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1.
Scand Cardiovasc J ; 58(1): 2341696, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38616531

RESUMO

Infected or mycotic aortic aneurysms (MAAs) are a rare type of aneurysms. Due to the high risk of rupture, MAAs are life-threatening conditions. Early diagnosis and treatment are necessary, yet MAAs are usually found coincidentally. We report 10 patients with MAAs in whom macroscopically, similar coined-sized lesions of the inner aortic wall were seen in all cases. When a coin-sized lesion in the inner aortic wall is seen during open surgical repair of an aortic aneurysm, the surgeon should consider an infectious cause. Microbiological tissue samples should be collected, and additional targeted antibiotic therapy should be started.


Assuntos
Aorta , Cirurgiões , Humanos
2.
Am J Pathol ; 188(4): 981-994, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29366679

RESUMO

Hepatic cystogenesis in polycystic liver disease (PLD) is associated with abnormalities in multiple cellular processes, including elevated cAMP and overexpression of histone deacetylase 6 (HDAC6). Disease progression in polycystic kidney (PCK) rats (an animal model of PLD) is attenuated by inhibition of either cAMP production or HDAC6. Therefore, we hypothesized that concurrent targeting of HDAC6 and cAMP would synergistically reduce cyst growth. Changes in hepatorenal cystogenesis were examined in PCK rats treated with a pan-HDAC inhibitor, panobinostat; three specific HDAC6 inhibitors, ACY-1215, ACY-738, and ACY-241; and a combination of ACY-1215 and the somatostatin receptor analogue, pasireotide. We also assessed effects of ACY-1215 and pasireotide alone and in combination on cell proliferation, cAMP production, and expression of acetylated α-tubulin in vitro in cultured cholangiocytes and the length of primary cilia and the frequency of ciliated cholangiocytes in vivo in PCK rats. Panobinostat and all three HDAC6 inhibitors decreased hepatorenal cystogenesis in PCK rats. ACY-1215 was more effective than other HDAC inhibitors and was chosen for combinational treatment. ACY-1215 + pasireotide combination synergistically reduced cyst growth and increased length of primary cilia in PCK rats. In cultured cystic cholangiocytes, ACY-1215 + pasireotide combination concurrently decreased cell proliferation and inhibited cAMP levels. These data suggest that the combination of drugs that inhibit HDAC6 and cAMP may be an effective therapy for PLD.


Assuntos
Cistos/tratamento farmacológico , Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases/uso terapêutico , Hepatopatias/tratamento farmacológico , Receptores de Somatostatina/agonistas , Acetilação , Animais , Ductos Biliares/efeitos dos fármacos , Ductos Biliares/metabolismo , Ductos Biliares/patologia , Proliferação de Células/efeitos dos fármacos , Cílios/metabolismo , AMP Cíclico/metabolismo , Cistos/patologia , Modelos Animais de Doenças , Sinergismo Farmacológico , Feminino , Desacetilase 6 de Histona/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Ácidos Hidroxâmicos/uso terapêutico , Hepatopatias/patologia , Masculino , Panobinostat/farmacologia , Panobinostat/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Ratos , Somatostatina/análogos & derivados , Somatostatina/farmacologia , Somatostatina/uso terapêutico , Tubulina (Proteína)/metabolismo
3.
Hepatology ; 66(4): 1197-1218, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28543567

RESUMO

Hepatic cystogenesis in polycystic liver disease is associated with increased levels of cyclic adenosine monophosphate (cAMP) in cholangiocytes lining liver cysts. Takeda G protein receptor 5 (TGR5), a G protein-coupled bile acid receptor, is linked to cAMP and expressed in cholangiocytes. Therefore, we hypothesized that TGR5 might contribute to disease progression. We examined expression of TGR5 and Gα proteins in cultured cholangiocytes and in livers of animal models and humans with polycystic liver disease. In vitro, we assessed cholangiocyte proliferation, cAMP levels, and cyst growth in response to (1) TGR5 agonists (taurolithocholic acid, oleanolic acid [OA], and two synthetic compounds), (2) a novel TGR5 antagonist (m-tolyl 5-chloro-2-[ethylsulfonyl] pyrimidine-4-carboxylate [SBI-115]), and (3) a combination of SBI-115 and pasireotide, a somatostatin receptor analogue. In vivo, we examined hepatic cystogenesis in OA-treated polycystic kidney rats and after genetic elimination of TGR5 in double mutant TGR5-/- ;Pkhd1del2/del2 mice. Compared to control, expression of TGR5 and Gαs (but not Gαi and Gαq ) proteins was increased 2-fold to 3-fold in cystic cholangiocytes in vitro and in vivo. In vitro, TGR5 stimulation enhanced cAMP production, cell proliferation, and cyst growth by ∼40%; these effects were abolished after TGR5 reduction by short hairpin RNA. OA increased cystogenesis in polycystic kidney rats by 35%; in contrast, hepatic cystic areas were decreased by 45% in TGR5-deficient TGR5-/- ;Pkhd1del2/del2 mice. TGR5 expression and its colocalization with Gαs were increased ∼2-fold upon OA treatment. Levels of cAMP, cell proliferation, and cyst growth in vitro were decreased by ∼30% in cystic cholangiocytes after treatment with SBI-115 alone and by ∼50% when SBI-115 was combined with pasireotide. CONCLUSION: TGR5 contributes to hepatic cystogenesis by increasing cAMP and enhancing cholangiocyte proliferation; our data suggest that a TGR5 antagonist alone or concurrently with somatostatin receptor agonists represents a potential therapeutic approach in polycystic liver disease. (Hepatology 2017;66:1197-1218).


Assuntos
AMP Cíclico/metabolismo , Cistos/metabolismo , Subunidades alfa Gs de Proteínas de Ligação ao GTP/metabolismo , Hepatopatias/metabolismo , Pirimidinas/uso terapêutico , Receptores Acoplados a Proteínas G/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Animais , Proliferação de Células/efeitos dos fármacos , Cistos/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos , Quimioterapia Combinada , Humanos , Hepatopatias/tratamento farmacológico , Camundongos , Ácido Oleanólico , Doenças Renais Policísticas/metabolismo , Cultura Primária de Células , Pirimidinas/farmacologia , Ratos , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores Acoplados a Proteínas G/genética , Somatostatina/análogos & derivados , Somatostatina/farmacologia , Somatostatina/uso terapêutico
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