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1.
J Biochem Mol Toxicol ; 35(9): e22846, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34250697

RESUMO

The liver is the primary organ affected by cholestasis. However, the brain, skeletal muscle, heart, and kidney are also severely influenced by cholestasis/cirrhosis. However, little is known about the molecular mechanisms of organ injury in cholestasis. The current study was designed to evaluate the mitochondrial glutathione redox state as a significant index in cell death. Moreover, tissue energy charge (EC) was calculated. Rats underwent bile duct ligation (BDL) and the brain, heart, liver, kidney, and skeletal muscle mitochondria were assessed at scheduled time intervals (3, 7, 14, and 28 days after BDL). A significant decrease in mitochondrial glutathione redox state and EC was detected in BDL animals. Moreover, disturbed mitochondrial indices were evident in different organs of BDL rats. These data could offer new insight into the mechanisms of organ injury and the source of oxidative stress during cholestasis and might provide novel therapeutic strategies against these complications.


Assuntos
Colestase/metabolismo , Metabolismo Energético , Mitocôndrias Hepáticas/metabolismo , Mitocôndrias Musculares/metabolismo , Animais , Colestase/patologia , Modelos Animais de Doenças , Masculino , Mitocôndrias Hepáticas/patologia , Mitocôndrias Musculares/patologia , Especificidade de Órgãos , Oxirredução , Ratos , Ratos Sprague-Dawley
2.
Life Sci ; 281: 119768, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34186042

RESUMO

AIMS: The purpose of this work was to study the effects of mesenchymal stem cells conditioned medium (MSC CM) treatment in animals with cholestatic liver fibrosis. MATERIALS AND METHODS: We induced cholestatic liver fibrosis by bile duct ligation in C57Bl/6 mice. In the 5th and 6th days after bile duct ligation proceeding, conditioned medium obtained of cultures of mesenchymal stem cells derived from adipose tissue was injected in the animals. Blood levels of hepatic transaminases, alkaline phosphatase and albumin were measured in each group. Analysis of collagen deposition was realized by Picro Sirius red staining and cytokine profiling was performed by cytometric bead array (CBA). KEY FINDINGS: Our results showed that MSC CM treatment decreased levels of hepatic enzymes and collagen deposition in the liver. After MSC CM treatment, profibrotic IL-17A was decreased andIL-6 and IL-4 were increased. SIGNIFICANCE: In summary, MSC CM treatment demonstrated therapeutic potential to cholestatic liver fibrosis, favoring matrix remodeling and cytokine profile towards liver regeneration.


Assuntos
Colestase/patologia , Cirrose Hepática/patologia , Células-Tronco Mesenquimais/citologia , Tecido Adiposo/citologia , Animais , Colestase/metabolismo , Colágeno/metabolismo , Meios de Cultivo Condicionados , Citocinas/metabolismo , Citometria de Fluxo , Cirrose Hepática/metabolismo , Masculino , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL
3.
Toxicol Lett ; 349: 12-29, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34089816

RESUMO

The cholestatic liver injury could occur in response to a variety of diseases or xenobiotics. Although cholestasis primarily affects liver function, it has been well-known that other organs such as the kidney could be influenced in cholestatic patients. Severe cholestasis could lead to tissue fibrosis and organ failure. Unfortunately, there is no specific therapeutic option against cholestasis-induced organ injury. Hence, finding the mechanism of organ injury during cholestasis could lead to therapeutic options against this complication. The accumulation of potentially cytotoxic compounds such as hydrophobic bile acids is the most suspected mechanism involved in the pathogenesis of cholestasis-induced organ injury. A plethora of evidence indicates a role for the inflammatory response in the pathogenesis of several human diseases. Here, the role of nuclear factor-kB (NFkB)-mediated inflammatory response is investigated in an animal model of cholestasis. Bile duct ligated (BDL) animals were treated with sulfasalazine (SSLZ, 10 and 100 mg/kg, i.p) as a potent inhibitor of NFkB signaling. The NFkB proteins family activity in the liver and kidney, serum and tissue levels of pro-inflammatory cytokines, tissue biomarkers of oxidative stress, serum markers of organ injury, and the liver and kidney histopathological alterations and fibrotic changes. The oxidative stress-mediated inflammatory-related indices were monitored in the kidney and liver at scheduled time intervals (3, 7, and 14 days after BDL operation). Significant increase in serum and urine markers of organ injury, besides changes in biomarkers of oxidative stress and tissue histopathology, were evident in the liver and kidney of BDL animals. The activity of NFkB proteins (p65, p50, p52, c-Rel, and RelB) was significantly increased in the liver and kidney of cholestatic animals. Serum and tissue levels of pro-inflammatory cytokines (IL-1ß, IL-2, IL-6, IL-7, IL-12, IL-17, IL-18, IL-23, TNF-α, and INF-γ) were also higher than sham-operated animals. Moreover, TGF- ß, α-SMA, and tissue fibrosis (Trichrome stain) were evident in cholestatic animals' liver and kidneys. It was found that SSLZ (10 and 100 mg/kg/day, i.p) alleviated cholestasis-induced hepatic and renal injury. The effect of SSLZ on NFkB signaling and suppression of pro-inflammatory cytokines could play a significant role in its protective role in cholestasis. Based on these data, NFkB signaling could receive special attention to develop therapeutic options to blunt cholestasis-induced organ injury.


Assuntos
Anti-Inflamatórios/farmacologia , Colestase/tratamento farmacológico , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Nefropatias/prevenção & controle , Rim/efeitos dos fármacos , Cirrose Hepática/prevenção & controle , Fígado/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , Sulfassalazina/farmacologia , Animais , Colestase/metabolismo , Colestase/patologia , Ducto Colédoco/cirurgia , Modelos Animais de Doenças , Regulação para Baixo , Rim/metabolismo , Rim/patologia , Nefropatias/metabolismo , Nefropatias/patologia , Ligadura , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Masculino , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais
4.
Neurochem Res ; 46(8): 2154-2166, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34031842

RESUMO

Cholestasis is a bile flow reduction that is induced following Bile Duct Ligation (BDL). Cholestasis impairs memory and induces apoptosis. Apoptosis consists of two pathways: intrinsic and extrinsic. The intrinsic pathway is modulated by BCL-2 (B cell lymphoma-2) family proteins. BCL-2 (a pro-survival BCL-2 protein) has anti-apoptotic effect, while BAD (BCL-2-associated death) and BAX (BCL-2-associated X), the other members of BCL-2 family have pro-apoptotic effect. Furthermore, TFAM (mitochondrial transcriptional factor A) is involved in transcription and maintenance of mitochondrial DNA and PGC-1α (peroxisome proliferator-activated receptor γ coactivator-1α) is a master regulator of mitochondrial biogenesis. On the other hand, NeuroAid is a Traditional Chinese Medicine with neuroprotective and anti-apoptosis effects. In this study, we evaluated the effect of cholestasis on spatial memory and expression of BCL-2, BAD, BAX, TFAM, and PGC-1α in the hippocampus of rats. Additionally, we assessed the effect of NeuroAid on cholestasis-induced cognitive and genetic alterations. Cholestasis was induced by BDL surgery and NeuroAid was injected intraperitoneal at the dose of 0.4 mg/kg. Furthermore, spatial memory was evaluated using Morris Water Maze (MWM) apparatus. The results showed cholestasis impaired spatial memory, increased the expression of BAD and BAX, decreased the expression of TFAM and PGC-1α, and did not alter the expression of BCL-2. Also, NeuroAid decreased the expression of BAD and BAX and increased the expression of TFAM, PGC-1α, and BCL-2. In conclusion, cholestasis impaired spatial memory and increased the expression of pro-apoptotic genes. Also, cholestasis decreased the expression of TFAM and PGC-1α. Interestingly, NeuroAid restored the effects of cholestasis.


Assuntos
Colestase/metabolismo , Medicamentos de Ervas Chinesas/uso terapêutico , Expressão Gênica/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Memória Espacial/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Ductos Biliares/cirurgia , Colestase/complicações , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Ligadura , Masculino , Transtornos da Memória/etiologia , Teste do Labirinto Aquático de Morris/efeitos dos fármacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Ratos Wistar , Fatores de Transcrição/genética , Proteína X Associada a bcl-2/genética , Proteína de Morte Celular Associada a bcl/genética
5.
Chem Biol Interact ; 345: 109525, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34058177

RESUMO

Metformin, an oral antidiabetic drug, recently demonstrated a reducing effect on bile acids (BA) plasma concentrations in one patient with intrahepatic cholestasis of pregnancy (ICP) by unknown mechanism. Therefore, the aim of the present study was to examine the effect of metformin on BA homeostasis and related molecular pathways in the liver and intestine using a mouse model of ICP. The cholestasis was induced in female C57BL/6 mice by repeated administration of ethinylestradiol (10 mg/kg BW s.c.) and/or metformin (150 mg/kg BW orally) over 5 consecutive days with subsequent bile collection and molecular analysis of samples. We demonstrated that metformin significantly increased the rate of bile secretion in control mice. This increase was BA dependent and was produced both by increased liver BA synthesis via induced cholesterol 7α-hydroxylase (Cyp7a1) and by increased BA reabsorption in the ileum via induction of the apical sodium-dependent BA transporter (Asbt). In contrast, metformin further worsened ethinylestradiol-induced impairment of bile secretion. This reduction was also BA dependent and corresponded with significant downregulation of Bsep, and Ntcp, major excretory and uptake transporters for BA in hepatocytes, respectively. The plasma concentrations of BA were consequently significantly increased in the metformin-treated mice. Altogether, our data indicate positive stimulation of bile secretion by metformin in the intact liver, but this drug also induces serious impairment of BA biliary secretion, with a marked increase in plasma concentrations in estrogen-induced cholestasis. Our results imply that metformin should be used with caution in situations with hormone-dependent cholestasis, such as ICP.


Assuntos
Ácidos e Sais Biliares/metabolismo , Colestase/induzido quimicamente , Colestase/metabolismo , Etinilestradiol/efeitos adversos , Homeostase/efeitos dos fármacos , Metformina/farmacologia , Animais , Colestase/patologia , Feminino , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Absorção Intestinal/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL
6.
Free Radic Biol Med ; 169: 158-168, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33872698

RESUMO

BACKGROUND: Clinical studies indicate that vitamin D receptor (VDR) expression is reduced in primary biliary cirrhosis patient livers. However, the mechanism by which activated VDR effect cholestatic liver injury remains unclear. METHODS: Mice were injected intraperitoneally with the VDR agonist paricalcitol or a vehicle 3 days prior to bile duct ligation (BDL) and for 5 or 28 days after surgery. The analyses of liver morphology and necrotic areas were based on H&E staining. Serum biochemical indicators of liver damage were analyzed by commercial kits. The mechanisms of paricalcitol on cholestatic liver injury were determined by Western blot analysis. RESULTS: Paricalcitol ameliorated the BDL-induced liver damage in mice. Paricalcitol increased the proliferation of BECs to promote the repair of the bile duct. Paricalcitol also reduced the BDL-induced oxidative stress level in the mice. Mechanistic analysis revealed that paricalcitol decreased the number of SA-ß-gal-positive cells and downregulated the expression of p53, p21 and p16 proteins which was associated with reducing oxidative stress. Additionally, paricalcitol exerted the inhibitory effect of cell senescence was through reducing DNA damage and promoting DNA repair. Interesting, we found that paricalcitol prevented the downregulation of oxidative stress-induced Sirt1 expression in the BDL mice and t-BHP-induced BECs models. Moreover, paricalcitol suppressed cell senescence through a Sirt1-dependent pathway. These results were confirmed by antioxidant ALCAR and the Sirt1 inhibitor EX-527. CONCLUSION: Paricalcitol alleviated cholestatic liver injury through promoting the repair of damaged bile ducts and reducing oxidative stress-induced cell senescence of the bile duct via modulating Sirt1 pathway.


Assuntos
Colestase , Sirtuína 1 , Animais , Ductos Biliares , Senescência Celular , Colestase/tratamento farmacológico , Colestase/metabolismo , Epitélio , Ergocalciferóis , Fígado/metabolismo , Camundongos , Estresse Oxidativo , Sirtuína 1/genética , Sirtuína 1/metabolismo
7.
J Tradit Chin Med ; 41(1): 167-180, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33522210

RESUMO

OBJECTIVE: To investigate the targets and mechanisms of action of Qingkailing injection (,QKL) in the treatment of cholestatic hepatitis. METHODS: A network pharmacology method was implemented using drug and disease databases to target QKL and cholestasis hepatitis, respectively. The functional protein association network STRING database was used to construct a protein-protein interaction network using R language and the Bioconductor toolkit. The org.Hs.eg.db and clusterProfiler packages were used for gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis, which explored biological functions and pathways of potential targets. Targets were then visualized using Cytoscape 3.6.0 software. RESULTS: We screened 121 compounds in QKL and identified 112 targets for the treatment of cholestatic hepatitis. QKL played a role in the treatment of cholestatic hepatitis through 305 biology process terms, 15 cellular component and 29 molecular function terms. The mechanism of QKL action was mainly related to tumor necrosis factor, mitogen-activated protein kinase, and PI3K-Akt signaling pathways. CONCLUSION: The treatment of cholestatic hepatitis by QKL involved multiple targets, biological functions, and signaling pathways that are closely associated with the disease.


Assuntos
Colestase/tratamento farmacológico , Medicamentos de Ervas Chinesas/administração & dosagem , Hepatite/tratamento farmacológico , Animais , Colestase/genética , Colestase/metabolismo , Hepatite/genética , Hepatite/metabolismo , Humanos , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos
8.
Food Funct ; 12(5): 2323-2334, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33620063

RESUMO

Cholestasis can induce liver fibrosis and cirrhosis. Apigenin has anti-oxidant and anti-inflammatory effects. Herein, we determined whether apigenin can protect mice against cholestasis. In vitro, apigenin protected TFK-1 cells (a human bile duct cancer cell line) against H2O2-induced ROS generation and inhibited transforming growth factor-ß-activated collagen type 1 alpha 1 and α-smooth muscle actin in LX2 cells (a human hepatic stellate cell line). In vivo, cholestatic mice induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) were treated with apigenin. Apigenin potently blocked DDC-induced gallbladder atrophy and associated liver injury, fibrosis and collagen accumulation. Moreover, apigenin relieved the DDC-caused abnormality of bile acid metabolism and restored the balance between bile secretion and excretion by regulating the farnesoid X receptor signaling pathway. Furthermore, apigenin reduced inflammation or oxidative stress in the liver by blocking the DDC-activated Toll-like receptor 4, nuclear factor κB and tumor necrosis factor α, or DDC-suppressed superoxidase dismutase 1/2, catalase and glutathione peroxidase. Taken together, apigenin improves DDC-induced cholestasis by reducing inflammation and oxidative damage and improving bile acid metabolism, indicating its potential application for cholestasis treatment.


Assuntos
Apigenina/farmacologia , Colestase , Substâncias Protetoras/farmacologia , Piridinas/efeitos adversos , Animais , Ácidos e Sais Biliares/metabolismo , Linhagem Celular Tumoral , Colestase/induzido quimicamente , Colestase/metabolismo , Humanos , Fígado/efeitos dos fármacos , Cirrose Hepática/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
9.
Biomolecules ; 11(2)2021 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-33578971

RESUMO

: In a previous study, obeticholic acid (OCA) increased liver growth before partial hepatectomy (PHx) in rats through the bile acid receptor farnesoid X-receptor (FXR). In that model, OCA was administered during obstructive cholestasis. However, patients normally undergo PHx several days after biliary drainage. The effects of OCA on liver regeneration were therefore studied in post-cholestatic Wistar rats. Rats underwent sham surgery or reversible bile duct ligation (rBDL), which was relieved after 7 days. PHx was performed one day after restoration of bile flow. Rats received 10 mg/kg OCA per day or were fed vehicle from restoration of bile flow until sacrifice 5 days after PHx. Liver regeneration was comparable between cholestatic and non-cholestatic livers in PHx-subjected rats, which paralleled liver regeneration a human validation cohort. OCA treatment induced ileal Fgf15 mRNA expression but did not enhance post-PHx hepatocyte proliferation through FXR/SHP signaling. OCA treatment neither increased mitosis rates nor recovery of liver weight after PHx but accelerated liver regrowth in rats that had not been subjected to rBDL. OCA did not increase biliary injury. Conclusively, OCA does not induce liver regeneration in post-cholestatic rats and does not exacerbate biliary damage that results from cholestasis. This study challenges the previously reported beneficial effects of OCA in liver regeneration in cholestatic rats.


Assuntos
Ácido Quenodesoxicólico/análogos & derivados , Colestase/tratamento farmacológico , Colestase/metabolismo , Regeneração Hepática/efeitos dos fármacos , Receptores Citoplasmáticos e Nucleares/metabolismo , Animais , Ácidos e Sais Biliares/metabolismo , Ductos Biliares/cirurgia , Proliferação de Células , Ácido Quenodesoxicólico/farmacologia , Humanos , Verde de Indocianina/química , Fígado/diagnóstico por imagem , Fígado/efeitos dos fármacos , Fígado/metabolismo , Testes de Função Hepática , Masculino , Tamanho do Órgão , Ratos , Ratos Wistar , Regeneração , Estudos Retrospectivos , Transdução de Sinais , Tecnécio/química
10.
PLoS One ; 16(1): e0244743, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33411796

RESUMO

BACKGROUND & AIMS: Limited understanding of the role for specific macrophage subsets in the pathogenesis of cholestatic liver injury is a barrier to advancing medical therapy. Macrophages have previously been implicated in both the mal-adaptive and protective responses in obstructive cholestasis. Recently two macrophage subsets were identified in non-diseased human liver; however, no studies to date fully define the heterogeneous macrophage subsets during the pathogenesis of cholestasis. Here, we aim to further characterize the transcriptional profile of macrophages in pediatric cholestatic liver disease. METHODS: We isolated live hepatic immune cells from patients with biliary atresia (BA), Alagille syndrome (ALGS), and non-cholestatic pediatric liver by fluorescence activated cell sorting. Through single-cell RNA sequencing analysis and immunofluorescence, we characterized cholestatic macrophages. We next compared the transcriptional profile of pediatric cholestatic and non-cholestatic macrophage populations to previously published data on normal adult hepatic macrophages. RESULTS: We identified 3 distinct macrophage populations across cholestatic liver samples and annotated them as lipid-associated macrophages, monocyte-like macrophages, and adaptive macrophages based on their transcriptional profile. Immunofluorescence of liver tissue using markers for each subset confirmed their presence across BA (n = 6) and ALGS (n = 6) patients. Cholestatic macrophages demonstrated reduced expression of immune regulatory genes as compared to normal hepatic macrophages and were distinct from macrophage populations defined in either healthy adult or pediatric non-cholestatic liver. CONCLUSIONS: We are the first to perform single-cell RNA sequencing on human pediatric cholestatic liver and identified three macrophage subsets with distinct transcriptional signatures from healthy liver macrophages. Further analyses will identify similarities and differences in these macrophage sub-populations across etiologies of cholestatic liver disease. Taken together, these findings may allow for future development of targeted therapeutic strategies to reprogram macrophages to an immune regulatory phenotype and reduce cholestatic liver injury.


Assuntos
Atresia Biliar/metabolismo , Colestase/metabolismo , Fígado/metabolismo , Macrófagos/metabolismo , Transcriptoma , Atresia Biliar/genética , Atresia Biliar/patologia , Criança , Pré-Escolar , Colestase/genética , Colestase/patologia , Feminino , Perfilação da Expressão Gênica , Humanos , Lactente , Fígado/patologia , Masculino
11.
Biochim Biophys Acta Mol Basis Dis ; 1867(4): 166067, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33418034

RESUMO

BACKGROUND & AIMS: Cholangiopathies are chronic liver diseases in which damaged cholangiocytes trigger a proinflammatory and profibrotic reaction. The nuclear vitamin D receptor (VDR) is highly expressed in cholangiocytes and exerts immune-regulatory functions in these cells. In the present study, we examined the protective function of VDR and other vitamin D signaling pathways in chronic cholangiopathy and cholangiocytes. METHODS: Vdr was invalidated in Abcb4 knockout mice, a widely used animal model of chronic cholangiopathy. The impact of vitamin D signaling on cholangiopathy features was examined in vivo and in cholangiocytes (primary and cell lines). RESULTS: Cholangiopathy features (i.e, cholestasis, ductular reaction and fibrosis) were aggravated in Vdr;Abcb4 double knockout mice compared to the Abcb4 simple knockout, and associated with an overexpression of proinflammatory factors. The proinflammatory phenotype of cholangiocytes was also exacerbated following VDR silencing in vitro. The expression of proinflammatory factors and the severity of cholangiopathy were reduced in the double knockout mice treated with the vitamin D analog calcipotriol or with vitamin D. In vitro, the inflammatory response to TNFα was significantly reduced by calcipotriol in biliary cells silenced for VDR, and this effect was abolished by co-silencing the plasma membrane receptor of vitamin D, protein disulfide-isomerase A3 (PDIA3). CONCLUSIONS: Our results demonstrate an anti-inflammatory role of VDR signaling in cholangiocytes and cholangiopathy. They also provide evidence for PDIA3-mediated anti-inflammatory effects of vitamin D and vitamin D analog in these settings.


Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Colestase/genética , Receptores de Calcitriol/genética , Vitamina D/metabolismo , Animais , Colestase/tratamento farmacológico , Colestase/metabolismo , Colestase/patologia , Fibrose , Deleção de Genes , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Calcitriol/metabolismo , Transdução de Sinais/efeitos dos fármacos , Vitamina D/uso terapêutico , Vitaminas/metabolismo , Vitaminas/uso terapêutico
12.
Int Immunopharmacol ; 92: 107328, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33412394

RESUMO

Cholestasis is one of the most common clinical symptom of liver diseases. If patients do not receive effective treatment, cholestasis can evolve into liver fibrosis, cirrhosis and ultimately liver failure requiring liver transplantation. Currently, only ursodeoxycholic acid, obeticholic acid and bezafibrate are FDA-approved drugs, thereby requiring a breakthrough in new mechanisms and therapeutic development. Inflammation is one of the common complications of cholestasis. Hepatic accumulation of toxic hydrophobic bile acids is a highly immunogenic process involving both resident and immigrating immune cells. And the resulting inflammation may further aggravate hepatocyte injury. Though, great investigations have been made in the immune responses during cholestasis, the relationship between immune responses and cholestasis remains unclear. Moreover, scarce reviews summarize the immune responses during cholestasis and the efficacy of therapies on immune response. The main purpose of this paper is to review the existing literature on dysfunctional immune response during cholestasis and the effect of treatment on immune response which may provide an insight for researchers and drug development.


Assuntos
Colestase/patologia , Imunidade/imunologia , Inflamação/imunologia , Animais , Colestase/imunologia , Colestase/metabolismo , Humanos , Inflamação/patologia
13.
Sci Rep ; 11(1): 2269, 2021 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-33500487

RESUMO

Chronic liver disease leads to neuropsychiatric complications called hepatic encephalopathy (HE). Current treatments have some limitations in their efficacy and tolerability, emphasizing the need for alternative therapies. Modulation of gut bacterial flora using probiotics is emerging as a therapeutic alternative. However, knowledge about how probiotics influence brain metabolite changes during HE is missing. In the present study, we combined the advantages of ultra-high field in vivo 1H MRS with behavioural tests to analyse whether a long-term treatment with a multistrain probiotic mixture (VIVOMIXX) in a rat model of type C HE had a positive effect on behaviour and neurometabolic changes. We showed that the prophylactic administration of this probiotic formulation led to an increase in gut Bifidobacteria and attenuated changes in locomotor activity and neurometabolic profile in a rat model of type C HE. Both the performance in behavioural tests and the neurometabolic profile of BDL + probiotic rats were improved compared to the BDL group at week 8 post-BDL. They displayed a significantly lesser increase in brain Gln, a milder decrease in brain mIns and a smaller decrease in neurotransmitter Glu than untreated animals. The clinical implications of these findings are potentially far-reaching given that probiotics are generally safe and well-tolerated by patients.


Assuntos
Encéfalo/metabolismo , Colestase/metabolismo , Hepatopatias/metabolismo , Probióticos/uso terapêutico , Compostos de Amônio/sangue , Animais , Comportamento Animal , Bifidobacterium/fisiologia , Ductos Biliares/patologia , Bilirrubina/sangue , Glicemia/metabolismo , Peso Corporal , Colestase/sangue , Colestase/microbiologia , Progressão da Doença , Fezes/microbiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Glutamina/metabolismo , Inositol/metabolismo , Ligadura , Hepatopatias/sangue , Hepatopatias/microbiologia , Masculino , Metaboloma , Espectroscopia de Prótons por Ressonância Magnética , Ratos Wistar
14.
J Ethnopharmacol ; 267: 113544, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33152436

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Gut microbiome dysbiosis is closely associated with cholestatic liver disease. Huangqi decoction (HQD), a traditional herbal formula, has protection against cholestatic liver injury. However, the effect of HQD on gut microbiome remains unknown. AIM OF THE STUDY: To investigate the effect of HQD on 3, 5-diethoxycarbonyl-1, 4-dihydrocollidine (DDC) induced cholestatic liver injury and its effect on the gut microbiome profiles. MATERIALS AND METHODS: Mice with DDC-induced cholestatic liver injury were treated with low and high doses of HQD for 8 weeks. Fecal samples were analyzed by 16 S ribosomal DNA sequencing. Barrier function as well as intestinal and hepatic inflammation was analyzed by real-time PCR and western blotting. RESULTS: HQD treatment ameliorated the DDC-induced liver injury and collagen deposition around hepatic bile ducts. Moreover, decreased diversity, reduced richness, and abnormal composition of intestinal microbiota of cholestatic mice were remarkably attenuated by HQD supplementation. Differences in bacterial abundance, including levels of Prevotellaceae_NK3B31_group, Alistipes, and Gordonibacter, were increased in DDC-induced mice, as compared with control mice, and were decreased after HQD treatment. Moreover, intestinal dysbiosis promoted disruption of the intestinal barrier in cholestatic mice. However, HQD treatment alleviated intestinal barrier dysfunction. Importantly, increased hepatic expression of pro-inflammatory factors and the NLRP3 inflammasome, which have a positive correlation with differential bacteria, were characteristics found in DDC-induced cholestatic mice that were alleviated upon treatment with HQD. CONCLUSION: HQD treatment alleviated gut microbiota dysbiosis, ameliorated the intestinal barrier dysfunction, inhibited liver inflammation, and protected against DDC-induced cholestatic liver injury.


Assuntos
Bactérias/efeitos dos fármacos , Colestase/tratamento farmacológico , Colo/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Fármacos Gastrointestinais/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Hepatopatias/prevenção & controle , Fígado/efeitos dos fármacos , Animais , Bactérias/crescimento & desenvolvimento , Colestase/metabolismo , Colestase/microbiologia , Colestase/patologia , Colo/metabolismo , Colo/microbiologia , Citocinas/metabolismo , Modelos Animais de Doenças , Disbiose , Inflamassomos/metabolismo , Mediadores da Inflamação/metabolismo , Fígado/metabolismo , Fígado/patologia , Hepatopatias/metabolismo , Hepatopatias/microbiologia , Hepatopatias/patologia , Masculino , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Permeabilidade
15.
J Ethnopharmacol ; 268: 113658, 2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33307056

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Cholestasis caused by bile secretion and excretion disorders is a serious manifestation of liver disease. With limited treatment methods, it affects millions of people worldwide. Huangqi decoction (HQD), an effective traditional Chinese medicine, is used to treat chronic cholestatic liver diseases. However, the action mechanisms of it were not fully elucidated. AIM OF THE STUDY: We aim to investigate the therapeutic effect of HQD, and its active component, astragalosides, against α-naphthylisothiocyanate (ANIT)-induced cholestasis in rats based on targeted metabolomics analysis and revel the potential mechanism. MATERIALS AND METHODS: The therapeutic effect of HQD and astragalosides on ANIT-induced cholestasis model rats were evaluated by serum biochemical analysis. Liver damage was identified by histopathology. The levels of bile acids (BAs) and free fatty acids (FFAs) in serum and liver tissues were measured by ultra-high performance liquid chromatography-triple quadrupole mass spectrometry (UPLC-TQMS). qRT-PCR and Western blot analysis were used to measure the expression of nuclear hormone receptor, membrane receptor and BA transporter protein in cholestatic rats before and after HQD and astragalosides treatment. RESULTS: The obtained data showed that the administration of ANIT caused obvious cholestasis with significantly increased intrahepatic retention of hydrophobic BAs and altered FFAs, which were consistent with the liver histopathological and serum biochemical findings. HQD and astragalosides treatment were able to attenuate ANIT-induced BAs and FFAs perturbation, ameliorate the impaired liver function, histopathological ductular reaction, and lipid peroxidation damage by ANIT. Elevated mRNA and protein expression of transporters related to BA metabolism and genes related to lipogenesis and lipid oxidation metabolism in cholestasis were attenuated or normalized by HQD and astragalosides treatment. CONCLUSIONS: Intervention by ANIT can significantly change the homeostasis of BAs and FFAs. HQD and astragalosides exerted a hepatoprotective effect against cholestatic liver injury by restoring the altered BA and FFA metabolism through the improvement of BA transporter, nucleus hormone receptor, and membrane receptor.


Assuntos
1-Naftilisotiocianato/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Colestase/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Metabolômica/métodos , Saponinas/uso terapêutico , Animais , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Colestase/induzido quimicamente , Colestase/metabolismo , Masculino , Ratos , Ratos Wistar
16.
JCI Insight ; 6(1)2020 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-33290278

RESUMO

Activation of farnesoid X receptor (FXR) by obeticholic acid (OCA) reduces hepatic inflammation and fibrosis in patients with primary biliary cholangitis (PBC), a life-threatening cholestatic liver failure. Inhibition of bromodomain-containing protein 4 (BRD4) also has antiinflammatory, antifibrotic effects in mice. We determined the role of BRD4 in FXR function in bile acid (BA) regulation and examined whether the known beneficial effects of OCA are enhanced by inhibiting BRD4 in cholestatic mice. Liver-specific downregulation of BRD4 disrupted BA homeostasis in mice, and FXR-mediated regulation of BA-related genes, including small heterodimer partner and cholesterol 7 alpha-hydroxylase, was BRD4 dependent. In cholestatic mice, JQ1 or OCA treatment ameliorated hepatotoxicity, inflammation, and fibrosis, but surprisingly, was antagonistic in combination. Mechanistically, OCA increased binding of FXR, and the corepressor silencing mediator of retinoid and thyroid hormone receptor (SMRT) decreased NF-κB binding at inflammatory genes and repressed the genes in a BRD4-dependent manner. In patients with PBC, hepatic expression of FXR and BRD4 was significantly reduced. In conclusion, BRD4 is a potentially novel cofactor of FXR for maintaining BA homeostasis and hepatoprotection. Although BRD4 promotes hepatic inflammation and fibrosis in cholestasis, paradoxically, BRD4 is required for the antiinflammatory, antifibrotic actions of OCA-activated FXR. Cotreatment with OCA and JQ1, individually beneficial, may be antagonistic in treatment of liver disease patients with inflammation and fibrosis complications.


Assuntos
Colestase/tratamento farmacológico , Colestase/metabolismo , Proteínas Nucleares/antagonistas & inibidores , Receptores Citoplasmáticos e Nucleares/agonistas , Fatores de Transcrição/antagonistas & inibidores , Animais , Azepinas/administração & dosagem , Azepinas/farmacologia , Ácidos e Sais Biliares/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Ácido Quenodesoxicólico/administração & dosagem , Ácido Quenodesoxicólico/análogos & derivados , Ácido Quenodesoxicólico/farmacologia , Colestase/genética , Colesterol 7-alfa-Hidroxilase/metabolismo , Modelos Animais de Doenças , Interações Medicamentosas , Técnicas de Silenciamento de Genes , Humanos , Fígado/metabolismo , Cirrose Hepática Biliar/tratamento farmacológico , Cirrose Hepática Biliar/genética , Cirrose Hepática Biliar/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , NF-kappa B/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Correpressor 2 de Receptor Nuclear/metabolismo , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Triazóis/administração & dosagem , Triazóis/farmacologia
17.
Toxicol Appl Pharmacol ; 408: 115248, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32976922

RESUMO

Alpha-naphthylisothiocyanate (ANIT) is a typical hepatotoxicant that causes cholestasis, which causes toxic bile acid accumulation in the liver and leads to liver injury. Picroside II (PIC), one of the dominant effective components extracted from Picrorhiza scrophulariiflora Pennell, exhibits many pharmacological effects. However, the role of AMP-activated protein kinase (AMPK)-Farnesoid X receptor (FXR) pathway in the hepatoprotective effect of PIC against ANIT-induced cholestasis remains largely unknown. This study aimed to investigate the mechanisms of PIC on ANIT-induced cholestasis in vivo and in vitro. Our results showed that PIC protected against ANIT-induced liver injury in primary mouse hepatocytes, and decreased serum biochemical markers and lessened histological injuries in mice. ANIT inhibited FXR and its target genes of bile acid synthesis enzymes sterol-12α-hydroxylase (CYP8B1), and increase bile acid uptake transporter Na + -dependent taurocholate transporter (NTCP), efflux transporter bile salt export pump (BSEP) and bile acid metabolizing enzymes UDP-glucuronosyltransferase 1a1 (UGT1A1) expressions. PIC prevented its downregulation of FXR, NTCP, BSEP and UGT1A1, and further reduced CYP8B1 by ANIT. Furthermore, ANIT activated AMPK via ERK1/2-LKB1 pathway. PIC inhibited ERK1/2, LKB1 and AMPK phosphorylation in ANIT-induced cholestasis in vivo and in vitro. AICAR, an AMPK agonist, blocked PIC-mediated changes in FXR, CYP8B1 and BSEP expression in vitro. Meanwhile, U0126, an ERK1/2 inhibitor, further repressed ERK1/2-LKB1-AMPK pathway phosphorylation. In conclusion, PIC regulated bile acid-related transporters and enzymes to protect against ANIT-induced liver injury, which related to ERK1/2-LKB1-AMPK pathway. Thus, this study extends the understanding of the anti-cholestasis effect of PIC and provides new therapeutic targets for cholestasis treatment.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Colestase/tratamento farmacológico , Cinamatos/uso terapêutico , Glucosídeos Iridoides/uso terapêutico , Substâncias Protetoras/uso terapêutico , Receptores Citoplasmáticos e Nucleares/metabolismo , 1-Naftilisotiocianato , Animais , Células Cultivadas , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Colestase/induzido quimicamente , Colestase/metabolismo , Cinamatos/farmacologia , Hepatócitos , Glucosídeos Iridoides/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Substâncias Protetoras/farmacologia , Receptores Citoplasmáticos e Nucleares/genética , Transdução de Sinais/efeitos dos fármacos
18.
Sci Rep ; 10(1): 16024, 2020 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-32994489

RESUMO

The orexigenic peptide ghrelin (Ghr) stimulates hunger signals in the hypothalamus via growth hormone secretagogue receptor (GHS-R1a). Gastric Ghr is synthetized as a preprohormone which is proteolytically cleaved, and acylated by a membrane-bound acyl transferase (MBOAT). Circulating Ghr is reduced in cholestatic injuries, however Ghr's role in cholestasis is poorly understood. We investigated Ghr's effects on biliary hyperplasia and hepatic fibrosis in Mdr2-knockout (Mdr2KO) mice, a recognized model of cholestasis. Serum, stomach and liver were collected from Mdr2KO and FVBN control mice treated with Ghr, des-octanoyl-ghrelin (DG) or vehicle. Mdr2KO mice had lower expression of Ghr and MBOAT in the stomach, and lower levels of circulating Ghr compared to WT-controls. Treatment of Mdr2KO mice with Ghr improved plasma transaminases, reduced biliary and fibrosis markers. In the liver, GHS-R1a mRNA was expressed predominantly in cholangiocytes. Ghr but not DG, decreased cell proliferation via AMPK activation in cholangiocytes in vitro. AMPK inhibitors prevented Ghr-induced FOXO1 nuclear translocation and negative regulation of cell proliferation. Ghr treatment reduced ductular reaction and hepatic fibrosis in Mdr2KO mice, regulating cholangiocyte proliferation via GHS-R1a, a G-protein coupled receptor which causes increased intracellular Ca2+ and activation of AMPK and FOXO1, maintaining a low rate of cholangiocyte proliferation.


Assuntos
Colestase/tratamento farmacológico , Grelina/administração & dosagem , Cirrose Hepática/prevenção & controle , Receptores de Grelina/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Acetiltransferases/metabolismo , Animais , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Colestase/genética , Colestase/metabolismo , Modelos Animais de Doenças , Proteína Forkhead Box O1/metabolismo , Grelina/metabolismo , Grelina/farmacologia , Cirrose Hepática/genética , Cirrose Hepática/metabolismo , Camundongos , Camundongos Knockout , Transaminases/sangue
19.
Int J Mol Sci ; 21(18)2020 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-32906817

RESUMO

Connexins are goal keepers of tissue homeostasis, including in the liver. As a result, they are frequently involved in disease. The current study was set up to investigate the effects of cholestatic disease on the production of connexin26, connexin32 and connexin43 in the liver. For this purpose, bile duct ligation, a well-known trigger of cholestatic liver injury, was applied to mice. In parallel, human hepatoma HepaRG cell cultures were exposed to cholestatic drugs and bile acids. Samples from both the in vivo and in vitro settings were subsequently subjected to assessment of mRNA and protein quantities as well as to in situ immunostaining. While the outcome of cholestasis on connexin26 and connexin43 varied among experimental settings, a more generalized repressing effect was seen for connexin32. This has also been observed in many other liver pathologies and could suggest a role for connexin32 as a robust biomarker of liver disease and toxicity.


Assuntos
Colestase/fisiopatologia , Conexinas/metabolismo , Animais , Ácidos e Sais Biliares/metabolismo , Ductos Biliares/metabolismo , Células Cultivadas , Colestase/metabolismo , Conexina 26/metabolismo , Conexina 43/metabolismo , Hepatócitos/metabolismo , Humanos , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/metabolismo
20.
Biochim Biophys Acta Mol Basis Dis ; 1866(12): 165958, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32896605

RESUMO

Cholestasis, a condition characterized by an abnormal decrease in bile flow, is accompanied by various symptoms such as pruritus. Although cholestatic pruritus is a prominent condition, its precise mechanisms have largely been elusive. Recently, advancements have been made for understanding the etiology and pathogenesis of cholestatic pruritus. The current review therefore focuses on summarizing the overall progress made in the elucidation of its molecular mechanisms. We have reviewed the available animal models on cholestasis to compare the differences between them, characterized potential pruritogens involved in cholestatic pruritus, and have summarized the receptor and ion channels implicated in the condition. Finally, we have discussed the available treatment options for alleviation of cholestatic pruritus. As our understanding of the mechanisms of cholestatic pruritus deepens, novel strategies to cure this condition are awaited.


Assuntos
Colestase/metabolismo , Prurido/metabolismo , Animais , Colestase/patologia , Humanos , Prurido/patologia
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