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1.
Gastroenterol Clin North Am ; 50(2): 383-402, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34024447

RESUMO

Nonhepatotropic viruses such as adenovirus, herpes simplex virus, flaviviruses, filoviruses, and human herpes virus, and bacteria such as Coxiella burnetii, can cause liver injury mimicking acute hepatitis. Most of these organisms cause a self-limited infection. However, in immunocompromised patients, they can cause severe hepatitis or in some cases fulminant hepatic failure requiring an urgent liver transplant. Hepatic dysfunction is also commonly seen in patients with severe acute respiratory syndrome coronavirus-2 infection. Patients with preexisting liver diseases are likely at risk for severe coronavirus disease 2019 (COVID-19) and may be associated with poor outcomes.


Assuntos
Infecções por Adenovirus Humanos/complicações , Hepatite/diagnóstico , Hepatite/virologia , Herpes Simples/complicações , Febre Q/complicações , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Infecções por Flavivirus/complicações , Hepatite/patologia , Hepatite/terapia , Humanos , Fígado/fisiopatologia , Transplante de Fígado
2.
Int J Mol Sci ; 22(8)2021 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-33920431

RESUMO

Corticotropin-releasing factor (CRF) in the brain acts on physiological and pathophysiological modulation of the hepatobiliary system. Central CRF administration aggravates experimental acute liver injury by decreasing hepatic blood flow. Conversely, minimal evidence is available regarding the effect of centrally acting CRF on hepatic lipid metabolism and inflammation. We examined whether central CRF affects hepatic lipid metabolism and inflammation-related gene expression in rats. Male Long Evans rats were intracisternally injected with CRF (10 µg) or saline. Rats were sacrificed 2 h, 6 h, and 24 h after the CRF injection, the liver was isolated, and mRNA was extracted. Next, hepatic lipid metabolism and inflammation-related gene expression were examined. Hepatic SREBF1 (sterol regulatory element-binding transcription factor 1) mRNA levels were significantly increased 6 h and 24 h after intracisternal CRF administration when compared with those in the control group. Hepatic TNFα and IL1ß mRNA levels increased significantly 6 h after intracisternal CRF administration. Hepatic sympathectomy or guanethidine treatment, not hepatic branch vagotomy or atropine treatment, inhibited central CRF-induced increase in hepatic SREBF1, TNFα and IL1ß mRNA levels. These results indicated that central CRF affects hepatic de novo lipogenesis and inflammation-related gene expression through the sympathetic-noradrenergic nervous system in rats.


Assuntos
Hormônio Liberador da Corticotropina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Hepatite/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Animais , Hepatite/patologia , Inflamação/metabolismo , Inflamação/patologia , Fígado/patologia , Masculino , Ratos , Ratos Long-Evans
3.
Nutrients ; 13(3)2021 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-33809904

RESUMO

The main biologically active components of plants belonging to the genus Allium, responsible for their biological activities, including anti-inflammatory, antioxidant and immunomodulatory, are organosulfur compounds. The aim of this study was to synthetize the mixture of dipropyl polysulfides (DPPS) and to test their biological activity in acute hepatitis. C57BL/6 mice were administered orally with DPPS 6 h before intravenous injection of Concanavalin A (ConA). Liver inflammation, necrosis and hepatocytes apoptosis were determined by histological analyses. Cytokines in liver tissue were determined by ELISA, expression of adhesive molecules and enzymes by RT PCR, while liver mononuclear cells were analyzed by flow cytometry. DPPS pretreatment significantly attenuated liver inflammation and injury, as evidenced by biochemical and histopathological observations. In DPPS-pretreated mice, messenger RNA levels of adhesion molecules and NADPH oxidase complex were significantly reduced, while the expression of SOD enzymes was enhanced. DPPS pretreatment decreased protein level of inflammatory cytokines and increased percentage of T regulatory cells in the livers of ConA mice. DPPS showed hepatoprotective effects in ConA-induced hepatitis, characterized by attenuation of inflammation and affection of Th17/Treg balance in favor of T regulatory cells and implicating potential therapeutic usage of DPPS mixture in inflammatory liver diseases.


Assuntos
Anti-Inflamatórios/uso terapêutico , Hepatite/tratamento farmacológico , Fígado/efeitos dos fármacos , Propano/análogos & derivados , Sulfetos/uso terapêutico , Animais , Apoptose , Concanavalina A , Modelos Animais de Doenças , Hepatite/complicações , Hepatite/patologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/patologia , Inflamação/etiologia , Inflamação/prevenção & controle , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Necrose , Propano/uso terapêutico
4.
Phytomedicine ; 81: 153426, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33341026

RESUMO

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the Western world, and it is closely associated to obesity, type 2 diabetes mellitus, and dyslipidemia. Medicinal cannabis and some neutral cannabinoids have been suggested as a potential therapy for liver diseases. HYPOTHESIS: Δ9-tetrahydrocannabinolic acid (Δ9-THCA), the non-psychotropic precursor of Δ9-THC, is one of the most abundant cannabinoids presents in Cannabis Sativa. However, its biological activities have been poorly investigated. Herein, we studied the antifibrotic and antiinflammatory activities of Δ9-THCA in two different animal models of liver injury, providing a rationale for additional studies on the medicinal use of this cannabinoid in the treatment of liver fibrosis and the management of NAFLD. STUDY DESIGN: The antifibrotic activity of Δ9-THCA in vitro was investigated in the cell lines LX-2 and NIH-3T3-Col1A2-luc. Non-alcoholic liver fibrosis was induced in mice by CCl4 treatment or, alternatively, by 23-week high fat diet (HFD) feeding. Δ9-THCA was administered daily intraperitoneally during the CCl4 treatment or during the last 3 weeks in HFD-fed mice. METHODS: TGFß-induced profibrotic gene expression was analyzed by luciferase and qPCR assays. Liver fibrosis and inflammation were assessed by immunochemistry and qPCR. Blood glucose, insulin, leptin and triglyceride levels were measured in HFD mice. RESULTS: Δ9-THCA inhibited the expression of Tenascin C (TNC) and Col3A1 induced by TGFß in LX-2 cells and the transcriptional activity of the Col1A2 promoter in fibroblasts. Δ9-THCA significantly attenuated CCl4-induced liver fibrosis and inflammation and reduced T cell and macrophage infiltration. Mice fed HFD for 23 weeks developed severe obesity (DIO), fatty liver and marked liver fibrosis, accompanied by immune cell infiltration. Δ9-THCA, significantly reduced body weight and adiposity, improved glucose tolerance, and drastically attenuated DIO-induced liver fibrosis and immune cell infiltration. CONCLUSIONS: Δ9-THCA prevents TGFß-induced fibrotic markers in vitro and liver inflammation and fibrogenesis in vivo, providing a rationale for additional studies on the medicinal use of this cannabinoid, as well as cannabis preparations containing it, for the treatment of liver fibrosis and the management of NAFLD.


Assuntos
Dronabinol/farmacologia , Hepatite/tratamento farmacológico , Cirrose Hepática/prevenção & controle , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Animais , Cannabis/química , Tetracloreto de Carbono/toxicidade , Dieta Hiperlipídica/efeitos adversos , Regulação da Expressão Gênica/efeitos dos fármacos , Hepatite/etiologia , Hepatite/patologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células NIH 3T3 , Hepatopatia Gordurosa não Alcoólica/etiologia , Obesidade/complicações , Obesidade/etiologia
5.
J Ethnopharmacol ; 264: 113287, 2021 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-32858197

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Folk medicine reports have described the use of Chenopodium ambrosioides as an anti-inflammatory, analgesic, and anthelmintic herb. These effects, including its activity against intestinal worms, are already scientifically observed. However, the immunological mechanisms of this species in the treatment of Schistosoma mansoni infection are unknown. AIM OF THE STUDY: To evaluate the immunological and anti-Schistosoma mansoni effects of a crude Chenopodium ambrosioides hydro-alcoholic extract (HCE). MATERIALS AND METHODS: For the in vitro analysis, cercariae and adult worms were exposed to different concentrations (0 to 10,000 µg/mL) of the HCE. For the in vivo evaluation, Swiss mice were infected with 50 cercariae of S. mansoni and separated into groups according to treatment as follows: a negative control (without treatment), a positive control (treated with Praziquantel®), HCE1 Group (treated with HCE during the cutaneous phase), HCE2 Group (treated with HCE during the lung phase), HCE3 Group (treated with HCE during the young worm phase), and HCE4 Group (treated with HCE during the adult worm phase). The animals treated with HCE received daily doses of 50 mg/kg, by gavage, for seven days, corresponding to the different developmental stages of S. mansoni. For comparison, a clean control group (uninfected and untreated) was also included. All animals were euthanized 60 days post-infection to allow the following assessments to be performed: a complete blood cells count, counts of eggs in the feces and liver, the quantification of cytokines and IgE levels, histopathological evaluations of the livers, and the analysis of inflammatory mediators. RESULTS: HCE treatment increased the mortality of cercariae and adult worms in vitro. The HCE treatment in vivo reduced the eggs in feces and liver. The number and area of liver granulomas, independent of the phase of treatment, were also reduced. The treatment with HCE reduced the percentage of circulating eosinophils, IgE, IFN-γ, TNF-α, and IL-4. In contrast, the treatment with the HCE, dependent on the phase, increased IL-10 levels and the number of peritoneal and bone marrow cells, mainly of T lymphocytes, B lymphocytes, and macrophages. This effect could be due to secondary compounds presents in this extract, such as kaempferol, quercetin and derivatives. CONCLUSIONS: This study demonstrates that Chenopodium ambrosioides has antiparasitic and immunomodulatory activity against the different phases of schistosomiasis, reducing the granulomatous inflammatory profile caused by the infection and, consequently, improving the disease prognosis.


Assuntos
Antiparasitários/uso terapêutico , Chenopodium ambrosioides , Hepatite/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Extratos Vegetais/uso terapêutico , Esquistossomose mansoni/tratamento farmacológico , Animais , Antiparasitários/isolamento & purificação , Antiparasitários/farmacologia , Hepatite/metabolismo , Hepatite/parasitologia , Hepatite/patologia , Fatores Imunológicos/isolamento & purificação , Fatores Imunológicos/farmacologia , Masculino , Camundongos , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Distribuição Aleatória , Schistosoma mansoni/efeitos dos fármacos , Schistosoma mansoni/fisiologia , Esquistossomose mansoni/metabolismo , Esquistossomose mansoni/patologia
6.
Methods Mol Biol ; 2225: 275-292, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33108669

RESUMO

Ischemia-reperfusion injury (IRI) drives early and long-term damage to organs as well as compounding damage from acute transplant rejection and surgical trauma. IRI initiates an aggressive and prolonged inflammation leading to tissue injury, organ failure, and death. However, there are few effective therapeutic interventions for IRI. The destructive inflammatory cell activity in IRI is part of an aberrant innate immune response that triggers multiple pathways. Hence, immune-modulating treatments to control pathways triggered by IRI hold great therapeutic potential. Viruses, especially large DNA viruses, have evolved highly effective immune-modulating proteins for the purpose of immune evasion and to protect the virus from the host immune defenses. A number of these immune-modulating proteins have proven therapeutically effective in preclinical models, many with function targeting pathways known to be involved in IRI. The use of virus-derived immune-modulating proteins thus represents a promising source for new treatments to target ischemia-reperfusion injury. Laboratory small animal models of IRI are well established and are able to reproduce many aspects of ischemia-reperfusion injury seen in humans. This chapter will discuss the methods used to perform the IRI procedure in mice, as well as clinically relevant diagnostic tests to evaluate liver injury and approaches for assessing histological damage while testing novel immune modulating protein treatments.


Assuntos
Anti-Inflamatórios/farmacologia , Hepatite/prevenção & controle , Fatores Imunológicos/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Proteínas Virais/farmacologia , Isquemia Quente/métodos , Alanina Transaminase/genética , Alanina Transaminase/metabolismo , Animais , Anti-Inflamatórios/imunologia , Anti-Inflamatórios/metabolismo , Aspartato Aminotransferases/genética , Aspartato Aminotransferases/metabolismo , Biomarcadores/metabolismo , Modelos Animais de Doenças , Expressão Gênica , Hepatite/genética , Hepatite/imunologia , Hepatite/patologia , Imunidade Inata/efeitos dos fármacos , Fatores Imunológicos/biossíntese , Fatores Imunológicos/imunologia , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/imunologia , Fígado/patologia , Camundongos , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/farmacologia , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/patologia , Coloração e Rotulagem/métodos , Proteínas Virais/biossíntese , Proteínas Virais/imunologia
7.
Sci Rep ; 10(1): 21778, 2020 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-33311540

RESUMO

Sterile liver inflammation and fibrosis are associated with many liver disorders of different etiologies. Both type 1 and type 2 inflammatory responses have been reported to contribute to liver pathology. However, the mechanisms controlling the balance between these responses are largely unknown. Natural killer T (NKT) cells can be activated to rapidly secrete cytokines and chemokines associated with both type 1 and type 2 inflammatory responses. As these proteins have been reported to accumulate in different types of sterile liver inflammation, we hypothesized that these cells may play a role in this pathological process. We have found that a transgenic NKT (tgNKT) cell population produced in the immunodeficient 2,4αßNOD.Rag2-/- mice, but not in 2,4αßNOD.Rag2+/- control mice, promoted a type 1 inflammatory response with engagement of the NOD-, LRR- and pyrin domain-containing protein-3 (NLRP3) inflammasome. The induction of the type 1 inflammatory response was followed by an altered cytokine profile of the tgNKT cell population with a biased production of anti-inflammatory/profibrotic cytokines and development of liver fibrosis. These findings illustrate how the plasticity of NKT cells modulates the inflammatory response, suggesting a key role for the NKT cell population in the control of sterile liver inflammation.


Assuntos
Cirrose Hepática/imunologia , Cirrose Hepática/patologia , Células T Matadoras Naturais/metabolismo , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Fibrose/metabolismo , Hepatite/patologia , Imunidade Celular/fisiologia , Imunidade Inata/fisiologia , Inflamassomos/metabolismo , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/metabolismo , Hepatopatias/patologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Células T Matadoras Naturais/fisiologia
8.
Toxicol Lett ; 332: 1-6, 2020 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-32579995

RESUMO

Non-alcoholic fatty liver disease (NAFLD) can be typically classified into two subgroups: non-alcoholic fatty liver and non-alcoholic steatohepatitis. Mouse models of NAFLD are useful tools for understanding the pathogenesis and progression of NAFLD and for developing drugs for its treatment. Here, we investigated the time-dependent changes in serum lipids and biochemical markers of hepatic function, hepatic inflammation, and fibrosis in mice fed a normal diet (ND) or a NAFLD diet (choline deficient, L-amino acid-defined, high-fat diet; CDAHFD) for 12 weeks. CDAHFD-fed mice showed significantly reduced serum levels of total cholesterol, triglyceride, and high-density lipoprotein cholesterol throughout the treatment period compared with ND-fed mice. The changes in aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and total bilirubin showed an inverse U-shaped curve in the CDAHFD-fed mice. The serum alkaline phosphatase levels decreased in both ND- and CDAHFD-fed mice in a time-dependent manner. Furthermore, CDAHFD-fed mice showed a significant increase in the number of inflammatory foci and hepatic fibrosis at 6-12 weeks, although inflammatory foci and hepatic fibrogenesis were observable at relatively early stages as well (1-4 weeks). In conclusion, the long-term profile of serological biomarkers, hepatic inflammation, and fibrosis in CDAHFD-fed mice identified in this study may provide a better understanding of NAFLD pathogenesis.


Assuntos
Hepatite/patologia , Cirrose Hepática/patologia , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica/patologia , Animais , Biomarcadores/análise , Peso Corporal/efeitos dos fármacos , Colesterol/sangue , HDL-Colesterol/sangue , Dieta , Hepatite/sangue , Hepatite/enzimologia , Metabolismo dos Lipídeos , Fígado/enzimologia , Fígado/metabolismo , Cirrose Hepática/sangue , Testes de Função Hepática , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/enzimologia , Triglicerídeos/sangue
10.
Adv Gerontol ; 33(1): 159-164, 2020.
Artigo em Russo | MEDLINE | ID: mdl-32362099

RESUMO

The applying of many drugs in elderly and old people often is the reason of liver dysfunction. Thereat, the risk of liver fibroid induration, acute and chronic hepatitis increases during aging. It is the reason to find new, effective and harmless hepatoprotectors. In the review is shown the data of hepatoprotective, immunoprotective and antiageing properties of liver polypeptide complex (Ventvil) and KEDA tetrapeptide (Lys-Glu-Asp-Ala, Livagen). In liver pathology experimental models (liver fibroid induration, acute and chronic hepatitis) in amimals and in vitro was shown high efficiency of Ventvil and KEDA peptide. Ventvil and KEDA peptide had concordant effects - normalized immune and antioxidant status, restored liver function during hepatitis. It was demonstrated, that maximal hepato- and immunoprotective effect of peptides verified in aging.


Assuntos
Envelhecimento , Hepatite/tratamento farmacológico , Fígado/patologia , Peptídeos/farmacologia , Animais , Antioxidantes , Hepatite/patologia , Humanos
11.
Nat Commun ; 11(1): 1747, 2020 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-32269263

RESUMO

Receptor interacting protein kinase 1 (RIPK1) regulates cell death and inflammatory responses downstream of TNFR1 and other receptors, and has been implicated in the pathogenesis of inflammatory and degenerative diseases. RIPK1 kinase activity induces apoptosis and necroptosis, however the mechanisms and phosphorylation events regulating RIPK1-dependent cell death signaling remain poorly understood. Here we show that RIPK1 autophosphorylation at serine 166 plays a critical role for the activation of RIPK1 kinase-dependent apoptosis and necroptosis. Moreover, we show that S166 phosphorylation is required for RIPK1 kinase-dependent pathogenesis of inflammatory pathologies in vivo in four relevant mouse models. Mechanistically, we provide evidence that trans autophosphorylation at S166 modulates RIPK1 kinase activation but is not by itself sufficient to induce cell death. These results show that S166 autophosphorylation licenses RIPK1 kinase activity to induce downstream cell death signaling and inflammation, suggesting that S166 phosphorylation can serve as a reliable biomarker for RIPK1 kinase-dependent pathologies.


Assuntos
Apoptose , Inflamação/metabolismo , Inflamação/patologia , Fosfosserina/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Alanina Transaminase/metabolismo , Animais , Células da Medula Óssea/citologia , Colite/patologia , Genótipo , Hepatite/patologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Mutação/genética , Neoplasias/patologia , Fosforilação , Sepse/patologia , Pele/patologia , Fator de Necrose Tumoral alfa
12.
Am J Surg Pathol ; 44(5): 617-625, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32187043

RESUMO

Common variable immunodeficiency (CVID) has a heterogenous clinical presentation and can be challenging to diagnose. Distinct histologic changes have been linked with CVID in several organ systems, which can help identify the correct diagnosis. In this study we review a cohort of hepatic CVID biopsies, to better define the spectrum of histologic and biochemical alterations. We reviewed 26 liver biopsies from 24 patients with CVID, obtained at 4 institutions between 2010 and 2019. Histologic slides were examined, and pathologic, biochemical, and clinical features were recorded. A control cohort of 21 patients with nodular regenerative hyperplasia (NRH) but lacking CVID was also examined. Liver function tests were frequently abnormal, especially alkaline phosphatase (median: 193 IU/L) and aspartate transaminase (median: 56 U/L), elevated in 23 and 17 of 25 biopsies, respectively. Fifteen patients had CVID involvement of other organs. Histologic features of primary biliary cholangitis were present in 2 patients, with florid duct lesions and prominent bile duct injury, in association with positive antimitochondrial antibodies. Among the other 24 biopsies, mild to moderate portal and lobular inflammation were present in 18 and 17 of 24 biopsies, respectively. Overall, 22 of 24 biopsies showed NRH-like changes. Plasma cell were absent. A distinct pattern of pericellular fibrosis was present in 23 of 26 biopsies overall. Involvement ranged from focal centrizonal fibrosis to bridging fibrosis and was accompanied by increased intrasinusoidal lymphocytes in 13 of 24 biopsies. Pericellular fibrosis was identified in 1 of 21 biopsies in the control cohort. Additional findings included granulomatous inflammation or nonhepatocellular foreign body-type multinucleate giant cells, identified in 4 biopsies. Three of 6 examined biopsies also demonstrated focal hepatocellular copper deposition. Hepatic disease in CVID is often associated with elevated alkaline phosphatase and aspartate transaminase and is characterized histologically by the mild nonspecific portal and lobular hepatitis, absence of plasma cells, NRH-like changes, and less commonly, typical histologic features of primary biliary cholangitis. We have also identified a distinctive pattern of delicate pericellular fibrosis that is a helpful clue to the diagnosis of hepatic disease in CVID, especially when accompanied by NRH-like changes.


Assuntos
Imunodeficiência de Variável Comum/complicações , Hepatite/etiologia , Hipertensão Portal/etiologia , Cirrose Hepática/etiologia , Fígado/patologia , Adolescente , Adulto , Idoso , Biomarcadores/sangue , Biópsia , Estudos de Casos e Controles , Imunodeficiência de Variável Comum/diagnóstico , Imunodeficiência de Variável Comum/imunologia , Feminino , Hepatite/imunologia , Hepatite/patologia , Humanos , Hipertensão Portal/imunologia , Hipertensão Portal/patologia , Fígado/imunologia , Cirrose Hepática/imunologia , Cirrose Hepática/patologia , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Plasmócitos/imunologia , Plasmócitos/patologia , Valor Preditivo dos Testes , Turquia , Estados Unidos , Adulto Jovem
13.
Arch Immunol Ther Exp (Warsz) ; 68(1): 3, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31965304

RESUMO

The effects of infection with Toxoplasma gondii vary from asymptomatic to the development of alterations in various organs (including the liver and kidneys) which may be irreversible, and lead to the death of the host. Whereas homeopathy is an alternative and effective method for treating various diseases, including those caused by protozoa, we questioned the effect of using Lycopodium clavatum in mice infected with T. gondii. One hundred male Swiss mice, 60 days old, were divided into four groups (n = 25/group): NIC (uninfected and untreated control), IC (infected and treated with un-dynamized 7% alcohol solution [vehicle]), G48 (infected and treated 48 h before infection and treated three more times; at 2, 4, and 6 days post-infection (dpi) with L. clavatum 200dH), and G72 (infected and treated for 3 consecutive days before infection with L. clavatum 200dH). In this study, physiological, histopathological, and immunological parameters were evaluated. The L. clavatum 200dH intensified renal damage in mice infected with T. gondii from 7 dpi, causing severe and progressive alterations during this period, such as various degrees of inflammation, edema, atrophy, and tubular cystic dilation, degenerated tubules with intra-cytoplasmic vacuoles and coalescing spots, severe vascular lesions, glomerulonephritis, and peri-glomerular congestion. In the G72 animals, which received L. clavatum 200dH, more severe cortex damage was observed (91.66-96.66%) as compared to the IC group (55-80%) and more renal corpuscle, and renal tubule injury was observed (80 ± 5 to 96.7% ± 2.89 of the total area) during all periods, as compared to the IC group (p < 0.05). Both groups presented high liver enzyme levels, and the highest values for AST were observable at 60 dpi. We observed significant increases of type I and III collagen, as well as high levels of TGF-ß1 in both organs of the treated animals, the main factor involved in fibrosis in areas damaged by the process. L. clavatum 200dH intensifies kidney and liver alterations in mice infected with T. gondii. Our results reinforce caution when indicating administration schemes and dosages for ultra-diluted drugs.


Assuntos
Glomerulonefrite/patologia , Hepatite/patologia , Homeopatia/efeitos adversos , Lycopodium/efeitos adversos , Toxoplasmose/tratamento farmacológico , Animais , Colágeno/metabolismo , Modelos Animais de Doenças , Fibrose , Glomerulonefrite/metabolismo , Glomerulonefrite/parasitologia , Hepatite/metabolismo , Hepatite/parasitologia , Masculino , Camundongos , Preparações de Plantas/efeitos adversos , Toxoplasma/patogenicidade , Toxoplasmose/patologia , Fator de Crescimento Transformador beta1/metabolismo
14.
Am J Physiol Gastrointest Liver Physiol ; 318(2): G211-G224, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31709830

RESUMO

Nonalcoholic steatohepatitis (NASH) has increased in Western countries due to the prevalence of obesity. Current interests are aimed at identifying the type and function of immune cells that infiltrate the liver and key factors responsible for mediating their recruitment and activation in NASH. We investigated the function and phenotype of CD8+ T cells under obese and nonobese NASH conditions. We found an elevation in CD8 staining in livers from obese human subjects with NASH and cirrhosis that positively correlated with α-smooth muscle actin, a marker of hepatic stellate cell (HSC) activation. CD8+ T cells were elevated 3.5-fold in the livers of obese and hyperlipidemic NASH mice compared with obese hepatic steatosis mice. Isolated hepatic CD8+ T cells from these mice expressed a cytotoxic IL-10-expressing phenotype, and depletion of CD8+ T cells led to significant reductions in hepatic inflammation, HSC activation, and macrophage accumulation. Furthermore, hepatic CD8+ T cells from obese and hyperlipidemic NASH mice activated HSCs in vitro and in vivo. Interestingly, in the lean NASH mouse model, depletion and knockdown of CD8+ T cells did not impact liver inflammation or HSC activation. We demonstrated that under obese/hyperlipidemia conditions, CD8+ T cell are key regulators of the progression of NASH, while under nonobese conditions they play a minimal role in driving the disease. Thus, therapies targeting CD8+ T cells may be a novel approach for treatment of obesity-associated NASH.NEW & NOTEWORTHY Our study demonstrates that CD8+ T cells are the primary hepatic T cell population, are elevated in obese models of NASH, and directly activate hepatic stellate cells. In contrast, we find CD8+ T cells from lean NASH models do not regulate NASH-associated inflammation or stellate cell activation. Thus, for the first time to our knowledge, we demonstrate that hepatic CD8+ T cells are key players in obesity-associated NASH.


Assuntos
Linfócitos T CD8-Positivos/patologia , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade/patologia , Animais , Células Estreladas do Fígado/efeitos dos fármacos , Hepatite/patologia , Humanos , Hiperlipidemias/patologia , Interleucina-10/biossíntese , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Hepatopatia Gordurosa não Alcoólica/complicações , Obesidade/etiologia , Receptores de LDL/genética , Receptores de LDL/metabolismo
15.
J Ethnopharmacol ; 248: 112361, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-31683033

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The traditional Chinese medicine Forsythiae Fructus is the dried fruit of Forsythia suspensa (Thunb.) Vahl. It is commonly used to clear heat and detoxify, reduce swelling and disperse knot, and evacuate wind and heat. AIM OF THE STUDY: Inflammation is involved in liver fibrosis. Phillygenin (PHI) is a kind of lignans extracted and separated from Forsythiae Fructus, which has been reported to have a good anti-inflammatory effect. Therefore, we aimed to explore whether PHI has a therapeutic effect on liver fibrosis caused by inflammation. MATERIALS AND METHODS: Firstly, the induction of the LX2 cells inflammatory model and fibrosis model by LPS with different concentrations were studied. Then, high, medium and low doses PHI was given for intervention therapy. The secretion of IL-6, IL-1ß and TNF-α inflammatory factors were detected by ELISA kit, and the expression of collagen I and α-SMA was detected by Western blot and RT-qPCR. The possible mechanism of PHI on TLR4/MyD88/NF-κB signal pathway was studied by computer-aided drug design software and the results were further verified by Western blot and RT-qPCR experiments. RESULTS: The results showed that LPS could promote the expression of IL-6, IL-1ß and TNF-α and the expression of collagen I and α-SMA, indicating that LPS could induce inflammation and fibrosis in LX2 cells. PHI could inhibit LX2 cell activation and fibrotic cytokine expression by inhibiting LPS-induced pro-inflammatory reaction. Molecular docking results showed that PHI could successfully dock with TLR4, MyD88, IKKß, p65, IκBα, and TAK1 proteins. Subsequently, Western blot and qPCR results further proved that PHI could inhibit the proteins expression in TLR4/MyD88/NF-κB signal pathway which were consistent with the molecular docking results. CONCLUSION: PHI can inhibit LPS-induced pro-inflammatory reaction and LX2 cell activation through TLR4/MyD88/NF-κB signaling pathway, thereby inhibiting liver fibrosis.


Assuntos
Anti-Inflamatórios/farmacologia , Células Estreladas do Fígado/efeitos dos fármacos , Hepatite/prevenção & controle , Lignanas/farmacologia , Lipopolissacarídeos/toxicidade , Cirrose Hepática/prevenção & controle , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Receptor 4 Toll-Like/metabolismo , Actinas/metabolismo , Linhagem Celular , Colágeno Tipo I/metabolismo , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Hepatite/metabolismo , Hepatite/patologia , Humanos , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo
16.
Histopathology ; 76(3): 470-480, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31550390

RESUMO

AIMS: Immune check-point inhibitors are known to cause immune-mediated adverse liver injury, but our knowledge is mainly based on cases treated with ipilimumab or nivolumab. METHODS AND RESULTS: Clinicopathological features of 10 patients with hepatobiliary adverse reactions caused by second-generation drugs, pembrolizumab (n = 6) and atezolizumab (n = 4), were reviewed. Liver dysfunction developed during a median period of 3.5 weeks after administration of the check-point inhibitor (3 days-1 year). Antinuclear antibodies were detected in two patients at a low titre (1/80), and serum IgG concentrations were also only mildly elevated in two patients. Liver biopsies showed panlobular hepatitis (n = 5), cholangiopathic changes (n = 2), granulomatous injury (n = 2) and bland cholestasis (n = 1). Two cases of cholangiopathy (both pembrolizumab-treated) showed diffuse sclerosing cholangitis on imaging, and one also presented lymphocytic cholangitis resembling primary biliary cholangitis on biopsy. In two atezolizumab-treated cases, Küpffer cells were hyperplastic and aggregated, forming microgranulomas. Confluent necrosis and eosinophilic or plasma cell infiltration were rare. On immunostaining, the ratio of CD8+ /CD4+ cells was 12.2 ± 5.1, which was significantly higher than that in autoimmune hepatitis (2.7 ± 1.1; P < 0.001) or idiosyncratic drug-induced liver injury (5.0 ± 1.1; P = 0.014). All patients responded to steroid therapy, but it was less effective in patients with sclerosing cholangitis. CONCLUSIONS: Pembrolizumab and atezolizumab manifested not only lobular hepatitis but also sclerosing cholangitis, lymphocytic duct injury and granulomatous hepatitis, probably representing various impaired cellular functions in CD8+ lymphocytes and macrophages due to blockage of PD-1-PD-L1 interaction.


Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/patologia , Colangite/patologia , Doenças do Sistema Digestório/patologia , Hepatite/patologia , Idoso , Biópsia , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Colangite/tratamento farmacológico , Estudos de Coortes , Doenças do Sistema Digestório/induzido quimicamente , Feminino , Hepatite/tratamento farmacológico , Humanos , Imuno-Histoquímica , Fígado/efeitos dos fármacos , Fígado/patologia , Hepatopatias/patologia , Masculino , Pessoa de Meia-Idade
17.
Am J Physiol Gastrointest Liver Physiol ; 318(2): G298-G304, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31813234

RESUMO

In liver cirrhosis, oxidative stress plays a major role in promoting liver inflammation and fibrosis. Mitochondria dysregulation is responsible for excessive reactive oxygen species production. Therefore, in an experimental model of cirrhosis, we investigated the effect of mitochondria-targeted antioxidant mitoquinone. Liver cirrhosis was induced in Spraque-Dawley rats by common bile duct ligation (CBDL). Mitoquinone (10 mg·kg-1·day-1, oral gavage) or vehicle was administered from 3rd to 28th day after CBDL, when animals were euthanized; liver oxidative stress, inflammation, fibrosis, mitophagy were evaluated; and in vivo and ex vivo hemodynamic studies were performed. In cirrhotic rats, mitoquinone prevented liver inflammation, hepatocyte necrosis, and fibrosis at histological examination; decreased circulating TNF-α, gene expression of transforming growth factor-ß1, collagen type 1a1, TNF-α, IL-6, IL-1ß, tissue inhibitor of metalloproteinase-1, matrix metalloproteinase (MMP)-2, and MMP-13; and reduced hepatic oxidative stress, as shown by reduced oxidative carbonylation of the proteins, by modulating antioxidants catalase, Mn superoxide dismutase, and Cu/Zn superoxide dismutase. Furthermore, mitoquinone attenuated apoptosis by reducing hepatic protein expression of cleaved caspase-3. A selective removal of dysfunctional mitochondria was improved by mitoquinone, as shown by the increase in Parkin translocation to mitochondria. Treatment with mitoquinone normalized the weight of the spleen; however, it increased portal blood flow and reduced splenic artery intrahepatic resistance, suggesting an effect on resistance index. Mitochondria-targeted antioxidant mitoquinone improves liver inflammation and fibrosis in cirrhotic rats by reducing hepatic oxidative stress, preventing apoptosis, and promoting removal of dysfunctional mitochondria. Therefore, it may represent a promising strategy for the prevention and treatment of liver cirrhosis.


Assuntos
Antioxidantes/farmacologia , Hepatite/patologia , Hepatite/prevenção & controle , Cirrose Hepática/patologia , Mitocôndrias Hepáticas/efeitos dos fármacos , Compostos Organofosforados/farmacologia , Ubiquinona/análogos & derivados , Animais , Apoptose/efeitos dos fármacos , Citocinas/sangue , Fibrose , Hemodinâmica/efeitos dos fármacos , Fígado/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Baço/patologia , Ubiquinona/farmacologia
20.
Cells ; 8(11)2019 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-31671832

RESUMO

Akt kinase isoforms (Akt1, Akt2, and Akt3) have generally been thought to play overlapping roles in phosphoinositide 3-kinase (PI3K)-mediated-signaling. However, recent studies have suggested that they display isoform-specific roles in muscle and fat. To determine whether such isoform-specificity is observed with respect to alcoholic liver disease (ALD) progression, we examined the role of Akt1, Akt2, and Akt3 in hepatic inflammation, and pro-fibrogenic proliferation and migration using Kupffer cells, hepatic stellate cells (HSC), and hepatocytes in an ethanol and lipopolysaccharide (LPS)-induced two-hit model in vitro and in vivo. We determined that siRNA-directed silencing of Akt2, but not Akt1, significantly suppressed cell inflammatory markers in HSC and Kupffer cells. Although both Akt1 and Akt2 inhibited cell proliferation in HSC, only Akt2 inhibited cell migration. Both Akt1 and Akt2, but not Akt3, inhibited fibrogenesis in hepatocytes and HSC. In addition, our in vivo results show that administration of chronic ethanol, binge ethanol and LPS (EBL) in wild-type C57BL/6 mice activated all three Akt isoforms with concomitant increases in activated forms of phosphoinositide dependent kinase-1 (PDK1), mammalian target-of-rapamycin complex 2 (mTORC2), and PI3K, resulting in upregulation in expression of inflammatory, proliferative, and fibrogenic genes. Moreover, pharmacological blocking of Akt2, but not Akt1, inhibited EBL-induced inflammation while blocking of both Akt1 and Akt2 inhibited pro-fibrogenic marker expression and progression of fibrosis. Our findings indicate that Akt isoforms play unique roles in inflammation, cell proliferation, migration, and fibrogenesis during EBL-induced liver injury. Thus, close attention must be paid when targeting all Akt isoforms as a therapeutic intervention.


Assuntos
Hepatite/genética , Cirrose Hepática/genética , Hepatopatias Alcoólicas/genética , Proteínas Proto-Oncogênicas c-akt/fisiologia , Animais , Células Cultivadas , Progressão da Doença , Etanol/farmacologia , Feminino , Células Hep G2 , Hepatite/etiologia , Hepatite/patologia , Humanos , Isoenzimas/fisiologia , Cirrose Hepática/etiologia , Cirrose Hepática/patologia , Hepatopatias Alcoólicas/complicações , Hepatopatias Alcoólicas/patologia , Camundongos , Camundongos Endogâmicos C57BL
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