RESUMO
Gut-dysbiosis-induced lipopolysaccharides (LPS) translocation into systemic circulation has been suggested to be implicated in nonalcoholic fatty liver disease (NAFLD) pathogenesis. This study aimed to assess if oleuropein (OLE), a component of extra virgin olive oil, lowers high-fat-diet (HFD)-induced endotoxemia and, eventually, liver steatosis. An immunohistochemistry analysis of the intestine and liver was performed in (i) control mice (CTR; n = 15), (ii) high-fat-diet fed (HFD) mice (HFD; n = 16), and (iii) HFD mice treated with 6 µg/day of OLE for 30 days (HFD + OLE, n = 13). The HFD mice developed significant liver steatosis compared to the controls, an effect that was significantly reduced in the HFD + OLE-treated mice. The amount of hepatocyte LPS localization and the number of TLR4+ macrophages were higher in the HFD mice in the than controls and were lowered in the HFD + OLE-treated mice. The number of CD42b+ platelets was increased in the liver sinusoids of the HFD mice compared to the controls and decreased in the HFD + OLE-treated mice. Compared to the controls, the HFD-treated mice showed a high percentage of intestine PAS+ goblet cells, an increased length of intestinal crypts, LPS localization and TLR4+ expression, and occludin downregulation, an effect counteracted in the HFD + OLE-treated mice. The HFD-fed animals displayed increased systemic levels of LPS and zonulin, but they were reduced in the HFD + OLE-treated animals. It can be seen that OLE administration improves liver steatosis and inflammation in association with decreased LPS translocation into the systemic circulation, hepatocyte localization of LPS and TLR4 downregulation in HFD-induced mouse model of NAFLD.
Assuntos
Glucosídeos Iridoides , Iridoides , Lipopolissacarídeos , Hepatopatia Gordurosa não Alcoólica , Azeite de Oliva , Receptor 4 Toll-Like , Animais , Receptor 4 Toll-Like/metabolismo , Glucosídeos Iridoides/farmacologia , Camundongos , Azeite de Oliva/farmacologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Masculino , Iridoides/farmacologia , Regulação para Baixo/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Fígado/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Camundongos Endogâmicos C57BL , Inflamação/metabolismo , Fígado Gorduroso/metabolismo , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/etiologia , Fígado Gorduroso/patologiaRESUMO
Chronic Thromboembolic Pulmonary Hypertension (CTEPH) is a severe and complex condition that evolves from unresolved pulmonary embolism, leading to fibrotic obstruction of pulmonary arteries, pulmonary hypertension, and potential right heart failure. The cornerstone of CTEPH management lies in a multifaceted therapeutic approach tailored to individual patient profiles, reflecting the disease's heterogeneity. This review delves into the current therapeutic strategies for CTEPH, including surgical pulmonary endarterectomy (PEA), balloon pulmonary angioplasty (BPA), and targeted pharmacological treatments such as PDE5 inhibitors, endothelin receptor antagonists, sGC stimulators, and prostanoids. Lifelong anticoagulation is also highlighted as a preventive strategy against recurrent thromboembolism. Special emphasis is placed on the interdisciplinary nature of CTEPH care, necessitating collaboration among PEA surgeons, BPA interventionists, PH specialists, and thoracic radiologists to ensure comprehensive treatment planning and execution. The review underscores the importance of selecting an appropriate treatment modality based on the patient's specific disease characteristics and the evolving landscape of CTEPH treatment, aiming to improve patient outcomes through integrated care strategies.
RESUMO
Chronic smokers have increased risk of fibrosis-related atrial fibrillation. The use of heated-tobacco products (HTPs) is increasing exponentially, and their health impact is still uncertain. We aim to investigate the effects of circulating molecules in exclusive HTP chronic smokers on the fibrotic behavior of human atrial cardiac stromal cells (CSCs). CSCs were isolated from atrial tissue of elective cardiac surgery patients, and exposed to serum lots from young healthy subjects, stratified in exclusive HTP smokers, tobacco combustion cigarette (TCC) smokers, or nonsmokers (NS). CSCs treated with TCC serum displayed impaired migration and increased expression of pro-inflammatory cytokines. Cells cultured with HTP serum showed increased levels of pro-fibrotic markers, and reduced expression of connexin-43. Both TCC and HTP sera increased collagen release and reduced secretion of angiogenic protective factors from CSCs, compared to NS serum. Paracrine support to tube-formation by endothelial cells and to viability of cardiomyocytes was significantly impaired. Treatment with sera of both smokers groups impaired H2O2/NO release balance by CSCs and reduced early phosphorylation of several pathways compared to NS serum, leading to mTOR activation. Cotreatment with rapamycin was able to reduce mTOR phosphorylation and differentiation into aSMA-positive myofibroblasts in CSCs exposed to TCC and HTP sera. In conclusion, the circulating molecules in the serum of chronic exclusive HTP smokers induce fibrotic behavior in CSCs through activation of the mTOR pathway, and reduce their beneficial paracrine effects on endothelial cells and cardiomyocytes. These results point to a potential risk for cardiac fibrosis in chronic HTP users.