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BACKGROUND: Type 2 diabetes is associated with a variety of complications, including micro- and macrovascular complications, neurological manifestations and poor wound healing. Adhering to a Mediterranean Diet (MED) is generally considered an effective intervention in individuals at risk for type 2 diabetes mellitus (T2DM). However, little is known about its effect with respect to the different specific manifestations of T2DM. This prompted us to explore the effect of MED on the three most significant microvascular complications of T2DM: diabetic retinopathy (DR), diabetic kidney disease (DKD), and vascular diabetic neuropathies (DN). METHODS: We examined the association between the MED and the incidence of these microvascular complications in a prospective cohort of 33,441 participants with hyperglycemia free of microvascular complications at baseline, identified in the UK Biobank. For each individual, we calculated the Alternate Mediterranean Diet (AMED) score, which yields a semi-continuous measure of the extent to which an individual's diet can be considered as MED. We used Cox proportional hazard models to analyze hazard ratios (HRs) and 95% confidence intervals (CIs), adjusting for demographics, lifestyle factors, medical histories and cardiovascular risk factors. RESULTS: Over a median of 12.3 years of follow-up, 3,392 cases of microvascular complications occurred, including 1,084 cases of diabetic retinopathy (DR), 2,184 cases of diabetic kidney disease (DKD), and 632 cases of diabetic neuropathies (DN), with some patients having 2 or 3 microvascular complications simultaneously. After adjusting for confounders, we observed that higher AMED scores offer protection against DKD among participants with hyperglycemia (comparing the highest AMED scores to the lowest yielded an HR of 0.79 [95% CIs: 0.67, 0.94]). Additionally, the protective effect of AMED against DKD was more evident in the hyperglycemic participants with T2DM (HR, 0.64; 95% CI: 0.50, 0.83). No such effect, however, was seen for DR or DN. CONCLUSIONS: In this prospective cohort study, we have demonstrated that higher adherence to a MED is associated with a reduced risk of DKD among individuals with hyperglycemia. Our study emphasizes the necessity for continued research focusing on the benefits of the MED. Such efforts including the ongoing clinical trial will offer further insights into the role of MED in the clinical management of DKD.
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Diabetes Mellitus Tipo 2 , Nefropatías Diabéticas , Dieta Mediterránea , Hiperglucemia , Humanos , Estudios Prospectivos , Masculino , Femenino , Persona de Mediana Edad , Nefropatías Diabéticas/dietoterapia , Nefropatías Diabéticas/epidemiología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/dietoterapia , Anciano , Hiperglucemia/epidemiología , Hiperglucemia/complicaciones , Adulto , Reino Unido/epidemiología , Retinopatía Diabética/epidemiología , Retinopatía Diabética/dietoterapia , Incidencia , Neuropatías Diabéticas/epidemiología , Neuropatías Diabéticas/dietoterapia , Factores de RiesgoRESUMEN
Hepatitis E virus (HEV) infection is the leading cause of acute hepatitis worldwide. The mitochondrial antiviral signaling protein (MAVS)-mediated interferon (IFN) response plays a pivotal role in hepatic antiviral immunity. However, little is known about the effect of overexpression of MAVS on HEV infection. Full-length MAVS (FL-MAVS) is the main form of MAVS that increases the production of IFNs. Here, we studied the effect of FL-MAVS on HEV infection. We found that overexpression of FL-MAVS profoundly inhibited HEV replication. Furthermore, we showed that the anti-HEV effect of FL-MAVS is largely dependent on JAK-STAT signaling activation.
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Virus de la Hepatitis E , Hepatitis E , Antivirales/farmacología , Humanos , Inmunidad Innata , Interferones/farmacología , Replicación ViralRESUMEN
Classical mitochondrial disease (MD) represents a group of complex metabolic syndromes primarily linked to dysfunction of the mitochondrial ATP-generating oxidative phosphorylation (OXPHOS) system. To date, effective therapies for these diseases are lacking. Here we discuss the ketogenic diet (KD), being a high-fat, moderate protein, and low carbohydrate diet, as a potential intervention strategy. We concisely review the impact of the KD on bioenergetics, ROS/redox metabolism, mitochondrial dynamics and mitophagy. Next, the consequences of the KD in (models of) MD, as well as KD adverse effects, are described. It is concluded that the current experimental evidence suggests that the KD can positively impact on mitochondrial bioenergetics, mitochondrial ROS/redox metabolism and mitochondrial dynamics. However, more information is required on the bioenergetic consequences and mechanistic mode-of-action aspects of the KD at the cellular level and in MD patients.
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Dieta Cetogénica/métodos , Metabolismo Energético , Enfermedades Mitocondriales/dietoterapia , Dinámicas Mitocondriales , Animales , Humanos , Oxidación-ReducciónRESUMEN
COVID-19 has rapidly become a pandemic worldwide, causing extensive and long-term health issues. There is an urgent need to identify therapies that limit SARS-CoV-2 infection and improve the outcome of COVID-19 patients. Unbalanced lung inflammation is a common feature in severe COVID-19 patients; therefore, reducing lung inflammation can undoubtedly benefit the clinical manifestations. Histamine H1 receptor (H1 receptor) antagonists are widely prescribed medications to treat allergic diseases, while recently it has emerged that they show significant promise as anti-SARS-CoV-2 agents. Here, we briefly summarize the novel use of H1 receptor antagonists in combating SARS-CoV-2 infection. We also describe the potential antiviral mechanisms of H1 receptor antagonists on SARS-CoV-2. Finally, the opportunities and challenges of the use of H1 receptor antagonists in managing COVID-19 are discussed.
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Antiinflamatorios/farmacología , Antivirales/farmacología , Tratamiento Farmacológico de COVID-19 , Antagonistas de los Receptores Histamínicos H1/farmacología , FN-kappa B/metabolismo , SARS-CoV-2/efectos de los fármacos , COVID-19/metabolismo , Humanos , Receptores Histamínicos H1/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Hepatitis E virus (HEV) as an emerging zoonotic pathogen causes a major public health issue. Transmission from domestic, wildlife and zoo animals to human has been widely reported. Whether pets also serve as reservoirs remains an intriguing question. In this study, we found the sero-positive rates of HEV-specific antibodies in pet dogs, cats and horses of 18.52% (30/162), 14.89% (7/47) and 18.18% (4/22) in the Netherlands. Although HEV viral RNA was not detected in these animals, we have demonstrated that dog liver cells are susceptible to HEV infection in vitro. These results call more attention to address the potential role of pets in the zoonotic transmission of HEV.
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Enteric viruses including hepatitis E virus (HEV), human norovirus (HuNV), and rotavirus are causing global health issues. The host interferon (IFN) response constitutes the first-line defense against viral infections. Melanoma Differentiation-Associated protein 5 (MDA5) is an important cytoplasmic receptor sensing viral infection to trigger IFN production, and on the other hand it is also an IFN-stimulated gene (ISG). In this study, we investigated the effects and mode-of-action of MDA5 on the infection of enteric viruses. We found that MDA5 potently inhibited HEV, HuNV and rotavirus replication in multiple cell models. Overexpression of MDA5 induced transcription of important antiviral ISGs through IFN-like response, without triggering of functional IFN production. Interestingly, MDA5 activates the expression and phosphorylation of STAT1, which is a central component of the JAK-STAT cascade and a hallmark of antiviral IFN response. However, genetic silencing of STAT1 or pharmacological inhibition of the JAK-STAT cascade only partially attenuated the induction of ISG transcription and the antiviral function of MDA5. Thus, we have demonstrated that MDA5 effectively inhibits HEV, HuNV and rotavirus replication through provoking a non-canonical IFN-like response, which is partially dependent on JAK-STAT cascade.
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Inmunidad Innata , Helicasa Inducida por Interferón IFIH1/inmunología , Interferones/inmunología , Quinasas Janus/inmunología , Factor de Transcripción STAT1/inmunología , Virosis/inmunología , Antivirales/inmunología , Línea Celular , Línea Celular Tumoral , Células HEK293 , Virus de la Hepatitis E , Humanos , Norovirus , Rotavirus , Transducción de Señal , Replicación ViralRESUMEN
Metabolic reprogramming universally occurs in cancer. Mitochondria act as the hubs of bioenergetics and metabolism. The morphodynamics of mitochondria, comprised of fusion and fission processes, are closely associated with mitochondrial functions and are often dysregulated in cancer. In this study, we aim to investigate the mitochondrial morphodynamics and its functional consequences in human liver cancer. We observed excessive activation of mitochondrial fusion in tumor tissues from hepatocellular carcinoma (HCC) patients and in vitro cultured tumor organoids from cholangiocarcinoma (CCA). The knockdown of the fusion regulator genes, OPA1 (Optic atrophy 1) or MFN1 (Mitofusin 1), inhibited the fusion process in HCC cell lines and CCA tumor organoids. This resulted in inhibition of cell growth in vitro and tumor formation in vivo, after tumor cell engraftment in mice. This inhibitory effect is associated with the induction of cell apoptosis, but not related to cell cycle arrest. Genome-wide transcriptomic profiling revealed that the inhibition of fusion predominately affected cellular metabolic pathways. This was further confirmed by the blocking of mitochondrial fusion which attenuated oxygen consumption and cellular ATP production of tumor cells. In conclusion, increased mitochondrial fusion in liver cancer alters metabolism and fuels tumor cell growth.
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GTP Fosfohidrolasas/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Dinámicas Mitocondriales , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Adulto , Anciano , Animales , Línea Celular Tumoral , Proliferación Celular , Colangiocarcinoma/patología , Femenino , Silenciador del Gen , Células HEK293 , Humanos , Masculino , Ratones Desnudos , Persona de Mediana Edad , Organoides/patología , Consumo de OxígenoRESUMEN
Hepatitis E virus (HEV) infection is the leading cause of acute hepatitis worldwide and can develop into chronic infection in immunocompromised patients, promoting the development of effective antiviral therapies. In this study, we performed a screening of a library containing over 1000 FDA-approved drugs. We have identified deptropine, a classical histamine H1 receptor antagonist used to treat asthmatic symptoms, as a potent inhibitor of HEV replication. The anti-HEV activity of deptropine appears dispensable of the histamine pathway, but requires the inhibition on nuclear factor-κB (NF-κB) activity. This further activates caspase mediated by receptor-interacting protein kinase 1 (RIPK1) to restrict HEV replication. Given deptropine being widely used in the clinic, our results warrant further evaluation of its anti-HEV efficacy in future clinical studies. Importantly, the discovery that NF-κB-RIPK1-caspase pathway interferes with HEV infection reveals new insight of HEV-host interactions.
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Antivirales/farmacología , Caspasas/metabolismo , Virus de la Hepatitis E/efectos de los fármacos , FN-kappa B/metabolismo , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Transducción de Señal , Tropanos/farmacología , Línea Celular Tumoral , Evaluación Preclínica de Medicamentos , Hepatitis E/tratamiento farmacológico , Hepatocitos/efectos de los fármacos , Hepatocitos/virología , Ensayos Analíticos de Alto Rendimiento , Interacciones Microbiota-Huesped/efectos de los fármacos , Humanos , Bibliotecas de Moléculas Pequeñas , Estados Unidos , United States Food and Drug Administration , Replicación Viral/efectos de los fármacosRESUMEN
Hepatitis virus infections affect a large proportion of the global population. The host responds rapidly to viral infection by orchestrating a variety of cellular machineries, in particular, the mitochondrial compartment. Mitochondria actively regulate viral infections through modulation of the cellular innate immunity and reprogramming of metabolism. In turn, hepatitis viruses are able to modulate the morphodynamics and functions of mitochondria, but the mode of actions are distinct with respect to different types of hepatitis viruses. The resulting mutual interactions between viruses and mitochondria partially explain the clinical presentation of viral hepatitis, influence the response to antiviral treatment, and offer rational avenues for novel therapy. In this review, we aim to consider in depth the multifaceted interactions of mitochondria with hepatitis virus infections and emphasize the implications for understanding pathogenesis and advancing therapeutic development.
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Susceptibilidad a Enfermedades , Virus de Hepatitis/fisiología , Hepatitis Viral Humana/metabolismo , Hepatitis Viral Humana/terapia , Hepatitis Viral Humana/virología , Interacciones Huésped-Patógeno , Mitocondrias/metabolismo , Manejo de la Enfermedad , Virus de Hepatitis/efectos de los fármacos , Humanos , Dinámicas Mitocondriales , Replicación ViralRESUMEN
Hepatitis E virus (HEV) infection represents an emerging global health issue, whereas the clinical outcomes vary dramatically among different populations. The host innate immune system provides a first-line defense against the infection, but dysregulation may partially contribute to severe pathogenesis. A growing body of evidence has indicated the active response of the host innate immunity to HEV infection both in experimental models and in patients. In turn, HEV has developed sophisticated strategies to counteract the host immune system. In this review, we aim to comprehensively decipher the processes of pathogen recognition, interferon, and inflammatory responses, and the involvement of innate immune cells in HEV infection. We further discuss their implications in understanding the pathogenic mechanisms and developing antiviral therapies.
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Virus de la Hepatitis E/inmunología , Interacciones Huésped-Patógeno/inmunología , Inmunidad Innata , Antivirales/farmacología , Antivirales/uso terapéutico , Hepatitis E/terapia , Hepatitis E/virología , Humanos , Inflamación/inmunología , Interferones/inmunologíaRESUMEN
Hepatitis E virus (HEV) infection has emerged as a global health problem. However, no approved medication is available, and the infection biology remains largely elusive. Electron transport chain (ETC), a key component of the mitochondria, is the main site that produces ATP and reactive oxygen species (ROS). By profiling the role of the different complexes of the mitochondrial ETC, we found that pharmacological inhibition of complex III, a well-defined drug target for the treatment of malaria and Pneumocystis pneumonia, potently restricts HEV replication. This effect demonstrated in our HEV models is equivalent to the anti-HEV potency of ribavirin, a widely used off-label treatment for patients with chronic HEV. Mechanistically, we found that this effect is independent of ATP production, ROS level, and pyridine depletion. By using pharmacological inhibitors and genetic approaches, we found that mitochondrial permeability transition pore (MPTP), a newly identified component of ETC, provides basal defense against HEV infection. HEV interferes with the opening of the MPTP. Furthermore, inhibition of the MPTP attenuated the anti-HEV effect of complex III inhibitors, suggesting that the MPTP mediates the antiviral effects of these inhibitors. These findings reveal new insights on HEV-host interactions and provide viable anti-HEV targets for therapeutic development.-Qu, C., Zhang, S., Wang, W., Li, M., Wang, Y., van der Heijde-Mulder, M., Shokrollahi, E., Hakim, M. S., Raat, N. J. H., Peppelenbosch, M. P., Pan, Q. Mitochondrial electron transport chain complex III sustains hepatitis E virus replication and represents an antiviral target.
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Antivirales/farmacología , Complejo III de Transporte de Electrones/metabolismo , Virus de la Hepatitis E/fisiología , Mitocondrias/efectos de los fármacos , Replicación Viral/efectos de los fármacos , Línea Celular Tumoral , Virus de la Hepatitis E/efectos de los fármacos , Humanos , Mitocondrias/metabolismoRESUMEN
Hepatitis E virus (HEV) is one of the major pathogens causing acute viral hepatitis. The infectious particle consists of an RNA genome and capsid proteins. The 7.2â¯kb genome encodes three open reading frames (ORF) and ORF2 is translated into the capsid protein. The knowledge of structure and function of the ORF2 protein is essential for understanding the evolution and life cycle of HEV. However, biophysical research in this respect remains limited due to technical challenges. We have carried out a series of computational analysis on HEV ORF2. We have identified 144 conserved sites among the 660 amino acid (AA) residues. 43 models based on the previously proposed reference sequences and a cell culture adapted infectious clone were successfully built by 3D protein structure prediction and refinement. Structure alignment of domains revealed structural conservation of the S and M domains, but to a lesser extent of the P domain. Moreover, molecular docking has predicted distinct binding affinities of a monoclonal antibody towards ORF2 across different genotypes. Thus, we have expanded the information on ORF2 at both sequence and structure levels. These findings may help to better understand the evolution and life cycle of HEV, but also facilitate the development of genetically engineered vaccines or antibodies.
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Proteínas Virales/química , Secuencia de Aminoácidos , Complejo Antígeno-Anticuerpo , Secuencia Conservada , Cristalografía por Rayos X , Virus de la Hepatitis E/genética , Virus de la Hepatitis E/patogenicidad , Modelos Moleculares , Dominios Proteicos , Proteínas Virales/metabolismo , Tropismo ViralRESUMEN
Rotavirus infection has emerged as an important cause of complications in organ transplantation recipients and might play a role in the pathogenesis of inflammatory bowel disease (IBD). 6-Thioguanine (6-TG) has been widely used as an immunosuppressive drug for organ recipients and treatment of IBD in the clinic. This study aims to investigate the effects and mode-of-action of 6-TG on rotavirus replication. Human intestinal Caco2 cell line, 3D model of human primary intestinal organoids, laboratory rotavirus strain (SA11) and patient-derived rotavirus isolates were used. We have demonstrated that 6-TG significantly inhibits rotavirus replication in these intestinal epithelium models. Importantly, gene knockdown or knockout of Rac1, the cellular target of 6-TG, significantly inhibited rotavirus replication, indicating the supportive role of Rac1 for rotavirus infection. We have further demonstrated that 6-TG can effectively inhibit the active form of Rac1 (GTP-Rac1), which essentially mediates the anti-rotavirus effect of 6-TG. Consistently, ectopic over-expression of GTP-Rac1 facilitates but an inactive Rac1 (N17) or a specific Rac1 inhibitor (NSC23766) inhibits rotavirus replication. In conclusion, we have identified 6-TG as an effective inhibitor of rotavirus replication via the inhibition of Rac1 activation. Thus, for transplantation patients or IBD patients infected with rotavirus or at risk of rotavirus infection, the choice of 6-TG as a treatment appears rational.
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Antivirales/farmacología , Guanosina Difosfato/metabolismo , Guanosina Trifosfato/metabolismo , Rotavirus/efectos de los fármacos , Tioguanina/farmacología , Replicación Viral/efectos de los fármacos , Proteína de Unión al GTP rac1/antagonistas & inhibidores , Células Cultivadas , Células Epiteliales/virología , Humanos , Organoides , Rotavirus/crecimiento & desarrolloRESUMEN
The outcomes of hepatitis E virus (HEV) infection are diverse, ranging from asymptomatic carrier, self-limiting acute infection, and fulminant hepatitis to persistent infection. This is closely associated with the immunological status of the host. This study aimed to understand the innate cellular immunity as the first-line defense mechanism in response to HEV infection. Phosphorylation of signal transducer and activator of transcription 1, a hallmark of the activation of antiviral interferon (IFN) response, was observed in the liver tissues of the majority of HEV-infected patients but not in the liver of uninfected individuals. In cultured cell lines and primary liver organoids, we found that HEV RNA genome potently induced IFN production and antiviral response. This mechanism is conserved among different HEV strains, including genotypes 1, 3, and 7 as tested. Interestingly, single-stranded HEV RNA is sufficient to trigger the antiviral response, without the requirement of viral RNA synthesis and the generation of an RNA replicative form or replicative intermediate. Surprisingly, the m7 G cap and poly A tail are not required, although both are key features of the HEV genome. Mechanistically, this antiviral response occurs in a retinoic acid-inducible gene-I-independent, melanoma differentiation-associated protein 5-independent, mitochondrial antiviral signaling protein-independent, and ß-catenin-independent but IRF3-dependent and IRF7-dependent manner. Furthermore, the integrity of the Janus kinase-signal transducer and activator of transcription pathway is essentially required. CONCLUSION: HEV infection elicits an active IFN-related antiviral response in vitro and in patients, triggered by the viral RNA and mediated by IFN regulatory factors 3 and 7 and the Janus kinase-signal transducer and activator of transcription cascade; these findings have revealed new insights into HEV-host interactions and provided the basis for understanding the pathogenesis and outcome of HEV infection. (Hepatology 2018;67:2096-2112).
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Genoma Viral , Virus de la Hepatitis E/genética , Hepatitis E/inmunología , Hepatitis E/virología , Inmunidad Celular/fisiología , Interferones/fisiología , ARN Viral/fisiología , Biopsia , Hepatitis E/patología , Humanos , Hígado/inmunología , Hígado/patología , Hígado/virologíaRESUMEN
Hepatitis E virus (HEV) infection has emerged as a global health issue, but no approved medication is available. The nucleoside analogue 2'-C-methylcytidine (2CMC), a viral polymerase inhibitor, has been shown to inhibit infection with a variety of viruses, including hepatitis C virus (HCV). Here, we report that 2CMC significantly inhibits the replication of HEV in a subgenomic replication model and in a system using a full-length infectious virus. Importantly, long-term treatment with 2CMC did not result in a loss of antiviral potency, indicating a high barrier to drug resistance development. However, the combination of 2CMC with ribavirin, an off-label treatment for HEV, exerts antagonistic effects. Our results indicate that 2CMC serves as a potential antiviral drug against HEV infection.