Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 6.667
Filtrar
1.
Medicine (Baltimore) ; 100(41): e27464, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34731122

RESUMO

OBJECTIVE: This study aimed to determine the effectiveness of using total, individual serum, or urinary bile acids (BA) as potential markers of liver dysfunction. METHODS: We searched the PubMed and Web of Science databases using the following keywords- "serum bile acids," "liver dysfunction," "liver injury," "liver disease," "traditional liver function tests," "Chronic liver disease," "acute liver injury". The search was complemented by manual screening of the list of references for relevant articles. We selected only English-language manuscripts for adult patients based on predetermined inclusion and exclusion criteria. Animal studies and studies on neonates and children were not included. OUTCOME MEASURES: Changes in BA concentrations or ratios at or prior to changes in liver function tests. RESULTS: A total of 547 studies were identified, of which 28 were included after reading the entire manuscript. These studies included 1630 patients and 836 controls published between 1990 and 2017. The methods used in BA assays varied significantly, and the studies did not agree. on specific individual BA or BA ratios as biomarkers of specific liver injury or dysfunction. Except for the prognostic value of BA in intrahepatic cholestasis of pregnancy (ICP), studies have failed to provide evidence for BA as a liver biomarker. CONCLUSIONS: Despite the research conducted on BA for over 27 years, there are inconsistencies in the reported results and a lack of solid evidence to support the use of individual BA or BA ratios as biomarkers of liver injury. Adequately conducted studies needed to resolve this limitation in the literature.


Assuntos
Ácidos e Sais Biliares/sangue , Ácidos e Sais Biliares/urina , Hepatopatias/metabolismo , Fígado/lesões , Adulto , Biomarcadores/metabolismo , Estudos de Casos e Controles , Colestase Intra-Hepática/metabolismo , Gerenciamento de Dados , Feminino , Humanos , Fígado/metabolismo , Fígado/fisiopatologia , Hepatopatias/diagnóstico , Testes de Função Hepática/métodos , Testes de Função Hepática/estatística & dados numéricos , Masculino , Gravidez , Complicações na Gravidez/metabolismo , Sensibilidade e Especificidade
2.
Biol Pharm Bull ; 44(11): 1617-1634, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34719640

RESUMO

The CYP3A subfamily, which includes isoforms CYP3A4, CYP3A5, and CYP3A7 in humans, plays important roles in the metabolism of various endogenous and exogenous substances. Gene and protein expression of CYP3A4, CYP3A5, and CYP3A7 show large inter-individual differences, which are caused by many endogenous and exogenous factors. Inter-individual differences can cause negative outcomes, such as adverse drug events and disease development. Therefore, it is important to understand the variations in CYP3A expression caused by endo- and exogenous factors, as well as the variation in the metabolism and kinetics of endo- and exogenous substrates. In this review, we summarize the factors regulating CYP3A expression, such as bile acids, hormones, microRNA, inflammatory cytokines, drugs, environmental chemicals, and dietary factors. In addition, variations in CYP3A expression under pathological conditions, such as coronavirus disease 2019 and liver diseases, are described as examples of the physiological effects of endogenous factors. We also summarize endogenous and exogenous substrates metabolized by CYP3A isoforms, such as cholesterol, bile acids, hormones, arachidonic acid, vitamin D, and drugs. The relationship between the changes in the kinetics of these substrates and the toxicological effects in our bodies are discussed. The usefulness of these substrates and metabolites as endogenous biomarkers for CYP3A activity is also discussed. Notably, we focused on discrimination between CYP3A4, CYP3A5, and CYP3A7 to understand inter-individual differences in CYP3A expression and function.


Assuntos
Citocromo P-450 CYP3A/metabolismo , Animais , COVID-19/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Humanos , Hepatopatias/metabolismo , Isoformas de Proteínas/metabolismo
3.
Int J Mol Sci ; 22(19)2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34638810

RESUMO

Liver disease is a global health issue that has caused an economic burden worldwide. Organ transplantation is the only effective therapy for end-stage liver disease; however, it has been hampered by a shortage of donors. Human pluripotent stem cells (hPSCs) have been widely used for studying liver biology and pathology as well as facilitating the development of alternative therapies. hPSCs can differentiate into multiple types of cells, which enables the generation of various models that can be applied to investigate and recapitulate a range of biological activities in vitro. Here, we summarize the recent development of hPSC-derived hepatocytes and their applications in disease modeling, cell therapy, and drug discovery. We also discuss the advantages and limitations of these applications and critical challenges for further development.


Assuntos
Descoberta de Drogas , Hepatócitos/metabolismo , Hepatopatias , Organoides/metabolismo , Células-Tronco Pluripotentes/metabolismo , Humanos , Hepatopatias/metabolismo , Hepatopatias/terapia
4.
Nutrients ; 13(10)2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-34684371

RESUMO

BACKGROUND: Excessive intake of fructose, glucose and alcohol is associated with the development of non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD). At the same time, these dietetic factors create an environment favorable for the generation of advanced glycation end-products. For this reason, advanced glycation end-products (AGEs) are hypothesized to play role in the development of NAFLD and ALD. In this systematic review and meta-analysis, we explore the relationship between NAFLD and ALD with AGE levels, including their diagnostic accuracy. METHODS: The systematic review and meta-analysis has been pre-registered with PROSPERO (CRD42021240954) and was performed in accordance with the PRISMA guidelines. Meta-analyses were performed using the meta R package. RESULTS: We have obtained 11 studies meeting our inclusion criteria, reporting data on 1844 participants (909 with NAFLD, 169 with ALD and 766 healthy controls). NAFLD was associated with significantly higher AGE fluorescence and serum N-(carboxyethyl)lysine (CEL) levels. Patients with alcoholic cirrhosis had significantly higher levels of N-(carboxymethyl)lysine (CML). Only individual studies examined AGEs in the context of their diagnostic accuracy. AGE fluorescence distinguished low and moderate steatosis with an AUC of 0.76. The ratio of CML, CEL and pentosidine to a soluble variant of the AGE receptor differentiated patients with NAFLD from healthy controls with high AUC (0.83-0.85). Glyceraldehyde-derived AGE separated non-alcoholic fatty liver (NAFL) from non-alcoholic steatohepatitis (NASH) with acceptable performance (AUC 0.78). CONCLUSIONS: In conclusion, NAFLD and ALD are associated with significantly higher levels of several AGEs. More research is needed to examine the diagnostic accuracy of AGEs, however individual studies show that AGEs perform well in distinguishing NAFL from NASH.


Assuntos
Produtos Finais de Glicação Avançada/metabolismo , Hepatopatias/metabolismo , Animais , Estudos de Casos e Controles , Produtos Finais de Glicação Avançada/sangue , Humanos , Hepatopatias/sangue , Hepatopatias/diagnóstico , Viés de Publicação , Risco
5.
Nutrients ; 13(10)2021 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-34684386

RESUMO

In recent years, the beneficial effect of n-3 polyunsaturated fatty acids (n-3 PUFAs) intake on human health has been widely accepted in the field of immunonutrition. Today, we find a diversity of supplements based on n-3 PUFAs and/or minerals, vitamins and other substances. The main objective of this review is to discuss the importance of n-3 PUFAs and their derivatives on immunity and inflammatory status related to liver disease and other non-communicable illnesses. Based on the burden of liver diseases in 2019, more than two million people die from liver pathologies per year worldwide, because it is the organ most exposed to agents such as viruses, toxins and medications. Consequently, research conducted on n-3 PUFAs for liver disease has been gaining prominence with encouraging results, given that these fatty acids have anti-inflammatory and cytoprotective effects. In addition, it has been described that n-3 PUFAs are converted into a novel species of lipid intermediaries, specialized pro-resolving mediators (SPMs). At specific levels, SPMs improve the termination of inflammation as well as the repairing and regeneration of tissues, but they are deregulated in liver disease. Since evidence is still insufficient to carry out pharmacological trials to benefit the resolution of acute inflammation in non-communicable diseases, there remains a call for continuing preclinical and clinical research to better understand SPM actions and outcomes.


Assuntos
Ácidos Graxos Ômega-3/metabolismo , Sistema Imunitário/metabolismo , Hepatopatias/metabolismo , Hepatopatias/patologia , Doenças não Transmissíveis , Fenômenos Fisiológicos da Nutrição , Animais , Humanos , Estado Nutricional
6.
Nutrients ; 13(10)2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34684425

RESUMO

Sepsis-associated liver dysfunction presents a significant public health problem. 6-Shogaol is the key bioactive component in dry ginger, which has antioxidant and anti-inflammation capacity. The present study aims to investigate the preventive effect of 6-shogaol on sepsis-induced liver injury. 6-Shogaol was administered to mice for 7 consecutive days before being intraperitoneally injected with lipopolysaccharide (LPS). After 24 h, mice were sacrificed, and biochemical and transcriptomic analyses were performed. Our results demonstrated that 6-shogaol prevented LPS-induced impairment in antioxidant enzymes and elevation in malondialdehyde level in the liver. The hepatic inflammatory response was significantly suppressed by 6-shogaol through suppressing the MAPK/NFκB pathway. RNA-sequencing data analysis revealed that 41 overlapped genes between the LPS vs. control group and 6-shogaol vs. LPS group were identified, among which 36 genes were upregulated, and 5 genes were downregulated for the LPS vs. control group. These overlapped genes are enriched in inflammation-related pathways, e.g., TNF and NFκB. The mRNA expression of the overlapped genes was also verified in the LPS-induced BRL-3A cell model. In summary, 6-shogaol shows great potential as a natural chemopreventive agent to treat sepsis-associated hepatic disorders.


Assuntos
Catecóis/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Hepatopatias/etiologia , Hepatopatias/metabolismo , Sepse/complicações , Animais , Biomarcadores , Biologia Computacional/métodos , Gerenciamento Clínico , Modelos Animais de Doenças , Suscetibilidade a Doenças , Perfilação da Expressão Gênica , Hepatopatias/tratamento farmacológico , Hepatopatias/patologia , Testes de Função Hepática , Camundongos , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Transcrição Genética , Transcriptoma
7.
Life Sci ; 284: 119941, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34508761

RESUMO

Chronic liver diseases (CLD) are among the major cause of mortality and morbidity worldwide. Despite current achievements in the area of hepatitis virus, chronic alcohol abuse and high-fat diet are still fueling an epidemic of severe liver disease, for which, an effective therapy has yet not been discovered. In particular, the therapeutic regimens that could prevent the progression of fibrosis and, in turn, aid cirrhotic liver to develop a robust regenerative capability are intensively needed. To this context, a better understanding of the signaling pathways regulating hepatic disease development may be of critical value. In general, the liver responds to various insults with an orchestrated healing process involving variety of signaling pathways. One such pathway is the TLR2 signaling pathway, which essentially regulates adult liver pathogenesis and thus has emerged as an attractive target to treat liver disease. TLR2 is expressed by different liver cells, including Kupffer cells (KCs), hepatocytes, and hepatic stellate cells (HSCs). From a pathologic perspective, the crosstalk between antigens and TLR2 may preferentially trigger a distinctive set of signaling mechanisms in these liver cells and, thereby, induce the production of inflammatory and fibrogenic cytokines that can initiate and prolong liver inflammation, ultimately leading to fibrosis. In this review, we summarize the currently available evidence regarding the role of TLR2 signaling in hepatic disease progression. We first elaborate its pathological involvement in liver-disease states, such as inflammation, fibrosis, and cirrhosis. We then discuss how therapeutic targeting of this pathway may help to alleviate its disease-related functioning.


Assuntos
Fígado/metabolismo , Fígado/fisiopatologia , Transdução de Sinais , Receptor 2 Toll-Like/metabolismo , Animais , Hepatócitos/metabolismo , Humanos , Hepatopatias/metabolismo , Processamento de Proteína Pós-Traducional
8.
Life Sci ; 285: 119943, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34516992

RESUMO

Glycine betaine (N, N, N-trimethyl amine) is an osmolyte accumulated in cells that is key for cell volume and turgor regulation, is the principal methyl donor in the methionine cycle and is a DNA and proteins stabilizer. In humans, glycine betaine is synthesized from choline and can be obtained from some foods. Glycine betaine (GB) roles are illustrated in chemical, metabolic, agriculture, and clinical medical studies due to its chemical and physiological properties. Several studies have extensively described GB role and accumulation related to specific pathologies, focusing mainly on analyzing its positive and negative role in these pathologies. However, it is necessary to explain the relationship between glycine betaine and different pathologies concerning its role as an antioxidant, ability to methylate DNA, interact with transcription factors and cell receptors, and participate in the control of homocysteine concentration in liver, kidney and brain. This review summarizes the most important findings and integrates GB role in neurodegenerative, cardiovascular, hepatic, and renal diseases. Furthermore, we discuss GB impact on other dysfunctions as inflammation, oxidative stress, and glucose metabolism, to understand their cross-talks and provide reliable data to establish a base for further investigations.


Assuntos
Betaína/metabolismo , Doenças Cardiovasculares/metabolismo , Nefropatias/metabolismo , Hepatopatias/metabolismo , Doenças Neurodegenerativas/metabolismo , Tamanho Celular , Humanos , Hiper-Homocisteinemia/metabolismo , Concentração Osmolar , S-Adenosilmetionina/metabolismo
9.
Aliment Pharmacol Ther ; 54(10): 1243-1262, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34555862

RESUMO

BACKGROUND: Bile acids are important endocrine modulators of intestinal and hepatic signalling cascades orchestrating critical pathophysiological processes in various liver diseases. Increasing knowledge on bile acid signalling has stimulated the development of synthetic ligands of nuclear bile acid receptors and other bile acid analogues. AIM: This review summarises important aspects of bile acid-mediated crosstalk between the gut and the liver ("gut-liver axis") as well as recent findings from experimental and clinical studies. METHODS: We performed a literature review on bile acid signalling, and therapeutic applications in chronic liver disease. RESULTS: Intestinal and hepatic bile acid signalling pathways maintain bile acid homeostasis. Perturbations of bile acid-mediated gut-liver crosstalk dysregulate transcriptional networks involved in inflammation, fibrosis and endothelial dysfunction. Bile acids induce enterohepatic feedback signalling by the release of intestinal hormones, and regulate enterohepatic circulation. Importantly, bile acid signalling plays a central role in maintaining intestinal barrier integrity and antibacterial defense, which is particularly relevant in cirrhosis, where bacterial translocation has a profound impact on disease progression. The nuclear bile acid farnesoid X receptor (FXR) is a central intersection in bile acid signalling and has emerged as a relevant therapeutic target. CONCLUSIONS: Experimental evidence suggests that bile acid signalling improves the intestinal barrier and protects against bacterial translocation in cirrhosis. FXR agonists have displayed efficacy for the treatment of cholestatic and metabolic liver disease in randomised controlled clinical trials. However, similar effects remain to be shown in advanced liver disease, particularly in patients with decompensated cirrhosis.


Assuntos
Hepatopatias , Fígado , Ácidos e Sais Biliares/metabolismo , Circulação Êntero-Hepática , Humanos , Fígado/metabolismo , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Hepatopatias/tratamento farmacológico , Hepatopatias/metabolismo
10.
Cells ; 10(9)2021 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-34571946

RESUMO

Chronic liver diseases (CLDs) are complex diseases that cause long-term inflammation and infection, which in turn accelerate their development. The usage of albumin in patients with CLDs has been debated for years. Human serum albumin (HSA) plays a key role in immunomodulation during the process of CLDs. The correlation between albumin and C-reactive protein (CRP) in CLD patients was analyzed by linear regression with the Pearson statistic. The damage of THP-1 and primary cells was evaluated by measuring the lactate dehydrogenase (LDH) in the supernatant. Immunofluorescence staining was performed to determine underlying pathways in Kupffer cells (KCs). Albumin negatively correlated with infection in patients with CLDs. In vitro experiments with THP-1 cells and KCs showed that albumin reduced LDH release after stimulation with bacterial products, while no differences in hepatic stellate cells (HSCs) and sinusoidal endothelial cells (SECs) were detected. Moreover, immunofluorescence staining revealed an increase of p-ERK and p-NF-kB p65 density after albumin treatment of KCs stimulated by bacterial products. In conclusion, albumin could assist CLD patients in alleviating inflammation caused by bacterial products and might be beneficial to patients with CLDs by securing KCs from bacteria-induced damage, providing a compelling rationale for albumin therapy in patients with CLDs.


Assuntos
Albuminas/metabolismo , Macrófagos do Fígado/metabolismo , Hepatopatias/metabolismo , Bactérias/patogenicidade , Linhagem Celular , Células Endoteliais/imunologia , Feminino , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/microbiologia , Humanos , Inflamação/metabolismo , Fígado/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Células THP-1
11.
Int J Mol Sci ; 22(15)2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34361064

RESUMO

Carbohydrates and lipids are two components of the diet that provide the necessary energy to carry out various physiological processes to help maintain homeostasis in the body. However, when the metabolism of both biomolecules is altered, development of various liver diseases takes place; such as metabolic-associated fatty liver diseases (MAFLD), hepatitis B and C virus infections, alcoholic liver disease (ALD), and in more severe cases, hepatocelular carcinoma (HCC). On the other hand, PPARs are a family of ligand-dependent transcription factors with an important role in the regulation of metabolic processes to hepatic level as well as in other organs. After interaction with specific ligands, PPARs are translocated to the nucleus, undergoing structural changes to regulate gene transcription involved in lipid metabolism, adipogenesis, inflammation and metabolic homeostasis. This review aims to provide updated data about PPARs' critical role in liver metabolic regulation, and their involvement triggering the genesis of several liver diseases. Information is provided about their molecular characteristics, cell signal pathways, and the main pharmacological therapies that modulate their function, currently engaged in the clinic scenario, or in pharmacological development.


Assuntos
Hepatopatias/tratamento farmacológico , Hepatopatias/patologia , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Preparações Farmacêuticas/administração & dosagem , Animais , Humanos , Hepatopatias/metabolismo , Terapia de Alvo Molecular
12.
Biochem Pharmacol ; 192: 114728, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34400126

RESUMO

Hepatic ischemia/reperfusion (I/R) injury is an inevitable complication of hepatic surgery occasioned by liver transplantation and resection. The progression from liver ischemia to reperfusion injury is accompanied by abnormal metabolism, Kupffer cell activation, neutrophil recruitment and the release of cytokines. Activation of several interferon regulatory factors (IRFs) has been reported to either enhance or restrict I/R progression, but the role of IRF8 in the regulation of I/R injury progression is still unknown. In this study, we explore the IRF8 function in the I/R-mediated liver injury using overexpressed hepatic IRF8 and knockout mice. According to our results, IRF8 knockout mice had significantly lower inflammatory cells infiltration, inflammatory cytokines release and serum aspartate aminotransferase/alanine aminotransferase levels that improved the necrotic injury after I/R, unlike the control mice. Conversely, the overexpression of IRF8 in WT mice markedly aggravated the liver structure damage and its abnormal function. We further showed that IRF8-mediated inflammatory cells infiltration were partly dependent on early autophagy and NF-κΒ signal pathway during I/R. AAV8-IRF8-I/R mice pretreated with autophagy inhibitor hydroxychloroquine and NF-κΒ signal pathway inhibitor secukinumab could drastically reverse the IRF8-mediated increase of neutrophil infiltration and chemokine release at different degrees. This work uncovered a critical role of IRF8 in the modulation of the hepatic microenvironment and as a potential target in the initial treatment of I/R injury.


Assuntos
Fatores Reguladores de Interferon/biossíntese , Hepatopatias/metabolismo , Hepatopatias/prevenção & controle , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Animais , Fatores Reguladores de Interferon/genética , Fígado/lesões , Fígado/metabolismo , Hepatopatias/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Traumatismo por Reperfusão/genética
13.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1866(11): 159023, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34352389

RESUMO

Inflammation is a characteristic feature of virtually all acute and chronic liver diseases. It intersects different liver pathologies from the early stages of liver injury, when the inflammatory burden is mild-to-moderate, to very advanced stages of liver disease, when the inflammatory response is very intense and drives multiple organ dysfunction and failure(s). The current review describes the most relevant features of the inflammatory process in two different clinical entities across the liver disease spectrum, namely non-alcoholic steatohepatitis (NASH) and acute-on-chronic liver failure (ACLF). Special emphasis is given within these two disease conditions to gather the most relevant data on the specialized pro-resolving mediators that orchestrate the resolution of inflammation, a tightly controlled process which dysregulation commonly associates with chronic inflammatory conditions.


Assuntos
Mediadores da Inflamação/metabolismo , Hepatopatias/metabolismo , Animais , Humanos , Inflamação/metabolismo , Metabolismo dos Lipídeos
14.
Cells ; 10(8)2021 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-34440632

RESUMO

Ischemia/reperfusion (I/R) injury unavoidably occurs during hepatic resection and transplantation. Aged livers poorly tolerate I/R during surgical treatment. Although livers have a powerful endogenous inhibitor of calpains, calpastatin (CAST), I/R activates calpains, leading to impaired autophagy, mitochondrial dysfunction, and hepatocyte death. It is unknown how I/R in aged livers affects CAST. Human and mouse liver biopsies at different ages were collected during in vivo I/R. Hepatocytes were isolated from 3-month- (young) and 26-month-old (aged) mice, and challenged with short in vitro simulated I/R. Cell death, protein expression, autophagy, and mitochondrial permeability transition (MPT) between the two age groups were compared. Adenoviral vector was used to overexpress CAST. Significant cell death was observed only in reperfused aged hepatocytes. Before the commencement of ischemia, CAST expression in aged human and mouse livers and mouse hepatocytes was markedly greater than that in young counterparts. However, reperfusion substantially decreased CAST in aged human and mouse livers. In hepatocytes, reperfusion rapidly depleted aged cells of CAST, cleaved autophagy-related protein 5 (ATG5), and induced defective autophagy and MPT onset, all of which were blocked by CAST overexpression. Furthermore, mitochondrial morphology was shifted toward an elongated shape with CAST overexpression. In conclusion, CAST in aged livers is intrinsically short-lived and lost after short I/R. CAST depletion contributes to age-dependent liver injury after I/R.


Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Hepatócitos/metabolismo , Hepatopatias/metabolismo , Fígado/metabolismo , Traumatismo por Reperfusão/metabolismo , Fatores Etários , Animais , Autofagia , Proteína 5 Relacionada à Autofagia/metabolismo , Proteínas de Ligação ao Cálcio/genética , Calpaína/metabolismo , Morte Celular , Células Cultivadas , Modelos Animais de Doenças , Regulação da Expressão Gênica , Hepatócitos/patologia , Humanos , Fígado/patologia , Hepatopatias/genética , Hepatopatias/patologia , Masculino , Camundongos Endogâmicos C57BL , Mitocôndrias Hepáticas/genética , Mitocôndrias Hepáticas/metabolismo , Mitocôndrias Hepáticas/patologia , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/patologia , Transdução de Sinais , Fatores de Tempo
15.
Cells ; 10(8)2021 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-34440714

RESUMO

Circular RNA (circRNA) is a type of non-coding RNA characterized by a covalently closed continuous loop. CircRNA is generated by pre-mRNA through back-splicing and is probably cleared up by extracellular vesicles. CircRNAs play a pivotal role in the epigenetic regulation of gene expression at transcriptional and post-transcriptional levels. Recently, circRNAs have been demonstrated to be involved in the regulation of liver homeostasis and diseases. However, the epigenetic role and underlying mechanisms of circRNAs in chronic liver diseases remain unclear. This review discussed the role of circRNAs in non-neoplastic chronic liver diseases, including alcoholic liver disease (ALD), metabolic-associated fatty liver disease (MAFLD), viral hepatitis, liver injury and regeneration, liver cirrhosis, and autoimmune liver disease. The review also highlighted that further efforts are urgently needed to develop circRNAs as novel diagnostics and therapeutics for chronic liver diseases.


Assuntos
Epigênese Genética , Hepatopatias/genética , Fígado/metabolismo , RNA Circular/genética , Animais , Autoimunidade , Doença Crônica , Humanos , Fígado/imunologia , Fígado/patologia , Hepatopatias/imunologia , Hepatopatias/metabolismo , Hepatopatias/patologia , Regeneração Hepática , RNA Circular/metabolismo , Transdução de Sinais
16.
Cells ; 10(8)2021 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-34440614

RESUMO

Recent studies on liver disease burden worldwide estimated that cirrhosis is the 11th most common cause of death globally, and there is a great need for new therapies to limit the progression of liver injuries in the early stages. Cholestasis is caused by accumulation of hydrophobic bile acids (BA) in the liver due to dysfunctional BA efflux or bile flow into the gall bladder. Therefore, strategies to increase detoxification of hydrophobic BA and downregulate genes involved in BA production are largely investigated. Farnesoid X receptor (FXR) has a central role in BA homeostasis and recent publications revealed that changes in autophagy due to BA-induced reactive oxygen species and increased anti-oxidant response via nuclear factor E2-related factor 2 (NRF2), result in dysregulation of FXR signaling. Several mechanistic studies have identified new dysfunctions of the cholestatic liver at cellular and molecular level, opening new venues for developing more performant therapies.


Assuntos
Ácidos e Sais Biliares/metabolismo , Colestase/tratamento farmacológico , Fármacos Gastrointestinais/uso terapêutico , Hepatopatias/tratamento farmacológico , Fígado/efeitos dos fármacos , Receptores Citoplasmáticos e Nucleares/efeitos dos fármacos , Animais , Autofagia/efeitos dos fármacos , Colestase/complicações , Colestase/diagnóstico , Colestase/metabolismo , Fármacos Gastrointestinais/efeitos adversos , Humanos , Ligantes , Fígado/metabolismo , Fígado/patologia , Hepatopatias/diagnóstico , Hepatopatias/etiologia , Hepatopatias/metabolismo , Terapia de Alvo Molecular , Fator 2 Relacionado a NF-E2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Transdução de Sinais
17.
Cells ; 10(8)2021 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-34440927

RESUMO

Niemann-Pick type C disease (NPCD) is a lysosomal storage disorder caused by mutations in the NPC1 gene. The most affected tissues are the central nervous system and liver, and while significant efforts have been made to understand its neurological component, the pathophysiology of the liver damage remains unclear. In this study, hepatocytes derived from wild type and Npc1-/- mice were analyzed by mass spectrometry (MS)-based proteomics in conjunction with bioinformatic analysis. We identified 3832 proteins: 416 proteins had a p-value smaller than 0.05, of which 37% (n = 155) were considered differentially expressed proteins (DEPs), 149 of them were considered upregulated, and 6 were considered downregulated. We focused the analysis on pathways related to NPC pathogenic mechanisms, finding that the most significant changes in expression levels occur in proteins that function in the pathways of liver damage, lipid metabolism, and inflammation. Moreover, in the group of DEPs, 30% (n = 47) were identified as lysosomal proteins and 7% (n = 10) were identified as mitochondrial proteins. Importantly, we found that lysosomal DEPs, including CTSB/D/Z, LIPA, DPP7 and GLMP, and mitocondrial DEPs, AKR1B10, and VAT1 had been connected with liver fibrosis, damage, and steatosis in previous studies, validiting our dataset. Our study found potential therapeutic targets for the treatment of liver damage in NPCD.


Assuntos
Hepatócitos/metabolismo , Fígado/metabolismo , Doença de Niemann-Pick Tipo C/metabolismo , Proteoma/metabolismo , Animais , Western Blotting , Células Cultivadas , Fígado/patologia , Hepatopatias/metabolismo , Hepatopatias/patologia , Masculino , Camundongos
18.
Am J Physiol Gastrointest Liver Physiol ; 321(3): G298-G307, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34259586

RESUMO

Drug-induced liver injury is an emerging form of acute and chronic liver disease that may manifest as fatty liver. Amiodarone (AMD), a widely used antiarrhythmic drug, can cause hepatic injury and steatosis by a variety of mechanisms, not all completely understood. We hypothesized that repetitive AMD administration may induce hepatic lipotoxicity not only via effects on the liver but also via effects on adipose tissue. Indeed, repetitive AMD administration induced endoplasmic reticulum (ER) stress in both liver and adipose tissue. In adipose tissue, AMD reduced lipogenesis and increased lipolysis. Moreover, AMD treatment induced ER stress and ER stress-dependent lipolysis in 3T3L1 adipocytes in vitro. In the liver, AMD caused increased expression of genes encoding proteins involved in fatty acid (FA) uptake and transfer (Cd36, Fabp1, and Fabp4), and resulted in increased hepatic accumulation of free FAs, but not of triacylglycerols. In line with this, there was increased expression of hepatic de novo FA synthesis genes. However, AMD significantly reduced the expression of the desaturase Scd1 and elongase Elovl6, detected at mRNA and protein levels. Accordingly, the FA profile of hepatic total lipids revealed increased accumulation of palmitate, an SCD1 and ELOVL6 substrate, and reduced levels of palmitoleate and cis-vaccenate, products of the enzymes. In addition, AMD-treated mice displayed increased hepatic apoptosis. The studies show that repetitive AMD induces ER stress and aggravates lipolysis in adipose tissue while inducing a lipotoxic hepatic lipid environment, suggesting that AMD-induced liver damage is due to compound insult to liver and adipose tissue.NEW & NOTEWORTHY AMD chronic administration induces hepatic lipid accumulation by several mechanisms, including induction of hepatic ER stress, impairment of ß-oxidation, and inhibition of triacylglycerol secretion. Our study shows that repetitive AMD treatment induces not only hepatic ER stress but also adipose tissue ER stress and lipolysis and hepatic accumulation of free fatty acids and enrichment of palmitate in the total lipids. Understanding the toxicity mechanisms of AMD would help devise ways to limit liver damage.


Assuntos
Amiodarona/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Ácidos Graxos não Esterificados/metabolismo , Ácidos Graxos/metabolismo , Lipólise/efeitos dos fármacos , Adipócitos/metabolismo , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Amiodarona/metabolismo , Animais , Proteínas de Ligação a Ácido Graxo/metabolismo , Fígado Gorduroso/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipogênese/fisiologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Hepatopatias/metabolismo , Camundongos , Triglicerídeos/metabolismo
19.
Life Sci ; 282: 119807, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34245771

RESUMO

AIM: This study was designed to investigate the changes of liver injury and Nrf2 signaling pathway in the process of sepsis. We also aimed to examine the role of Nrf2 in resisting oxidative stress and relieving inflammation in sepsis-induced hepatic injury. MAIN METHODS: By operating cecal ligation and puncture (CLP) on Nrf2-/- mice and wild type mice, a sepsis-induced hepatic injury model was established. We compared and contrasted the wild type mice with the Nrf2-/- mice during sepsis-induced hepatic injury, and evaluated the liver damage by biochemical analyses and staining hematoxylin-eosin (HE). Western blot or real-time PCR was performed to detect Nrf2 and its regulated genes NQO-1, GCLM and HO-1. Additionally, we detected the expressions and secretion of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), Interleukin-6 (IL-6), IL-1ß and anti-inflammatory cytokines IL-10. We assessed the oxidative stress through the levels of MDA and NO. KEY FINDINGS: The results showed that Nrf2 expressions at mRNA and protein levels were increased 1 day after CLP, namely the early stage of sepsis. Compared with wild type mice after CLP, Nrf2-/- mice showed more severe liver injury, accompanied by higher expression of inflammatory cytokines and oxidative stress. Notably, Nrf2-regulated genes GCLM and NQO-1, were strongly downregulated in Nrf2-/- mice. SIGNIFICANCE: Nrf2 was probably implicated in decreasing inflammatory cytokine levels and counteracting oxidative stress to alleviate sepsis-induced hepatic injury, mainly through regulating GCLM and NQO-1 in the early stage after CLP.


Assuntos
Regulação da Expressão Gênica , Hepatopatias/prevenção & controle , Fígado , Fator 2 Relacionado a NF-E2/biossíntese , Estresse Oxidativo , Sepse/metabolismo , Animais , Fígado/lesões , Fígado/metabolismo , Hepatopatias/etiologia , Hepatopatias/genética , Hepatopatias/metabolismo , Camundongos , Camundongos Knockout , Fator 2 Relacionado a NF-E2/genética , Sepse/complicações , Sepse/genética
20.
Int J Mol Sci ; 22(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202537

RESUMO

The liver is an organ with impressive regenerative potential and has been shown to heal sizable portions after their removal. However, certain diseases can overstimulate its potential to self-heal and cause excessive cellular matrix and collagen buildup. Decompensation of liver fibrosis leads to cirrhosis, a buildup of fibrotic ECM that impedes the liver's ability to efficiently exchange fluid. This review summarizes the complex immunological activities in different liver diseases, and how failure to maintain liver homeostasis leads to progressive fibrotic tissue development. We also discuss a variety of pathologies that lead to liver cirrhosis, such as alcoholic liver disease and chronic hepatitis B virus (HBV). Mesenchymal stem cells are widely studied for their potential in tissue replacement and engineering. Herein, we discuss the potential of MSCs to regulate immune response and alter the disease state. Substantial efforts have been performed in preclinical animal testing, showing promising results following inhibition of host immunity. Finally, we outline the current state of clinical trials with mesenchymal stem cells and other cellular and non-cellular therapies as they relate to the detection and treatment of liver cirrhosis.


Assuntos
Suscetibilidade a Doenças , Hepatopatias/etiologia , Hepatopatias/metabolismo , Animais , Biomarcadores , Terapia Combinada , Gerenciamento Clínico , Progressão da Doença , Suscetibilidade a Doenças/imunologia , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Hepatopatias/diagnóstico , Hepatopatias/terapia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...