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1.
Virology ; 564: 33-38, 2021 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-34619630

RESUMO

Endemic seasonal coronaviruses cause morbidity and mortality in a subset of patients, but no specific treatment is available. Molnupiravir is a promising pipeline antiviral drug for treating SARS-CoV-2 infection potentially by targeting RNA-dependent RNA polymerase (RdRp). This study aims to evaluate the potential of repurposing molnupiravir for treating seasonal human coronavirus (HCoV) infections. Molecular docking revealed that the active form of molnupiravir, ß-D-N4-hydroxycytidine (NHC), has similar binding affinity to RdRp of SARS-CoV-2 and seasonal HCoV-NL63, HCoV-OC43 and HCoV-229E. In cell culture models, treatment of molnupiravir effectively inhibited viral replication and production of infectious viruses of the three seasonal coronaviruses. A time-of-drug-addition experiment indicates the specificity of molnupiravir in inhibiting viral components. Furthermore, combining molnupiravir with the protease inhibitor GC376 resulted in enhanced antiviral activity. Our findings highlight that the great potential of repurposing molnupiravir for treating seasonal coronavirus infected patients.

2.
Hepatology ; 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34453359

RESUMO

BACKGROUND & AIMS: Recently metabolic dysfunction associated fatty liver disease (MAFLD) has been introduced and was defined as hepatic steatosis with either overweight, diabetes and/or a combination of other metabolic risk factors. We investigated the application of the novel MAFLD criteria as compared to non-alcoholic fatty liver disease (NAFLD). APPROACH & RESULTS: We performed a cross-sectional analysis within The Rotterdam Study, a large prospective population-based cohort. Participants who attended the liver ultrasound and transient elastography program between 2009-2014 were eligible for inclusion. Subsequently, individuals with viral hepatitis, alcohol intake >60 grams/day, missing alcohol data and/or missing body mass index (BMI) were excluded. According to their NAFLD and MAFLD status based on metadata and ultrasound, participants were allocated in overlap fatty liver disease (FLD), NAFLD-only, MAFLD-only or no-FLD. Fibrosis was defined as liver stiffness ≥8.0 kilopascal. In our analysis, 5.445 participants were included, 1.866 (34.3%) had MAFLD and 1.623 (29.8%) NAFLD. This resulted in 1.566 (28.8%) individuals with overlap-FLD, 300 (5.5%) with MAFLD-only, 57 (1.0%) with NAFLD-only and 3.522 (64.7%) with no-FLD. MAFLD-only was strongly associated with fibrosis (adjusted OR 5.27, p<0.001) and log-transformed liver stiffness (adjusted beta 0.116, p<0.001), opposing NAFLD-only in which no cases of fibrosis were identified and no association with liver stiffness (adjusted beta 0.006, p=0.90) was found. CONCLUSIONS: FLD is highly prevalent in the general population. However, not NAFLD-only, but MAFLD-only was associated with fibrosis and higher liver stiffness independent of demographic and lifestyle factors. We believe using the novel MAFLD criteria will help improve the identification and treatment of FLD patients at risk for fibrosis.

3.
Hepatology ; 2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-34392558

RESUMO

BACKGROUND & AIMS: Hepatitis E virus (HEV) infection is the most common cause of liver inflammation, but the pathogenic mechanisms remain largely unclear. We aim to explore whether HEV infection activates inflammasomes, the crosstalk with antiviral interferon response and potential of therapeutic targeting. APPROACH & RESULTS: We measured IL-1ß secretion, the hallmark of inflammasome activation, in serum of HEV-infected patients and rabbits, and in cultured macrophage cell lines and primary monocyte-derived macrophages. We found that genotypes 3 and 4 HEV infection in rabbits elevated IL-1ß production. A profound increase of IL-1ß secretion was further observed in HEV-infected patients (1733 pg/mL ± 1234; n = 70) compared with healthy individuals (731 pg/mL ± 701; n = 70). As macrophages are the drivers of inflammatory response, we found inoculation with infectious HEV particles robustly triggered NLRP3 inflammasome activation in primary macrophages and macrophage cell lines. We further revealed that the ORF2 capsid protein and the formed integral viral particles are responsible for activating inflammasome response. We also identified NF-κB signaling activation as a key upstream event of HEV-induced NLRP3 inflammasome response. Interestingly, inflammasome activation antagonizes interferon response to facilitate viral replication in macrophages. Pharmacological inhibitors and clinically used steroids can effectively target inflammasome activation. Combining steroids with ribavirin simultaneously inhibit HEV and inflammasome response without cross-interference. CONCLUSIONS: HEV infection strongly activates NLRP3 inflammasome activation in macrophages, which regulates host innate defense and pathogenesis. Therapeutic targeting NLRP3, in particular when combined with antiviral agents, represents a viable option for treating severe HEV infection.

4.
Gut Microbes ; 13(1): 1959839, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34347572

RESUMO

Although cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling has been well recognized in defending DNA viruses, the role of cGAS-STING signaling in regulating infection of RNA viruses remains largely elusive. Noroviruses, as single-stranded RNA viruses, are the main causative agents of acute viral gastroenteritis worldwide. This study comprehensively investigated the role of cGAS-STING in response to murine norovirus (MNV) infection. We found that STING agonists potently inhibited MNV replication in mouse macrophages partially requiring the JAK/STAT pathway that induced transcription of interferon (IFN)-stimulated genes (ISGs). Loss- and gain-function assays revealed that both cGAS and STING were necessary for host defense against MNV propagation. Knocking out cGAS or STING in mouse macrophages led to defects in induction of antiviral ISGs upon MNV infection. Overexpression of cGAS and STING moderately increased ISG transcription but potently inhibited MNV replication in human HEK293T cells ectopically expressing the viral receptor CD300lf. This inhibitory effect was not affected by JAK inhibitor treatment or expression of different MNV viral proteins. Interestingly, STING but not cGAS interacted with mouse RIG-I, and attenuated its N-terminus-mediated anti-MNV effects. Our results implicate an essential role for mouse cGAS and STING in regulating innate immune response and defending MNV infection. This further strengthens the evidence of cGAS-STING signaling in response to RNA virus infection.

5.
Drugs R D ; 21(3): 273-283, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34324175

RESUMO

BACKGROUND AND OBJECTIVE: Coronavirus disease 2019 is a novel disease caused by the severe acute respiratory syndrome coronavirus (SARS-CoV)-2 virus. It was first detected in December 2019 and has since been declared a pandemic causing millions of deaths worldwide. Therefore, there is an urgent need to develop effective therapeutics against coronavirus disease 2019. A critical step in the crosstalk between the virus and the host cell is the binding of the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein to the peptidase domain of the angiotensin-converting enzyme 2 (ACE2) receptor present on the surface of host cells. METHODS: An in silico approach was employed to design a 13-amino acid peptide inhibitor (13AApi) against the RBD of the SARS-CoV-2 spike protein. Its binding specificity for RBD was confirmed by molecular docking using pyDockWEB, ClusPro 2.0, and HDOCK web servers. The stability of 13AApi and the SARS-CoV-2 spike protein complex was determined by molecular dynamics simulation using the GROMACS program while the physicochemical and ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties of 13AApi were determined using the ExPASy tool and pkCSM server. Finally, in vitro validation of the inhibitory activity of 13AApi against the spike protein was performed by an enzyme-linked immunosorbent assay. RESULTS: In silico analyses indicated that the 13AApi could bind to the RBD of the SARS-CoV-2 spike protein at the ACE2 binding site with high affinity. In vitro experiments validated the in silico findings, showing that 13AApi could significantly block the RBD of the SARS-CoV-2 spike protein. CONCLUSIONS: Blockage of binding of the SARS-CoV-2 spike protein with ACE2 in the presence of the 13AApi may prevent virus entry into host cells. Therefore, the 13AApi can be utilized as a promising therapeutic agent to combat coronavirus disease 2019.


Assuntos
Enzima de Conversão de Angiotensina 2/efeitos dos fármacos , Antivirais/farmacologia , Peptídeos/farmacologia , Glicoproteína da Espícula de Coronavírus/efeitos dos fármacos , Enzima de Conversão de Angiotensina 2/metabolismo , Antivirais/farmacocinética , Antivirais/toxicidade , Sítios de Ligação , Simulação por Computador , Desenho de Fármacos , Humanos , Modelos Moleculares , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Peptídeos/farmacocinética , Peptídeos/toxicidade , Ligação Proteica/efeitos dos fármacos , Glicoproteína da Espícula de Coronavírus/metabolismo , Especificidade por Substrato
7.
Int J Antimicrob Agents ; 58(3): 106383, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34157403

RESUMO

Hepatitis E virus (HEV) infection in immunocompromised patients, pregnant women and children requires treatment; however, no approved medication is currently available. The macrolide antibiotic azithromycin has been identified as a potent HEV inhibitor. Azithromycin inhibits HEV replication and viral protein expression in multiple cell culture models with genotype 1 and 3 strains. This is largely independent of its induction of an interferon-like response. Because it is safe and cheap, repurposing azithromycin for treating HEV infection is attractive, particularly in resource-limited settings.

8.
Arch Virol ; 166(7): 2005-2010, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33987753

RESUMO

We show that ivermectin, an FDA-approved anti-parasitic drug, effectively inhibits infection with hepatitis E virus (HEV) genotypes 1 and 3 in a range of cell culture models, including hepatic and extrahepatic cells. Long-term treatment showed no clear evidence of the development of drug resistance. Gene silencing of importin-α1, a cellular target of ivermectin and a key member of the host nuclear transport complex, inhibited viral replication and largely abolished the anti-HEV effect of ivermectin.


Assuntos
Vírus da Hepatite E/efeitos dos fármacos , Hepatite E/tratamento farmacológico , Ivermectina/farmacologia , Replicação Viral/efeitos dos fármacos , alfa Carioferinas/metabolismo , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Núcleo Celular/virologia , Hepatite E/metabolismo , Hepatite E/virologia , Humanos , Proteínas Nucleares/metabolismo
9.
Nat Commun ; 12(1): 2830, 2021 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-33990564

RESUMO

Coffee and tea are extensively consumed beverages worldwide which have received considerable attention regarding health. Intake of these beverages is consistently linked to, among others, reduced risk of diabetes and liver diseases; however, the mechanisms of action remain elusive. Epigenetics is suggested as a mechanism mediating the effects of dietary and lifestyle factors on disease onset. Here we report the results from epigenome-wide association studies (EWAS) on coffee and tea consumption in 15,789 participants of European and African-American ancestries from 15 cohorts. EWAS meta-analysis of coffee consumption reveals 11 CpGs surpassing the epigenome-wide significance threshold (P-value <1.1×10-7), which annotated to the AHRR, F2RL3, FLJ43663, HDAC4, GFI1 and PHGDH genes. Among them, cg14476101 is significantly associated with expression of the PHGDH and risk of fatty liver disease. Knockdown of PHGDH expression in liver cells shows a correlation with expression levels of genes associated with circulating lipids, suggesting a role of PHGDH in hepatic-lipid metabolism. EWAS meta-analysis on tea consumption reveals no significant association, only two CpGs annotated to CACNA1A and PRDM16 genes show suggestive association (P-value <5.0×10-6). These findings indicate that coffee-associated changes in DNA methylation levels may explain the mechanism of action of coffee consumption in conferring risk of diseases.


Assuntos
Café/efeitos adversos , Metilação de DNA , Epigenoma , Chá/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Ilhas de CpG , Epigênese Genética , Feminino , Técnicas de Silenciamento de Genes , Estudo de Associação Genômica Ampla , Humanos , Fígado/enzimologia , Masculino , Pessoa de Meia-Idade , Fosfoglicerato Desidrogenase/antagonistas & inibidores , Fosfoglicerato Desidrogenase/genética , Fatores de Risco
10.
Transbound Emerg Dis ; 2021 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-33966351

RESUMO

Highly pathogenic coronaviruses, including SARS-CoV-2, SARS-CoV and MERS-CoV, are thought to be transmitted from bats to humans, but the viral genetic signatures that contribute to bat-to-human transmission remain largely obscure. In this study, we identified an identical ribosomal frameshift motif among the three bat-human pairs of viruses and strong purifying selection after jumping from bats to humans. This represents genetic signatures of coronaviruses that are related to bat-to-human transmission. To further trace the early human-to-human transmission of SARS-CoV-2 in North America, a geographically stratified genome-wide association study (North American isolates and the remaining isolates) and a retrospective study were conducted. We determined that the single nucleotide polymorphisms (SNPs) 1,059.C > T and 25,563.G > T were significantly associated with approximately half of the North American SARS-CoV-2 isolates that accumulated largely during March 2020. Retrospectively tracing isolates with these two SNPs was used to reconstruct the early, reliable transmission history of North American SARS-CoV-2, and European isolates (February 26, 2020) showed transmission 3 days earlier than North American isolates and 17 days earlier than Asian isolates. Collectively, we identified the genetic signatures of the three pairs of coronaviruses and reconstructed an early transmission history of North American SARS-CoV-2. We envision that these genetic signatures are possibly diagnosable and predic markers for public health surveillance.

11.
Am J Clin Nutr ; 113(5): 1332-1342, 2021 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-33842951

RESUMO

BACKGROUND: Intermittent fasting is a popular dietary intervention with perceived relatively easy compliance and is linked to various health benefits, including weight loss and improvement in blood glucose concentrations. The mechanistic explanations underlying the beneficial effects of intermittent fasting remain largely obscure but may involve alterations in the gut microbiota. OBJECTIVES: We sought to establish the effects of 1 mo of intermittent fasting on the gut microbiome. METHODS: We took advantage of intermittent fasting being voluntarily observed during the Islamic faith-associated Ramadan and sampled feces and blood, as well as collected longitudinal physiologic data in 2 cohorts, sampled in 2 different years. The fecal microbiome was determined by 16S sequencing. Results were contrasted to age- and body weight-matched controls and correlated to physiologic parameters (e.g., body mass and calorie intake). RESULTS: We observed that Ramadan-associated intermittent fasting increased microbiome diversity and was specifically associated with upregulation of the Clostridiales order-derived Lachnospiraceae [no fasting 24.6 ± 13.67 compared with fasting 39.7 ± 15.9 in relative abundance (%); linear discriminant analysis = 4.9, P < 0.001 by linear discriminant analysis coupled with effect size measurements] and Ruminococcaceae [no fasting 13.4 ± 6.9 compared with fasting 23.2 ± 12.9 in relative abundance (%); linear discriminant analysis = 4.7, P < 0.001 by linear discriminant analysis coupled with effect size measurements] bacterial families. Microbiome composition returned to baseline upon cessation of intermittent feeding. Furthermore, changes in Lachnospiraceae concentrations mirrored intermittent fasting-provoked changes in physiologic parameters. CONCLUSIONS: Intermittent fasting provokes substantial remodeling of the gut microbiome. The intermittent fasting-provoked upregulation of butyric acid-producing Lachnospiraceae provides an obvious possible mechanistic explanation for health effects associated with intermittent fasting.


Assuntos
Jejum , Microbioma Gastrointestinal , Islamismo , Adolescente , Adulto , Bactérias/classificação , Bactérias/metabolismo , Biomarcadores , Ácido Butírico/metabolismo , Estudos de Coortes , Fezes/microbiologia , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
12.
Crit Rev Microbiol ; 47(5): 580-595, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33822674

RESUMO

Rotaviruses, double-stranded, non-enveloped RNA viruses, are a global health concern, associated with acute gastroenteritis and secretory-driven watery diarrhoea, especially in infants and young children. Conventionally, rotavirus is primarily viewed as a pathogen for intestinal enterocytes. This notion is challenged, however, by data from patients and animal models documenting extra-intestinal clinical manifestations and viral replication following rotavirus infection. In addition to acute gastroenteritis, rotavirus infection has been linked to various neurological disorders, hepatitis and cholestasis, type 1 diabetes, respiratory illness, myocarditis, renal failure and thrombocytopenia. Concomitantly, molecular studies have provided insight into potential mechanisms by which rotavirus can enter and replicate in non-enterocyte cell types and evade host immune responses. Nevertheless, it is fair to say that the extra-intestinal aspect of the rotavirus infectious process is largely being overlooked by biomedical professionals, and there are gaps in the understanding of mechanisms of pathogenesis. Thus with the aim of increasing public and professional awareness we here provide a description of our current understanding of rotavirus-related extra-intestinal clinical manifestations and associated molecular pathogenesis. Further understanding of the processes involved should prove exceedingly useful for future diagnosis, treatment and prevention of rotavirus-associated disease.

14.
Cell Mol Gastroenterol Hepatol ; 12(2): 443-464, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33781741

RESUMO

BACKGROUND & AIMS: TIGIT is a co-inhibitory receptor, and its suitability as a target for cancer immunotherapy in HCC is unknown. PD1 blockade is clinically effective in about 20% of advanced HCC patients. Here we aim to determine whether co-blockade of TIGIT/PD1 has added value to restore functionality of HCC tumor-infiltrating T cells (TILs). METHODS: Mononuclear leukocytes were isolated from tumors, paired tumor-free liver tissues (TFL) and peripheral blood of HCC patients, and used for flow cytometric phenotyping and functional assays. CD3/CD28 T-cell stimulation and antigen-specific assays were used to study the ex vivo effects of TIGIT/PD1 single or dual blockade on T-cell functions. RESULTS: TIGIT was enriched, whereas its co-stimulatory counterpart CD226 was down-regulated on PD1high CD8+ TILs. PD1high TIGIT+ CD8+ TILs co-expressed exhaustion markers TIM3 and LAG3 and demonstrated higher TOX expression. Furthermore, this subset showed decreased capacity to produce IFN-γ and TNF-α. Expression of TIGIT-ligand CD155 was up-regulated on tumor cells compared with hepatocytes in TFL. Whereas single PD1 blockade preferentially enhanced ex vivo functions of CD8+ TILs from tumors with PD1high CD8+ TILs (high PD1 expressers), co-blockade of TIGIT and PD1 improved proliferation and cytokine production of CD8+ TILs from tumors enriched for PD1int CD8+ TILs (low PD1 expressers). Importantly, ex vivo co-blockade of TIGIT/PD1 improved proliferation, cytokine production, and cytotoxicity of CD8+ TILs compared with single PD1 blockade. CONCLUSIONS: Ex vivo, co-blockade of TIGIT/PD1 improves functionality of CD8+ TILs that do not respond to single PD1 blockade. Therefore co-blockade of TIGIT/PD1 could be a promising immune therapeutic strategy for HCC patients.

16.
Artigo em Inglês | MEDLINE | ID: mdl-33618024

RESUMO

BACKGROUND & AIMS: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a new terminology updated from non-alcoholic fatty liver disease (NAFLD). In this study, we aim to estimate the global prevalence of MAFLD specifically in overweight and obese adults from the general population by performing a systematic review and meta-analysis through mining the existing epidemiological data on fatty liver disease. METHODS: We searched Medline, Embase, Web of Science, Cochrane and google scholar database from inception to November, 2020. DerSimonian-Laird random-effects model with Logit transformation was performed for data analysis. Sensitivity analysis and meta-regression were used to explore predictors of MAFLD prevalence in pooled statistics with high heterogeneity. RESULTS: We identified 116 relevant studies comprised of 2,667,052 participants in general population with an estimated global MAFLD prevalence as 50.7% (95% CI 46.9-54.4) among overweight/obese adults regardless of diagnostic techniques. Ultrasound was the most commonly used diagnostic technique generating prevalence rate of 51.3% (95% CI, 49.1-53.4). Male (59.0%; 95% CI, 52.0-65.6) had a significantly higher MAFLD prevalence than female (47.5%; 95% CI, 40.7-54.5). Interestingly, MAFLD prevalence rates are comparable based on classical NAFLD and non-NAFLD studies in general population. The pooled estimate prevalence of comorbidities such as type 2 diabetes and metabolic syndrome was 19.7% (95% CI, 12.8-29.0) and 57.5% (95% CI, 49.9-64.8), respectively. CONCLUSIONS: MAFLD has an astonishingly high prevalence rate in overweight and obese adults. This calls for attention and dedicated action from primary care physicians, specialists, health policy makers and the general public alike.

17.
Int J Biochem Cell Biol ; 133: 105937, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33529713

RESUMO

Lipid droplets are cellular organelles used for lipid storage with a hydrophobic core of neutral lipids enclosed by a phospholipid monolayer. Besides presenting as giant single organelles in fat tissue, lipid droplets are also widely present as a multitude of small structures in hepatocytes, where they play key roles in health and disease of the liver. In addition to lipid storage, lipid droplets are also directly involved in lipid metabolism, membrane biosynthesis, cell signaling, inflammation, pathogen-host interaction and cancer development. In addition, they interact with other cellular organelles to regulate cellular biology. It is fair to say that the exact functions of lipid droplets in cellular physiology remain largely obscure. Thus prompted, here we aim to analyze the corpus of contemporary biomedical literature to create a framework as to how the role of lipid droplets in hepatocyte physiology and pathophysiology should be understood. The resulting framework should help understanding the interaction of lipid droplets with other organelles in important liver diseases, including fatty liver disease, viral hepatitis and liver cancer and direct further research directions.


Assuntos
Homeostase , Gotículas Lipídicas/metabolismo , Metabolismo dos Lipídeos , Hepatopatias/patologia , Organelas/metabolismo , Transdução de Sinais , Animais , Humanos , Hepatopatias/metabolismo
18.
BMC Pediatr ; 21(1): 95, 2021 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-33627089

RESUMO

BACKGROUND: The emerging of psychological problems triggered by COVID-19 particularly in children have been extensively highlighted and emphasized, but original research in this respect is still lagging behind. Therefore, we designed this study to evaluate the impact of COVID-19 pandemic on mental health and the effectiveness and attitudes towards online education among Chinese children aged 7-15 years. METHODS: A detailed questionnaire, comprising of 62 questions was designed and parents or caretakers of 7 to 15 years old children were invited to participate via WeChat, a multi-purpose messaging, social media and mobile payment app, which is widely used by the Chinese population. A total of 668 parents across different regions of China were included. RESULTS: During COVID-19 pandemic, 20.7 and 7.2% children report experiencing post-traumatic stress disorder (PTSD) and depressive symptoms due to the COVID-19 pandemic. PTSD and SMFQ-P scores are significantly higher in middle school and boarding school students compared to primary and day school students. Multiple logistic regression analysis revealed that school system and province of origin are factors significantly associated with developing PSTD symptoms. 44.3% respondents feel online education is effective in gaining knowledge and improving practical and communications skills. 78.0% believe the online education system is efficient. Overall 79.8% respondents are satisfied and children can adapt to this new education system. During the COVID-19 pandemic, we found 1 in five children have PTSD and 1 in 14 children have depressive symptoms. CONCLUSION: In summary, COVID-19 epidemic has caused PTSD and depression symptoms among Chinese children aged 7 to 15 years. In general, a large proportion of respondents are satisfied with online education, but still a substantial proportion of students are not comfortable with this new form of learning. Authorities should optimize online education systems and implement effective interventions to cope with the psychological effects of COVID-19 on children, as it is affecting the global population and remains uncertain when it will end.


Assuntos
COVID-19/psicologia , Depressão/epidemiologia , Saúde Mental , Pandemias , Transtornos de Estresse Pós-Traumáticos/epidemiologia , Adolescente , Criança , China/epidemiologia , Estudos Transversais , Humanos , Inquéritos e Questionários
19.
Transbound Emerg Dis ; 2021 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-33539678

RESUMO

Epicentres are the focus of COVID-19 research, whereas emerging regions with mainly imported cases due to population movement are often neglected. Classical compartmental models are useful, however, likely oversimplify the complexity when studying epidemics. This study aimed to develop a multi-regional, hierarchical-tier mathematical model for better understanding the complexity and heterogeneity of COVID-19 spread and control. By incorporating the epidemiological and population flow data, we have successfully constructed a multi-regional, hierarchical-tier SLIHR model. With this model, we revealed insight into how COVID-19 was spread from the epicentre Wuhan to other regions in Mainland China based on the large population flow network data. By comprehensive analysis of the effects of different control measures, we identified that Level 1 emergency response, community prevention and application of big data tools significantly correlate with the effectiveness of local epidemic containment across different provinces of China outside the epicentre. In conclusion, our multi-regional, hierarchical-tier SLIHR model revealed insight into how COVID-19 spread from the epicentre Wuhan to other regions of China, and the subsequent control of local epidemics. These findings bear important implications for many other countries and regions to better understand and respond to their local epidemics associated with the ongoing COVID-19 pandemic.

20.
Transplantation ; 2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33577251

RESUMO

Mitochondria are essential organelles for cellular energy and metabolism. Like with any organ, the liver highly depends on the function of these cellular powerhouses. Hepatotoxic insults often lead to an impairment of mitochondrial activity and an increase in oxidative stress, thereby compromising the metabolic and synthetic functions. Mitochondria play a critical role in ATP synthesis and the production or scavenging of free radicals. Mitochondria orchestrate many cellular signalling pathways involved in the regulation of cell death, metabolism, cell division and progenitor cell differentiation. Mitochondrial dysfunction and oxidative stress are closely associated with ischemia-reperfusion injury during organ transplantation and with different liver diseases, including cholestasis, steatosis, viral hepatitis, and drug-induced liver injury. In order to develop novel mitochondria-targeting therapies or interventions, a better understanding of mitochondrial dysfunction and oxidative stress in hepatic pathogenesis is very much needed. Therapies targeting mitochondria impairment and oxidative imbalance in liver diseases have been extensively studied in preclinical and clinical research. In this review, we provide an overview of how oxidative stress and mitochondrial dysfunction affect liver diseases and liver transplantation. Furthermore, we summarize recent developments of antioxidant and mitochondria-targeted interventions.

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