Serotonina 5-HT1A/genética , Receptor de Serotonina 5-HT1A/metabolismo , SerotoninaRESUMEN
The persistent morbidity and mortality associated with tuberculosis (TB), despite our continued efforts, has been long recognized, and the rise in the incidence of drug-resistant TB adds to the preexisting concern. The bulk of the TB burden is confined to low-income countries, and rigorous efforts are made to detect, notify, and systematically treat TB. Efforts have been infused with renewed vigor and determination by the World Health Organization (WHO) to eliminate tuberculosis in the near future. Different health agencies worldwide are harvesting all possible strategies apart from consolidating ongoing practices, including prevention of the development of active disease by treating latent TB infection (LTBI). The guidelines for the same were already provided by the WHO and were then adapted in the Indian guidelines for the treatment of LTBI in 2021. While the long-term impact of TBI treatment is awaited, in this article, we aim to discuss the implications in the Indian context.
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The serotonergic psychedelic psilocybin shows efficacy in treating neuropsychiatric disorders, though the mechanism(s) underlying its therapeutic effects remain unclear. We show that a similar psychedelic tryptamine, N,N-dipropyltryptamine (DPT), completely prevents audiogenic seizures (AGS) in an Fmr1 knockout mouse model of fragile X syndrome at a 10 mg/kg dose but not at lower doses (3 or 5.6 mg/kg). Despite showing in vitro that DPT is a serotonin 5-HT2A, 5-HT1B, and 5-HT1A receptor agonist (with that rank order of functional potency, determined with TRUPATH Gα/ßγ biosensors), pretreatment with selective inhibitors of 5-HT2A/2C, 5-HT1B, or 5-HT1A receptors did not block DPT's antiepileptic effects; a pan-serotonin receptor antagonist was also ineffective. Because 5-HT1A receptor activation blocks AGS in Fmr1 knockout mice, we performed a dose-response experiment to evaluate DPT's engagement of 5-HT1A receptors in vivo. DPT elicited 5-HT1A-dependent effects only at doses greater than 10 mg/kg, further supporting that DPT's antiepileptic effects were not 5-HT1A-mediated. We also observed that the selective sigma1 receptor antagonist, NE-100, did not impact DPT's antiepileptic effects, suggesting DPT engagement of sigma1 receptors was not a crucial mechanism. Separately, we observed that DPT and NE-100 at high doses caused convulsions on their own that were qualitatively distinct from AGS. In conclusion, DPT dose-dependently blocked AGS in Fmr1 knockout mice, but neither serotonin nor sigma1 receptor antagonists prevented this action. Thus, DPT might have neurotherapeutic effects independent of its serotonergic psychedelic properties. However, DPT also caused seizures at high doses, showing that DPT has complex dose-dependent in vivo polypharmacology.
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Maintenance of redox balance plays central roles in a plethora of signaling processes. Although physiological levels of reactive oxygen and nitrogen species are crucial for functioning of certain signaling pathways, excessive production of free radicals and oxidants can damage cell components. The nuclear factor erythroid 2-related factor 2 (Nrf2) signaling cascade is the key pathway that mediates cellular response to oxidative stress. It is controlled at multiple levels, which serve to maintain redox homeostasis within cells. We show here that inositol polyphosphate multikinase (IPMK) is a modulator of Nrf2 signaling. IPMK binds Nrf2 and attenuates activation and expression of Nrf2 target genes. Furthermore, depletion of IPMK leads to elevated glutathione and cysteine levels, resulting in increased resistance to oxidants. Accordingly, targeting IPMK may restore redox balance under conditions of cysteine and glutathione insufficiency.
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Prenatal Zika virus (ZIKV) infection is a serious global concern as it can lead to brain injury and many serious birth defects, collectively known as congenital Zika syndrome. Brain injury likely results from viral mediated toxicity in neural progenitor cells. Additionally, postnatal ZIKV infections have been linked to neurological complications, yet the mechanisms driving these manifestations are not well understood. Existing data suggest that the ZIKV envelope protein can persist in the central nervous system for extended periods of time, but it is unknown if this protein can independently contribute to neuronal toxicity. Here we find that the ZIKV envelope protein is neurotoxic, leading to overexpression of poly adenosine diphosphate -ribose polymerase 1, which can induce parthanatos. Together, these data suggest that neuronal toxicity resulting from the envelope protein may contribute to the pathogenesis of post-natal ZIKV-related neurologic complications.
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Lesiones Encefálicas , Enfermedades del Sistema Nervioso , Síndromes de Neurotoxicidad , Infección por el Virus Zika , Virus Zika , Embarazo , Femenino , Humanos , Virus Zika/metabolismo , Infección por el Virus Zika/complicaciones , Infección por el Virus Zika/patología , Proteínas del Envoltorio Viral/metabolismo , Neuronas/patologíaRESUMEN
Tuberculosis has been afflicting mankind since times immemorial and yet can still present itself in such a disguised manner that even the bests of experts may be duped. Any site from head to toe can be affected but certain sites are far less common than the others. We came across three inconspicuous manifestations at atypical sites-parapharyngeal abscess, wrist joint and foot ulcer. No other primary site could be identified in any case. Two cases were diagnosed microbiologically and one with radiological evidence. All the three cases were medically managed and depicted positive response.
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Tuberculosis de la Columna Vertebral , Humanos , Tuberculosis de la Columna Vertebral/diagnóstico , Tomografía Computarizada por Rayos X , Absceso/diagnóstico , RadiografíaRESUMEN
BACKGROUND AND OBJECTIVES: Interstitial lung diseases (ILDs) are a varied group of disorders that have been clubbed together due to some common attributes. The data is abundant from the developed world. However, the developing countries have gradually amassed the knowledge of these disorders and epidemiological data is still missing. We aimed to profile the ILD patients at our center. METHODS: All ILD patients above the age of 14 years were included in the study. A detailed history, examination, exercise capacity assessment, pulmonary function test and relevant serological investigations were done. Tissue was obtained wherever possible. Diagnosis was made after discussion from concerned specialists. RESULTS: Among the total 884 subjects recruited, 54% were females with a mean age of 53 years. Most were residents of rural areas. Reticulations and traction bronchiectasis was seen in most subjects. Hypersensitivity pneumonitis was present in 35.9% and connective-tissue disease related ILD (CTD-ILD) in 30.9%. CONCLUSION: Most common ILDs at our center are hypersensitivity pneumonitis and CTD-ILD. Reticulations and traction bronchiectasis are the most common findings on HRCT thorax.
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Alveolitis Alérgica Extrínseca , Bronquiectasia , Enfermedades Pulmonares Intersticiales , Femenino , Humanos , Persona de Mediana Edad , Adolescente , Masculino , Centros de Atención Terciaria , Enfermedades Pulmonares Intersticiales/diagnóstico , Enfermedades Pulmonares Intersticiales/epidemiología , Bronquiectasia/epidemiología , India/epidemiologíaRESUMEN
Insulin resistance and impaired lipoprotein metabolism contribute to a plethora of metabolic and cardiovascular disorders. These alterations have been extensively linked with poor lifestyle choices, such as consumption of a high-fat diet, smoking, stress, and a redundant lifestyle. Moreover, these are also known to increase the co-morbidity of diseases like Type 2 diabetes mellitus and atherosclerosis. Under normal physiological conditions, insulin and lipoproteins exert a neuroprotective role in the central nervous system. However, the tripping of balance between the periphery and center may alter the normal functioning of the brain and lead to neurological disorders such as Alzheimer's disease, Parkinson's disease, stroke, depression, and multiple sclerosis. These neurological disorders are further characterized by certain behavioral and molecular changes that show consistent overlap with alteration in insulin and lipoprotein signaling pathways. Therefore, targeting these two mechanisms not only reveals a way to manage the co-morbidities associated with the circle of the metabolic, central nervous system, and cardiovascular disorders but also exclusively work as a disease-modifying therapy for neurological disorders. In this review, we summarize the role of insulin resistance and lipoproteins in the progression of various neurological conditions and discuss the therapeutic options currently in the clinical pipeline targeting these two mechanisms; in addition, challenges faced in designing these therapeutic approaches have also been touched upon briefly.
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Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Enfermedades del Sistema Nervioso , Humanos , Insulina , Lipoproteínas/metabolismoRESUMEN
Background: Pulmonary hypertension is a dreaded disease associated with considerable morbidity and mortality. The pulmonary hypertension developing due to chronic respiratory disease is a unique subset with symptoms often getting masqueraded by the underlying respiratory condition. The importance of early detection of this complication has been realized worldwide, and recently, the definition of pulmonary hypertension was revised to set the cutoff of mean pulmonary artery pressure (mPAP) at 20 mmHg instead of 25 mmHg at rest. In our study, we have tried to estimate the difference this new definition brings to the prevalence of pulmonary hypertension among interstitial lung disease patients at our centre. Methods: This was a cross-sectional study in which all the patients of ILDs (n = 239) attending the outdoor and indoor Department of Respiratory Medicine, King George's Medical University, India, for the duration of one year were subjected to transthoracic echocardiography along with measurement of serum pro-B-type natriuretic peptide (BNP) and troponin T values. The data were analyzed using the different definitions, and the prevalence was compared. Result: Incidence of pulmonary hypertension among ILD patients at mPAP cutoff ≥ 25 was 28.9%, while that at value ≥20 mmHg, incidence of pulmonary hypertension increased to 46.0%. An increment of 15-20% in incidence of pulmonary hypertension was observed among different types of ILD when cutoff of mPAP was changed. Conclusion: The new definition helps in a significant increase in the detection of pulmonary hypertension, which certainly helps in earlier detection and better management of patients.
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Hipertensión Pulmonar , Enfermedades Pulmonares Intersticiales , Estudios Transversales , Ecocardiografía , Humanos , Hipertensión Pulmonar/epidemiología , PrevalenciaRESUMEN
Interstitial lung diseases (ILDs) are an intriguing group of pulmonary disorders, which still require the study of epidemiological, genetic, pathophysiological, clinical, and radiological parameters. Pulmonary hypertension (PH) is an underreported complication in interstitial lung diseases which is associated with worse outcome. In our study, we have reported the spectrum of ILDs and estimated the prevalence of pulmonary hypertension among these subjects at a tertiary care centre. A cross-sectional study was performed in which demographical, clinical, radiological, and histological data of subjects with ILD, attending the department of Respiratory Medicine in the University was collected from 1st September 2018 to 31st August 2019. Serological tests were done wherever indicated. Standard criteria along with multidisciplinary opinion were needed to arrive at the final diagnosis. All subjects were screened for pulmonary hypertension via 2-D echocardiography. Mean pulmonary artery pressure ≥20 mmHg was used to define PH. In the defined period, 239 subjects were enrolled (58% females, n=141; mean age 52.38±13.40 years). A tissue diagnosis was obtained in 34% cases. The most common ILD was hypersensitivity pneumonitis (32.2%), followed by autoimmune-ILD (31.4%), idiopathic pulmonary fibrosis (IPF) (15.9%) and sarcoidosis (12.6%), non-IPF idiopathic interstitial pneumonitis (2.1%) and rest 21 (5.9%) subjects were diagnosed as other types of ILD. Pulmonary hypertension was seen in 46.0% of subjects.
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Alveolitis Alérgica Extrínseca , Hipertensión Pulmonar , Fibrosis Pulmonar Idiopática , Enfermedades Pulmonares Intersticiales , Adulto , Anciano , Estudios Transversales , Femenino , Humanos , Hipertensión Pulmonar/epidemiología , Enfermedades Pulmonares Intersticiales/complicaciones , Enfermedades Pulmonares Intersticiales/diagnóstico , Enfermedades Pulmonares Intersticiales/epidemiología , Masculino , Persona de Mediana EdadRESUMEN
The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from a seafood market in Wuhan, China, has ushered in a new era. It transformed into a pandemic, seized global attention, and was the biggest highlight of the year 2020. The SARS-CoV-2 outbreak has jeopardized health systems and greatly affected socioeconomic parameters. With global focus on fighting this unpredictable fight with this new virus, the biggest chronic infectious killer, mycobacterium tuberculosis (M. tb), was hugely affected from this shift in attention. Due to certain similarities in the behavior of the two infectious agents, there have been inevitable consequences. On one hand, administrative measures to contain SARS-CoV-2 have simultaneously led to a breaking in the chain of tuberculosis (TB) management. Consequently, a regression occurred in the milestones achieved in the battle against TB. On the other hand, the same measures and heightened hygiene awareness has helped to decrease the spread of the TB bacilli. With an improved understanding of the interrelations and the outcomes noticed in 2020, we can better gear ourselves to develop a more sophisticated and robust strategy to tilt the balance against TB. Keeping this in mind, in this review we aim to discuss in detail the implications of SARS-CoV-2 on an already unwavering health hazard: TB.
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Stem cells are capable of unlimited proliferation but can be induced to form brain cells. Factors that specifically regulate human development are poorly understood. We found that human stem cells expressed high levels of the envelope protein of an endogenized human-specific retrovirus (HERV-K, HML-2) from loci in chromosomes 12 and 19. The envelope protein was expressed on the cell membrane of the stem cells and was critical in maintaining the stemness via interactions with CD98HC, leading to triggering of human-specific signaling pathways involving mammalian target of rapamycin (mTOR) and lysophosphatidylcholine acyltransferase (LPCAT1)-mediated epigenetic changes. Down-regulation or epigenetic silencing of HML-2 env resulted in dissociation of the stem cell colonies and enhanced differentiation along neuronal pathways. Thus HML-2 regulation is critical for human embryonic and neurodevelopment, while it's dysregulation may play a role in tumorigenesis and neurodegeneration.
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Diferenciación Celular , Retrovirus Endógenos/fisiología , Neuronas/metabolismo , Transducción de Señal , Células Madre/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Biomarcadores , Diferenciación Celular/genética , Autorrenovación de las Células/genética , Cadena Pesada de la Proteína-1 Reguladora de Fusión/metabolismo , Regulación Viral de la Expresión Génica , Humanos , Células Madre Pluripotentes Inducidas/citología , Células Madre Pluripotentes Inducidas/metabolismo , Células-Madre Neurales/citología , Células-Madre Neurales/metabolismo , Neuronas/citología , Unión Proteica , Células Madre/citología , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteínas del Envoltorio Viral/genéticaRESUMEN
Autophagy plays a broad role in health and disease. Here, we show that inositol polyphosphate multikinase (IPMK) is a prominent physiological determinant of autophagy and is critical for liver inflammation and regeneration. Deletion of IPMK diminishes autophagy in cell lines and mouse liver. Regulation of autophagy by IPMK does not require catalytic activity. Two signaling axes, IPMK-AMPK-Sirt-1 and IPMK-AMPK-ULK1, appear to mediate the influence of IPMK on autophagy. IPMK enhances autophagy-related transcription by stimulating AMPK-dependent Sirt-1 activation, which mediates the deacetylation of histone 4 lysine 16. Furthermore, direct binding of IPMK to ULK and AMPK forms a ternary complex that facilitates AMPK-dependent ULK phosphorylation. Deletion of IPMK in cell lines and intact mice virtually abolishes lipophagy, promotes liver damage as well as inflammation, and impairs hepatocyte regeneration. Thus, targeting IPMK may afford therapeutic benefits in disabilities that depend on autophagy and lipophagy-specifically, in liver inflammation and regeneration.
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Homólogo de la Proteína 1 Relacionada con la Autofagia/metabolismo , Hepatitis/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Regeneración Hepática/fisiología , Hígado/fisiología , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Quinasas de la Proteína-Quinasa Activada por el AMP , Animales , Autofagia/fisiología , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/metabolismo , Femenino , Células HEK293 , Hepatitis/genética , Hepatitis/patología , Humanos , Neoplasias Renales/genética , Neoplasias Renales/metabolismo , Hígado/metabolismo , Hígado/patología , Masculino , Ratones , Ratones Noqueados , Fosforilación , Proteínas Quinasas/metabolismo , Transducción de Señal , Sirtuina 1/metabolismo , TransfecciónRESUMEN
Inositol polyphosphate multikinase (IPMK), the key enzyme for the biosynthesis of higher inositol polyphosphates and phosphatidylinositol 3,4,5-trisphosphate, also acts as a versatile signaling player in regulating tissue growth and metabolism. To elucidate neurobehavioral functions of IPMK, we generated mice in which IPMK was deleted from the excitatory neurons of the postnatal forebrain. These mice showed no deficits in either novel object recognition or spatial memory. IPMK conditional knockout mice formed cued fear memory normally but displayed enhanced fear extinction. Signaling analyses revealed dysregulated expression of neural genes accompanied by selective activation of the mechanistic target of rapamycin (mTOR) regulatory enzyme p85 S6 kinase 1 (S6K1) in the amygdala following fear extinction. The IPMK mutants also manifested facilitated hippocampal long-term potentiation. These findings establish a signaling action of IPMK that mediates fear extinction.
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Extinción Psicológica , Miedo/psicología , Memoria , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Animales , Activación Enzimática , Eliminación de Gen , Ratones , Ratones Noqueados , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Prosencéfalo/fisiología , Transducción de Señal , Regulación hacia ArribaRESUMEN
RATIONALE: Inositol polyphosphate multikinase (IPMK) and its major product inositol pentakisphosphate (IP5) regulate a variety of cellular functions, but their role in vascular biology remains unexplored. OBJECTIVE: We have investigated the role of IPMK in regulating angiogenesis. METHODS AND RESULTS: Deletion of IPMK in fibroblasts induces angiogenesis in both in vitro and in vivo models. IPMK deletion elicits a substantial increase of VEGF (vascular endothelial growth factor), which mediates the regulation of angiogenesis by IPMK. The regulation of VEGF by IPMK requires its catalytic activity. IPMK is predominantly nuclear and regulates gene transcription. However, IPMK does not apparently serve as a transcription factor for VEGF. HIF (hypoxia-inducible factor)-1α is a major determinant of angiogenesis and induces VEGF transcription. IPMK deletion elicits a major enrichment of HIF-1α protein and thus VEGF. HIF-1α is constitutively ubiquitinated by pVHL (von Hippel-Lindau protein) followed by proteasomal degradation under normal conditions. However, HIF-1α is not recognized and ubiquitinated by pVHL in IPMK KO (knockout) cells. IP5 reinstates the interaction of HIF-1α and pVHL. HIF-1α prolyl hydroxylation, which is prerequisite for pVHL recognition, is interrupted in IPMK-deleted cells. IP5 promotes HIF-1α prolyl hydroxylation and thus pVHL-dependent degradation of HIF-1α. Deletion of IPMK in mouse brain increases HIF-1α/VEGF levels and vascularization. The increased VEGF in IPMK KO disrupts blood-brain barrier and enhances brain blood vessel permeability. CONCLUSIONS: IPMK, via its product IP5, negatively regulates angiogenesis by inhibiting VEGF expression. IP5 acts by enhancing HIF-1α hydroxylation and thus pVHL-dependent degradation of HIF-1α.
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Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Fosfatos de Inositol/metabolismo , Neovascularización Fisiológica/fisiología , Fosfotransferasas (Aceptor de Grupo Alcohol)/fisiología , Animales , Barrera Hematoencefálica , Células Cultivadas , Técnicas de Cocultivo , Medios de Cultivo Condicionados/farmacología , Fibroblastos/metabolismo , Regulación de la Expresión Génica , Técnicas de Inactivación de Genes , Células HEK293 , Células Endoteliales de la Vena Umbilical Humana , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Fosfotransferasas (Aceptor de Grupo Alcohol)/deficiencia , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Proteolisis , ARN Interferente Pequeño/genética , Organismos Libres de Patógenos Específicos , Factor A de Crecimiento Endotelial Vascular/biosíntesis , Factor A de Crecimiento Endotelial Vascular/genética , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/metabolismoRESUMEN
BACKGROUND: Human endogenous retroviruses (HERVs) are genomic sequences of retroviral origin which were believed to be integrated into germline chromosomes millions of years ago and account for nearly 8% of the human genome. Although mostly defective and inactive, some of the HERVs may be activated under certain physiological and pathological conditions. While no drugs are designed specifically targeting HERVs, there are a panel of antiretroviral drugs designed against the human immunodeficiency virus and approved by the Federal Drug Administration (FDA). RESULTS: We determined if these antiretroviral drugs may also be effective in inhibiting HERVs. We constructed a plasmid with consensus HERV-K sequence for testing the effect of antiretroviral drugs on HERV-K. We first determined the effects of nucleoside and non-nucleotide reverse transcriptase (RT) inhibitors on HERV-K by product enhanced reverse transcription assay. We found that all RT inhibitors could significantly inhibit HERV-K RT activity. To determine the effects of antiretroviral drugs on HERV-K infection and viral production, we pseudotyped HERV-K with VSV-G and used the pseudotyped HERV-K virus to infect HeLa cells. HERV-K production was measured by quantitative real time polymerase chain reaction. We found that RT inhibitors Abacavir and Zidovudine, and integrase inhibitor Raltegravir could effectively block HERV-K infection and production. However, protease inhibitors were not as effective as RT and integrase inhibitors. CONCLUSIONS: In summary, we identified several FDA approved antiretroviral drugs that can effectively inhibit HERV-K. These antiretrovirals may open new prospects for studying HERV-K pathophysiology and potentially for exploring treatment of diseases in which HERV-K has been implicated.
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Antirretrovirales/farmacología , Retrovirus Endógenos/efectos de los fármacos , Células HeLa , Humanos , Pruebas de Sensibilidad Microbiana , Reacción en Cadena en Tiempo Real de la Polimerasa , Recombinación Genética , Vesiculovirus/genética , Vesiculovirus/crecimiento & desarrolloRESUMEN
Nodding syndrome is an epileptic disorder of unknown etiology that occurs in children in East Africa. There is an epidemiological association with Onchocerca volvulus, the parasitic worm that causes onchocerciasis (river blindness), but there is limited evidence that the parasite itself is neuroinvasive. We hypothesized that nodding syndrome may be an autoimmune-mediated disease. Using protein chip methodology, we detected autoantibodies to leiomodin-1 more abundantly in patients with nodding syndrome compared to unaffected controls from the same village. Leiomodin-1 autoantibodies were found in both the sera and cerebrospinal fluid of patients with nodding syndrome. Leiomodin-1 was found to be expressed in mature and developing human neurons in vitro and was localized in mouse brain to the CA3 region of the hippocampus, Purkinje cells in the cerebellum, and cortical neurons, structures that also appear to be affected in patients with nodding syndrome. Antibodies targeting leiomodin-1 were neurotoxic in vitro, and leiomodin-1 antibodies purified from patients with nodding syndrome were cross-reactive with O. volvulus antigens. This study provides initial evidence supporting the hypothesis that nodding syndrome is an autoimmune epileptic disorder caused by molecular mimicry with O. volvulus antigens and suggests that patients may benefit from immunomodulatory therapies.