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1.
Cardiol Rev ; 29(1): 39-42, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33136582

RESUMO

Patients older than 65 years hospitalized with COVID-19 have higher rates of intensive care unit admission and death when compared with younger patients. Cardiovascular conditions associated with COVID-19 include myocardial injury, acute myocarditis, cardiac arrhythmias, cardiomyopathies, cardiogenic shock, thromboembolic disease, and cardiac arrest. Few studies have described the clinical course of those at the upper extreme of age. We characterize the clinical course and outcomes of 73 patients with 80 years of age or older hospitalized at an academic center between March 15 and May 13, 2020. These patients had multiple comorbidities and often presented with atypical clinical findings such as altered sensorium, generalized weakness and falls. Cardiovascular manifestations observed at the time of presentation included new arrhythmia in 7/73 (10%), stroke/intracranial hemorrhage in 5/73 (7%), and elevated troponin in 27/58 (47%). During hospitalization, 38% of all patients required intensive care, 13% developed a need for renal replacement therapy, and 32% required vasopressor support. All-cause mortality was 47% and was highest in patients who were ever in intensive care (71%), required mechanical ventilation (83%), or vasopressors (91%), or developed a need for renal replacement therapy (100%). Patients older than 80 years old with COVID-19 have multiple unique risk factors which can be associated with increased cardiovascular involvement and death.


Assuntos
Lesão Renal Aguda/terapia , Mortalidade Hospitalar , Terapia de Substituição Renal/estatística & dados numéricos , Respiração Artificial/estatística & dados numéricos , Vasoconstritores/uso terapêutico , Centros Médicos Acadêmicos , Acidentes por Quedas , Lesão Renal Aguda/etiologia , Idoso de 80 Anos ou mais , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/fisiopatologia , Aspartato Aminotransferases/metabolismo , Proteína C-Reativa/metabolismo , /metabolismo , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Causas de Morte , Transtornos da Consciência/fisiopatologia , Dispneia/fisiopatologia , Feminino , Ferritinas/metabolismo , Febre/fisiopatologia , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Hospitalização , Humanos , Hipóxia/fisiopatologia , Hipóxia/terapia , Vida Independente , Unidades de Terapia Intensiva/estatística & dados numéricos , Hemorragias Intracranianas/etiologia , Hemorragias Intracranianas/fisiopatologia , Contagem de Leucócitos , Hepatopatias/etiologia , Hepatopatias/metabolismo , Contagem de Linfócitos , Masculino , Debilidade Muscular/fisiopatologia , Peptídeo Natriurético Encefálico/metabolismo , Casas de Saúde , Oxigenoterapia , Pró-Calcitonina/metabolismo , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/fisiopatologia , Troponina I/metabolismo
2.
Discov Med ; 30(160): 107-112, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33382966

RESUMO

Liver injury has been reported as a common complication in Coronavirus disease 2019 (COVID-19). Recently, more and more studies reported that the degree of liver damages was associated with the severity of COVID-19. Although the exact mechanism of liver injury in COVID-19 patients is unknown, recent studies have made some explorations and investigations. In this review, we summarized the potential mechanisms of liver dysfunction in COVID-19 patients gleaned from recently published research reports, which suggested that the progression of pre-existing liver diseases, direct damage of liver by SARS-CoV-2, systemic inflammation caused by SARS-CoV-2 infection, anti-viral drug toxicity, and hypoxia-reperfusion may be associated with liver injury in patients with COVID-19. Hypoxic liver injury due to ischemia and shock, cholestasis-related liver injury due to altered bile metabolism, and hepatocellular injury due to drug toxicity or overwhelming inflammation might occur in severe COVID-19 patients with sepsis. To understand the pathogenesis of liver dysfunction in COVID-19 patients, further research is needed to focus on liver-related comorbidities, the evidence of viral replication in hepatocytes and bile duct cells, histological features of liver injury, and the influence of hepatotoxic antiviral drugs. We also suggested that special attention should be paid to monitoring inflammatory cytokines and hypoxia for the prevention and treatment of liver injury in severe COVID-19 patients. A deep understanding of the mechanism of liver injury is helpful for the management and treatment of COVID-19 patients.


Assuntos
/metabolismo , Hipóxia/metabolismo , Hepatopatias/metabolismo , Fígado/irrigação sanguínea , Fígado/metabolismo , /metabolismo , Antivirais/uso terapêutico , /tratamento farmacológico , Humanos , Hipóxia/tratamento farmacológico , Hipóxia/patologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Fígado/patologia , Hepatopatias/tratamento farmacológico , Hepatopatias/etiologia , Hepatopatias/patologia
3.
PLoS One ; 15(11): e0239119, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33137133

RESUMO

Autophagy is an important factor in liver ischemia-reperfusion injury. In the current study we investigate the function of interferon regulatory factor-1 (IRF1) in regulating autophagy to promote hepatic ischemia reperfusion injury (IR). The high expression of IRF1 during hepatic IR exhibited increased liver damage and was associated with activation of autophagy shown by Western blot markers, as well as immunofluorescent staining for autophagosomes. These effects were diminished by IRF1 deficiency in IRF1 knock out (KO) mice. Moreover, the autophagy inhibitor 3-MA decreased IR-induced liver necrosis and markedly abrogated the rise in liver injury tests (AST/ALT). ß-catenin expression decreased during liver IR and was increased in the IRF1 KO mice. Immunoprecipitation assay showed the binding between IRF1 and ß-catenin. Overexpression of IRF1 induced autophagy and also inhibited the expression of ß-catenin. ß-catenin inhibitor increased autophagy while ß-catenin agonist suppressed autophagy in primary mouse hepatocytes. These results indicate that IRF1 induced autophagy aggravates hepatic IR injury in part by inhibiting ß-catenin and suggests that targeting IRF1 may be an effective strategy in reducing hepatic IR injury.


Assuntos
Autofagia/fisiologia , Fator Regulador 1 de Interferon/metabolismo , Hepatopatias/metabolismo , Fígado/metabolismo , Traumatismo por Reperfusão/metabolismo , beta Catenina/metabolismo , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
4.
Toxicol Appl Pharmacol ; 409: 115309, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-33130049

RESUMO

The antimalarial drug artesunate (Art) has proven its beneficial effects against ischemia/reperfusion (I/R) injury in diverse organs, but its potential role against hepatic I/R is still obscure. This study, hence, examined whether treatment with Art alone or in combination with rapamycin (Rapa), an mTOR inhibitor, can ameliorate hepatic I/R injury via targeting the NLRP3 inflammasome signaling pathway. Rats were divided into hepatic sham- and I/R-operated rats. The latter were either left untreated (I/R group) or treated with Art, Rapa, or their combination. On the molecular level, all treatment regimens succeeded to hinder inflammasome assembly and activation, assessed as NLRP3, ASC, cleaved caspase-1, caspase-11, N-terminal cleaved gasdermin-D (GSDMD-N), IL-1ß, and IL-18. This effect was associated by the inhibition in the harmful signaling pathways HMGB1/RAGE and TLR4/MyD88/TRAF6 to inactivate the transcription factor NF-κB and the production of its pro-inflammatory cytokines IL-1ß, IL-18, IL-6, and TNF-α. Additionally, this effect entailed the inhibition of ICAM-1/MPO/ROS cascade, which in turn hampered cell demise induced by apoptosis, manifested as correction of the imbalanced Bcl2/Bax, as well as pyroptosis (LDH, cleaved caspase-1, caspase-11, GSDMD-N, IL-1ß, and IL-18), and necrosis. The corrected pathways were reflected on the improved liver function (serum ALT, AST, and LDH) and microscopical hepatic architecture. Noteworthy, the effect of Art on all parameters exceeded significantly that of Rapa and even improved the effect of the latter in the combination group. In conclusion, our results suggest novel roles for Art in abating functional and structural I/R-induced hepatic abnormalities via several traversing cross-talking pathways that succeeded to abate NLRP3 inflammasome and cell death.


Assuntos
Artesunato/farmacologia , Inflamassomos/deficiência , Hepatopatias/tratamento farmacológico , Fígado/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Citocinas/metabolismo , Inflamassomos/metabolismo , Inflamação/metabolismo , Fígado/metabolismo , Hepatopatias/metabolismo , Masculino , Ratos , Ratos Wistar , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais/efeitos dos fármacos
5.
PLoS One ; 15(11): e0241663, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33147270

RESUMO

BACKGROUND/AIM: The coronavirus disease 2019 (COVID-19) had become a big threat worldwide. Liver injury is not uncommon in patients with COVID-19, and clarifying its characteristics is needed. This study aimed to identify factors associated with liver injury and to develop a new classification of predictive severity in patients with COVID-19. METHODS: Confirmed patients with COVID-19 (n = 60) were recruited retrospectively from Musashino Red Cross Hospital. The factors of liver injury especially on the elevation of liver enzymes (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) were analyzed. Grading was assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. RESULTS: During a median hospitalization follow-up of 15 (4-41) days, 51 (85.0%) patients had COVID-19 pneumonia. In clinical courses, oxygenation was needed for 25 (41.6%) patients and intubation was needed for 9 (15.0%) patients. A total of 27 (45.0%) patients had gastrointestinal symptoms (GS), such as appetite loss, diarrhea, and nausea. A logistic regression analysis revealed that C-reactive protein (CRP) at baseline, oxygenation, intubation, and GS were significant factors of liver injury. Based on these results, patients were classified into three groups: group 1, no oxygenation pneumonia; group 2, pneumonia with oxygenation or GS; and group 3, intubation. We classified 25 (41.7%), 26 (43.3%), and 9 (15.0%) patients into mild, moderate, and severe groups, respectively. The peak of AST and ALT levels was significantly stratified with this criteria (mild [median AST, 28 IU/L; median ALT, 33 IU/L], moderate [median AST, 48 IU/L; median ALT, 47.5 IU/L], and severe [median AST, 109 IU/L; median ALT, 106 IU/L]; P<0.001 and P = 0.0114, respectively). CONCLUSION: COVID-19-related liver injury was significantly stratified based on GS and severity of pneumonia.


Assuntos
Infecções por Coronavirus/patologia , Doenças do Sistema Digestório/patologia , Doenças do Sistema Digestório/virologia , Hepatopatias/patologia , Hepatopatias/virologia , Pneumonia Viral/patologia , Pneumonia/patologia , Pneumonia/virologia , Alanina Transaminase/metabolismo , Aspartato Aminotransferases/metabolismo , Proteína C-Reativa/metabolismo , Doenças do Sistema Digestório/metabolismo , Feminino , Seguimentos , Humanos , Fígado/metabolismo , Fígado/patologia , Fígado/virologia , Hepatopatias/metabolismo , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia/metabolismo , Estudos Retrospectivos , Índice de Gravidade de Doença
6.
PLoS Pathog ; 16(10): e1008947, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33075079

RESUMO

Endothelin receptors (ETRs) are activated by vasoactive peptide endothelins and involved in the pathogenesis of hepatic fibrosis. However, less is known about the role of ETRs in Schistosoma (S.) japonicum-induced hepatic fibrosis. Here, we show that the expression of ETRs is markedly enhanced in the liver and spleen tissues of patients with schistosome-induced fibrosis, as well as in murine models. Additional analyses have indicated that the expression levels of ETRs in schistosomiasis patients are highly correlated with the portal vein and spleen thickness diameter, both of which represent the severity of fibrosis. Splenomegaly is a characteristic symptom of schistosome infection, and splenic abnormality may promote the progression of hepatic fibrosis. We further demonstrate that elevated levels of ETRs are predominantly expressed on splenic B cells in spleen tissues during infection. Importantly, using a well-studied model of human schistosomiasis, we demonstrate that endothelin receptor antagonists can partially reverse schistosome-induced hepatic fibrosis by suppressing the activation of splenic B cells characterized by interleukin-10 (IL-10) secretion and regulatory T (Treg) cell-inducing capacity. Our study provides insights into the mechanisms by which ETRs regulate schistosomiasis hepatic fibrosis and highlights the potential of endothelin receptor antagonist as a therapeutic intervention for fibrotic diseases.


Assuntos
Linfócitos B/patologia , Fibrose/patologia , Hepatopatias/patologia , Receptores de Endotelina/metabolismo , Schistosoma japonicum/isolamento & purificação , Esquistossomose/complicações , Baço/patologia , Adulto , Idoso , Animais , Linfócitos B/metabolismo , Linfócitos B/parasitologia , Feminino , Fibrose/etiologia , Fibrose/metabolismo , Humanos , Hepatopatias/etiologia , Hepatopatias/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Receptores de Endotelina/genética , Esquistossomose/parasitologia , Baço/metabolismo , Baço/parasitologia
7.
Sci Rep ; 10(1): 17187, 2020 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-33057098

RESUMO

Heparan sulfate (HS) is a sulfated glycosaminoglycan abundant on the cell surface and in the extracellular matrix and has several biological activities including anticoagulation and anti-inflammation. Liver ischemia reperfusion injury is associated with coagulation and inflammatory responses. Here, we synthesized HS oligosaccharides with defined sulfation patterns and show that synthetic anticoagulant HS oligosaccharides limit liver ischemia reperfusion injury in a mouse model. Using a small targeted HS library, we demonstrate that an oligosaccharide that possesses both anticoagulant activity and binding affinity to HMGB1, the inflammatory target, decreases injury greater than oligosaccharides that only bind to HMGB1 or only have anticoagulant activity. HS oligosaccharides may represent a potential new therapeutic option for decreasing liver damage resulting from ischemia reperfusion injury.


Assuntos
Anticoagulantes/farmacologia , Heparitina Sulfato/farmacologia , Hepatopatias/tratamento farmacológico , Fígado/efeitos dos fármacos , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Coagulação Sanguínea/efeitos dos fármacos , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Proteína HMGB1/metabolismo , Fígado/metabolismo , Hepatopatias/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oligossacarídeos/farmacologia , Traumatismo por Reperfusão/metabolismo
8.
J Trauma Acute Care Surg ; 89(4): 768-774, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33017135

RESUMO

BACKGROUND: Burn injury still has a high attributable mortality. The elevated mortality rate of severe burns is still concerning. Hepatic inflammation and injury are common after burns and are associated with poor outcomes. Necroptosis is a programmed cell death linked with inflammation. Thus, assessing necroptotic pathways in the liver can lead to new therapeutic modalities to improve mortality after severe burns. METHODS: Mice underwent 15% total body surface area burn or sham injury. Three hours after burn, the mice were euthanized to collect blood and livers. Histology, injury markers, genes expression, and tissue protein levels were compared between groups. RESULTS: Compared with sham, burned mice had heightened liver inflammatory cell infiltration and edema. Serum aspartate aminotransferase and alanine aminotransferase were increased by 4.9- and 3.4-fold, respectively, in burned mice relative to sham (p < 0.05). Expression of tumor necrosis factor α, interleukin-6, interleukin-1ß, and CXCL1 (KC) genes were elevated in livers of burned mice by 10-, 86-, 10-, and 828-fold, respectively, compared with sham (p < 0.05). Expression of necroptotic genes, namely, receptor-interacting protein kinases 1 and 3, and mixed lineage kinase domain-like in livers of burned mice were increased by 10-, 13-, and 4.5-fold, respectively, relative to sham (p < 0.05). Receptor-interacting protein kinase 1 and phosphorylated mixed lineage kinase domain-like protein levels measured by Western-blot in livers after burn injury were elevated by 22- and 17-fold, respectively, compared with sham (p < 0.05). CONCLUSION: Liver damage occurs early after burns in mice and is associated with elevation of proinflammatory cytokines, chemokine, and proteins involved in the necroptotic pathway. This study suggests that necroptosis plays a role in the pathogenesis of liver failure secondary to burn injury.


Assuntos
Queimaduras/metabolismo , Inflamação/metabolismo , Hepatopatias/metabolismo , Fígado/patologia , Animais , Queimaduras/complicações , Quimiocina CXCL1/metabolismo , Feminino , Inflamação/etiologia , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Hepatopatias/etiologia , Camundongos , Camundongos Endogâmicos BALB C , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo
9.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1865(12): 158791, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32777482

RESUMO

Angiopoietin like protein 3 (ANGPTL3) is best known for its function as an inhibitor of lipoprotein and endothelial lipases. Due to the capacity of genetic or pharmacologic ANGPTL3 suppression to markedly reduce circulating lipoproteins, and the documented cardioprotection upon such suppression, ANGPTL3 has become an emerging therapy target for which both antibody and antisense oligonucleotide (ASO) therapeutics are being clinically tested. While the antibody is relatively selective for circulating ANGPTL3, the ASO also depletes the intra-hepatocellular protein, and there is emerging evidence for cell-autonomous functions of ANGPTL3 in the liver. These include regulation of hepatocyte glucose and fatty acid uptake, insulin sensitivity, LDL/VLDL remnant uptake, VLDL assembly/secretion, polyunsaturated fatty acid (PUFA) and PUFA-derived lipid mediator content, and gene expression. In this review we elaborate on (i) why ANGPTL3 is considered one of the most promising new cardiometabolic therapy targets, and (ii) the present evidences for its intra-hepatocellular or cell-autonomous functions.


Assuntos
Proteínas Semelhantes a Angiopoietina/metabolismo , Doenças Cardiovasculares/metabolismo , Hepatopatias/metabolismo , Metaboloma , Proteínas Semelhantes a Angiopoietina/antagonistas & inibidores , Proteínas Semelhantes a Angiopoietina/sangue , Animais , Anticorpos/uso terapêutico , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/tratamento farmacológico , Humanos , Resistência à Insulina , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipoproteínas/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Hepatopatias/sangue , Hepatopatias/tratamento farmacológico , Metaboloma/efeitos dos fármacos , Modelos Moleculares , Terapia de Alvo Molecular , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Oligonucleotídeos Antissenso/uso terapêutico
10.
Semin Perinatol ; 44(7): 151284, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32792262

RESUMO

The 2019 novel coronavirus disease (COVID-19) pandemic poses unique challenges to the medical community as the optimal treatment has not been determined and is often at the discretion of institutional guidelines. Pregnancy has previously been described as a high-risk state in the context of infectious diseases, given a particular susceptibility to pathogens and adverse outcomes. Although ongoing studies have provided insight on the course of this disease in the adult population, the implications of COVID-19 on pregnancy remains an understudied area. The objective of this study is to review the literature and describe clinical presentations among pregnant women afflicted with COVID-19.


Assuntos
/fisiopatologia , Complicações Infecciosas na Gravidez/fisiopatologia , Lesão Renal Aguda/fisiopatologia , Infecções Assintomáticas , Transtornos da Coagulação Sanguínea/fisiopatologia , /metabolismo , Cardiomiopatias/fisiopatologia , Doenças do Sistema Nervoso Central/fisiopatologia , Progressão da Doença , Feminino , Síndrome HELLP/metabolismo , Humanos , Hipercapnia , Hipóxia/diagnóstico , Hipóxia/fisiopatologia , Hipóxia/terapia , Hepatopatias/metabolismo , Hepatopatias/fisiopatologia , Programas de Rastreamento , Mialgia/fisiopatologia , Miocardite/fisiopatologia , Oxigenoterapia , Pré-Eclâmpsia/metabolismo , Gravidez , Complicações Infecciosas na Gravidez/imunologia , Complicações Infecciosas na Gravidez/metabolismo , Complicações Infecciosas na Gravidez/terapia , Índice de Gravidade de Doença , Distúrbios do Paladar/fisiopatologia
11.
Biochem Pharmacol ; 180: 114171, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32710968

RESUMO

The human population is burdened by morbidity and mortality from liver diseases that largely arise due to hepatitis virus infection, alcohol abuse, obesity, and diabetes. Despite 2 million global deaths per annum from liver disease, the number of drugs approved by the U.S. Food and Drug Administration (FDA) for the treatment of these disorders is sparse. Eastern medicine embodies a millennia long tradition in the use of natural product remedies for liver disease, which has attracted the interest of western medical practitioners and patients alike. Questions remain regarding the safety, efficacy, and quality of such natural products in a western medical context. Of particular concern is whether or not the mechanism of action of the product is known and, if the remedy has multiple natural constituents, how these interact at a biochemical, physiological, and clinical level. In this Commentary, we have examined the potential of metabolomics to help answer these queries, illustrated by investigations of yin chen hao tang, silymarin, and xiaozhang tie. In all cases, unique understandings of the mechanism of action of these natural products was obtained through metabolomic investigations in animal models, cell culture systems, and in clinical studies. Such mechanistic insights help assure the safety and efficacy of these natural product therapies.


Assuntos
Produtos Biológicos/metabolismo , Produtos Biológicos/uso terapêutico , Hepatopatias/tratamento farmacológico , Hepatopatias/metabolismo , Metabolômica/métodos , Animais , Humanos , Medicina Tradicional Chinesa/métodos , Medicina Tradicional Chinesa/tendências , Metabolômica/tendências , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/metabolismo , Extratos Vegetais/uso terapêutico
12.
Indian J Gastroenterol ; 39(3): 232-235, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32621206

RESUMO

The novel coronavirus Severe Acute Respiratory Syndrome Corona Virus-2 (SARS-CoV-2) infection has been mostly leading to respiratory distress syndrome, but liver injury has also been documented. The mechanism of liver injury is limited and poorly understood. However, the hepatic injury could be due to a consequence of systemic inflammatory response, viral infection of hepatocytes, or as a result of intensive care treatment or drug toxicity. Based on the current studies, this review article emphasizes on the demographic and potential mechanisms of Corona Virus Disease (COVID)-19-related liver dysfunction.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus , Hepatopatias , Pandemias , Pneumonia Viral , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/terapia , Infecções por Coronavirus/virologia , Interações entre Hospedeiro e Microrganismos/fisiologia , Humanos , Hepatopatias/diagnóstico , Hepatopatias/epidemiologia , Hepatopatias/etiologia , Hepatopatias/metabolismo , Testes de Função Hepática/métodos , Pneumonia Viral/epidemiologia , Pneumonia Viral/terapia , Pneumonia Viral/virologia
13.
Sci Rep ; 10(1): 10858, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32616907

RESUMO

Normal liver tissue is highly vulnerable towards irradiation, which remains a challenge in radiotherapy of hepatic tumours. Here, we examined the effects of radiation-induced liver injury on two specific liver functions and hepatocellular regeneration in a minipig model. Five Göttingen minipigs were exposed to whole-liver stereotactic body radiation therapy (SBRT) in one fraction (14 Gy) and examined 4-5 weeks after; five pigs were used as controls. All pigs underwent in vivo positron emission tomography (PET) studies of the liver using the conjugated bile acid tracer [N-methyl-11C]cholylsarcosine ([11C]CSar) and the galactose-analogue tracer [18F]fluoro-2-deoxy-D-galactose ([18F]FDGal). Liver tissue samples were evaluated histopathologically and by immunohistochemical assessment of hepatocellular mitosis, proliferation and apoptosis. Compared with controls, both the rate constant for secretion of [11C]CSar from hepatocytes into intrahepatic bile ducts as well as back into blood were doubled in irradiated pigs, which resulted in reduced residence time of [11C]CSar inside the hepatocytes. Also, the hepatic systemic clearance of [18F]FDGal in irradiated pigs was slightly increased, and hepatocellular regeneration was increased by a threefold. In conclusion, parenchymal injury and increased regeneration after whole-liver irradiation was associated with enhanced hepatobiliary secretion of bile acids. Whole-liver SBRT in minipigs ultimately represents a potential large animal model of radiation-induced liver injury and for testing of normal tissue protection methods.


Assuntos
Ácidos e Sais Biliares/metabolismo , Sistema Biliar/metabolismo , Hepatopatias/patologia , Fígado/citologia , Lesões por Radiação/patologia , Radioterapia Conformacional/efeitos adversos , Regeneração , Animais , Sistema Biliar/diagnóstico por imagem , Feminino , Fígado/diagnóstico por imagem , Fígado/metabolismo , Fígado/efeitos da radiação , Hepatopatias/etiologia , Hepatopatias/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Lesões por Radiação/etiologia , Lesões por Radiação/metabolismo , Compostos Radiofarmacêuticos/metabolismo , Suínos
14.
Life Sci ; 257: 118130, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32710950

RESUMO

BACKGROUND AND OBJECTIVES: Sepsis is a life-threatening organ dysfunction syndrome arising from uncontrolled inflammatory responses. Liver injury is a crucial factor for the prognosis of sepsis. Camptothecins (CPTs) have been reported to suppress the inflammatory response induced by sepsis. G2, a CPT-bile acid conjugate, has been demonstrated the property of liver targeting in our previous research. This study aimed to research the effects of G2 on liver injury induced by cecal ligation and puncture (CLP). METHODS: C57BL/6 mice were subjected to CLP surgery, and effects of G2 on liver damage and survival rates of CLP-induced mice were evaluated. To detect the related markers of hepatic injury or neutrophil infiltration, inflammatory cytokines and protein levels, hematoxylin-eosin staining assay, corresponding Detection Kits assay, ELISA and Western blot analysis were performed. RESULTS: Intraperitoneal administration of G2 reduced liver injury and enhanced the survival rates in mice with sepsis. Treatment with G2 decreased the levels of hepatic injury markers aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in the serum of mice induced by CLP. The hepatic level of neutrophil infiltration marker myeloperoxidase (MPO) was reduced in G2 administration group. And the levels of serum inflammatory cytokines, including Tumor Necrosis Factor-α (TNFα), Interleukin-6 (IL-6) and IL-1ß, were decreased by G2. Furthermore, the results of Western blot analysis indicated that G2 suppressed the up-regulation of NF-κB p-P65 and p-IκBα. It suggested that G2 suppressed the activation of NF-κB signaling pathway. CONCLUSION: G2 alleviated sepsis-induced liver injury via inhibiting the NF-κB signaling pathway.


Assuntos
Ácidos e Sais Biliares/uso terapêutico , Camptotecina/uso terapêutico , Hepatopatias/etiologia , NF-kappa B/metabolismo , Sepse/complicações , Transdução de Sinais/efeitos dos fármacos , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Ácidos e Sais Biliares/administração & dosagem , Western Blotting , Camptotecina/administração & dosagem , Citocinas/sangue , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Hepatopatias/metabolismo , Hepatopatias/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Peroxidase/metabolismo
16.
Am J Gastroenterol ; 115(8): 1153-1155, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32496340

Assuntos
Infecções por Coronavirus/fisiopatologia , Doenças do Sistema Digestório/fisiopatologia , Pneumonia Viral/fisiopatologia , Dor Abdominal/etiologia , Dor Abdominal/metabolismo , Dor Abdominal/fisiopatologia , Dor Abdominal/terapia , Assistência Ambulatorial , Anorexia/etiologia , Anorexia/metabolismo , Anorexia/fisiopatologia , Anorexia/terapia , Antibacterianos/efeitos adversos , Antipiréticos/efeitos adversos , Antivirais/efeitos adversos , Betacoronavirus , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/fisiopatologia , Doença Hepática Induzida por Substâncias e Drogas/terapia , China , Infecções por Clostridium/diagnóstico , Infecções por Clostridium/tratamento farmacológico , Infecções por Coronavirus/complicações , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/terapia , Diarreia/etiologia , Diarreia/metabolismo , Diarreia/fisiopatologia , Diarreia/terapia , Doenças do Sistema Digestório/etiologia , Doenças do Sistema Digestório/metabolismo , Doenças do Sistema Digestório/terapia , Endoscopia do Sistema Digestório , Gastroenterologia , Humanos , Hepatopatias/etiologia , Hepatopatias/metabolismo , Hepatopatias/fisiopatologia , Hepatopatias/terapia , Náusea/etiologia , Náusea/metabolismo , Náusea/fisiopatologia , Náusea/terapia , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/metabolismo , Pneumonia Viral/terapia , Probióticos/uso terapêutico , Sociedades Médicas , Vômito/etiologia
17.
J Hepatol ; 73(5): 1231-1240, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32553666

RESUMO

The current coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has become a major public health crisis over the past few months. Overall case fatality rates range between 2-6%; however, the rates are higher in the elderly and those with underlying comorbidities like diabetes, hypertension and heart disease. Recent reports showed that about 2-11% of patients with COVID-19 had underlying chronic liver disease. During the previous SARS epidemic, around 60% of patients were reported to develop various degrees of liver damage. In the current pandemic, hepatic dysfunction has been seen in 14-53% of patients with COVID-19, particularly in those with severe disease. Cases of acute liver injury have been reported and are associated with higher mortality. Hepatic involvement in COVID-19 could be related to the direct cytopathic effect of the virus, an uncontrolled immune reaction, sepsis or drug-induced liver injury. The postulated mechanism of viral entry is through the host angiotensin-converting enzyme 2 (ACE2) receptors that are abundantly present in type 2 alveolar cells. Interestingly, ACE2 receptors are expressed in the gastrointestinal tract, vascular endothelium and cholangiocytes of the liver. The effects of COVID-19 on underlying chronic liver disease require detailed evaluation and, with data currently lacking, further research is warranted in this area.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus , Hepatopatias , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral , Comorbidade , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/fisiopatologia , Humanos , Fígado/metabolismo , Hepatopatias/epidemiologia , Hepatopatias/metabolismo , Hepatopatias/virologia , Pneumonia Viral/epidemiologia , Pneumonia Viral/fisiopatologia , Fatores de Risco , Índice de Gravidade de Doença
18.
J Agric Food Chem ; 68(27): 7112-7120, 2020 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-32538091

RESUMO

Acute liver injury resulting from several factors such as medication, food toxins, and herbal supplementation often leads to a severe health condition and makes treatment difficult; thereby, the prevention of acute liver injury remains a critical issue and is of great importance. In this study, we investigated the preventive effects of nobiletin (NOB) on a mouse model of concanavalin A (ConA)-induced acute liver injury. We observed that NOB (10 mg/kg) pretreatment of ConA-treated mice significantly lowered the levels of liver enzymes including alanine aminotransferase (ALT) and aspartate aminotransferase (AST), decreased the intracellular generation of reactive oxygen species (ROS), and suppressed the release of inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ). Pathological data suggested that pretreatment with NOB ameliorated ConA-induced liver damage by promoting proliferation and alleviating apoptosis of hepatocytes. Furthermore, significant suppression of the c-Jun-activating kinase (JNK) signal was also observed in NOB-pretreated liver tissues compared with that of ConA treatment only. In addition, an in vitro mechanism study confirmed that the addition of NOB protected hepatocytes via inhibition of JNK activation, manifesting that alleviation of JNK-induced apoptosis of hepatocytes is correlated with NOB protection in acute liver injury.


Assuntos
Flavonas/administração & dosagem , Hepatócitos/efeitos dos fármacos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Hepatopatias/tratamento farmacológico , Fígado/lesões , Substâncias Protetoras/administração & dosagem , Alanina Transaminase/genética , Alanina Transaminase/metabolismo , Animais , Apoptose/efeitos dos fármacos , Aspartato Aminotransferases/genética , Aspartato Aminotransferases/metabolismo , Hepatócitos/citologia , Hepatócitos/metabolismo , Humanos , Interferon gama/genética , Interferon gama/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Hepatopatias/genética , Hepatopatias/metabolismo , Hepatopatias/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Espécies Reativas de Oxigênio/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
19.
Nat Rev Gastroenterol Hepatol ; 17(8): 457-472, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32483353

RESUMO

Liver disease is a major global health-care problem, affecting an estimated 844 million people worldwide. Despite this substantial burden, therapeutic options for liver disease remain limited, in part owing to a paucity of detailed analyses defining the cellular and molecular mechanisms that drive these conditions in humans. Single-cell transcriptomic technologies are transforming our understanding of cellular diversity and function in health and disease. In this Review, we discuss how these technologies have been applied in hepatology, advancing our understanding of cellular heterogeneity and providing novel insights into fundamental liver biology such as the metabolic zonation of hepatocytes, endothelial cells and hepatic stellate cells, and the cellular mechanisms underpinning liver regeneration. Application of these methodologies is also uncovering critical pathophysiological changes driving disease states such as hepatic fibrosis, where distinct populations of macrophages, endothelial cells and mesenchymal cells reside within a spatially distinct fibrotic niche and interact to promote scar formation. In addition, single-cell approaches are starting to dissect key cellular and molecular functions in liver cancer. In the near future, new techniques such as spatial transcriptomics and multiomic approaches will further deepen our understanding of disease pathogenesis, enabling the identification of novel therapeutic targets for patients across the spectrum of liver diseases.


Assuntos
Perfilação da Expressão Gênica , Hepatopatias/genética , Fígado/metabolismo , Análise de Célula Única , Células Endoteliais/metabolismo , Células Endoteliais/fisiologia , Fibroblastos/metabolismo , Fibroblastos/fisiologia , Gastroenterologia , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/fisiologia , Hepatócitos/metabolismo , Hepatócitos/fisiologia , Humanos , Inflamação/imunologia , Macrófagos do Fígado/imunologia , Fígado/citologia , Fígado/imunologia , Fígado/fisiologia , Cirrose Hepática/genética , Cirrose Hepática/imunologia , Cirrose Hepática/metabolismo , Hepatopatias/imunologia , Hepatopatias/metabolismo , Macrófagos/imunologia , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/fisiologia , Regeneração , Análise de Sequência de RNA
20.
Nat Biomed Eng ; 4(8): 801-813, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32572196

RESUMO

Monitoring the progression of non-alcoholic fatty liver disease is hindered by a lack of suitable non-invasive imaging methods. Here, we show that the endogenous pigment lipofuscin displays strong near-infrared and shortwave-infrared fluorescence when excited at 808 nm, enabling label-free imaging of liver injury in mice and the discrimination of pathological processes from normal liver processes with high specificity and sensitivity. We also show that the near-infrared and shortwave-infrared fluorescence of lipofuscin can be used to monitor the progression and regression of liver necroinflammation and fibrosis in mouse models of non-alcoholic fatty liver disease and advanced fibrosis, as well as to detect non-alcoholic steatohepatitis and cirrhosis in biopsied samples of human liver tissue.


Assuntos
Lipofuscina/metabolismo , Hepatopatias/diagnóstico por imagem , Hepatopatias/patologia , Animais , Biomarcadores/metabolismo , Doença Crônica , Progressão da Doença , Feminino , Fluorescência , Humanos , Lipodistrofia/diagnóstico por imagem , Lipodistrofia/metabolismo , Lipodistrofia/patologia , Fígado/diagnóstico por imagem , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/diagnóstico por imagem , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Hepatopatias/metabolismo , Masculino , Camundongos , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Imagem Óptica , Espectroscopia de Luz Próxima ao Infravermelho
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