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1.
Pancreatology ; 22(1): 148-159, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34774415

RESUMO

Pancreatitis is a debilitating disease involving inflammation and fibrosis of the exocrine pancreas. Recurrent or chronic forms of pancreatitis are a significant risk factor for pancreatic ductal adenocarcinoma. While genetic factors have been identified for both pathologies, environmental stresses play a large role in their etiology. All cells have adapted mechanisms to handle acute environmental stress that alters energy demands. A common pathway involved in the stress response involves endoplasmic reticulum stress and the unfolded protein response (UPR). While rapidly activated by many external stressors, in the pancreas the UPR plays a fundamental biological role, likely due to the high protein demands in acinar cells. Despite this, increased UPR activity is observed in response to acute injury or following exposure to risk factors associated with pancreatitis and pancreatic cancer. Studies in animal and cell cultures models show the importance of affecting the UPR in the context of both diseases, and inhibitors have been developed for several specific mediators of the UPR. Given the importance of the UPR to normal acinar cell function, efforts to affect the UPR in the context of disease must be able to specifically target pathology vs. physiology. In this review, we highlight the importance of the UPR to normal and pathological conditions of the exocrine pancreas. We discuss recent studies suggesting the UPR may be involved in the initiation and progression of pancreatitis and PDAC, as well as contributing to chemoresistance that occurs in pancreatic cancer. Finally, we discuss the potential of targeting the UPR for treatment.


Assuntos
Carcinoma Ductal Pancreático , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Neoplasias Pancreáticas/terapia , Pancreatite , Resposta a Proteínas não Dobradas , Fator 6 Ativador da Transcrição/genética , Fator 6 Ativador da Transcrição/metabolismo , Animais , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Estresse do Retículo Endoplasmático/genética , Endorribonucleases , Recidiva Local de Neoplasia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Pancreatite/tratamento farmacológico , Pancreatite/genética , Proteínas Serina-Treonina Quinases , eIF-2 Quinase , Neoplasias Pancreáticas
2.
PLoS Negl Trop Dis ; 14(7): e0008332, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32609727

RESUMO

Treatment and control of schistosomiasis still rely on only one effective drug, praziquantel (PZQ) and, due to mass treatment, the increasing risk of selecting for schistosome strains that are resistant to PZQ has alerted investigators to the urgent need to develop novel therapeutic strategies. The histone-modifying enzymes (HMEs) represent promising targets for the development of epigenetic drugs against Schistosoma mansoni. In the present study, we targeted the S. mansoni lysine-specific demethylase 1 (SmLSD1), a transcriptional corepressor, using a novel and selective synthetic inhibitor, MC3935, which was used to treat schistosomula and adult worms in vitro. By using cell viability assays and optical and electron microscopy, we showed that treatment with MC3935 affected parasite motility, egg-laying, tegument, and cellular organelle structures, culminating in the death of schistosomula and adult worms. In silico molecular modeling and docking analysis suggested that MC3935 binds to the catalytic pocket of SmLSD1. Western blot analysis revealed that MC3935 inhibited SmLSD1 demethylation activity of H3K4me1/2. Knockdown of SmLSD1 by RNAi recapitulated MC3935 phenotypes in adult worms. RNA-Seq analysis of MC3935-treated parasites revealed significant differences in gene expression related to critical biological processes. Collectively, our findings show that SmLSD1 is a promising drug target for the treatment of schistosomiasis and strongly support the further development and in vivo testing of selective schistosome LSD1 inhibitors.


Assuntos
Inibidores Enzimáticos/farmacologia , Histona Desmetilases/antagonistas & inibidores , Schistosoma mansoni/efeitos dos fármacos , Schistosoma mansoni/ultraestrutura , Esquistossomose mansoni/tratamento farmacológico , Animais , Anti-Helmínticos/farmacologia , Resistência a Medicamentos , Microscopia Eletrônica de Varredura , Oviposição/efeitos dos fármacos , Praziquantel/farmacologia , Esquistossomose mansoni/parasitologia , Esquistossomose mansoni/patologia
3.
Plos Negl Trop Dis, v. 14, n. 7, e0008332, jul. 2020
Artigo em Inglês | Sec. Est. Saúde SP, SESSP-IBPROD, Sec. Est. Saúde SP | ID: bud-3085

RESUMO

Treatment and control of schistosomiasis still rely on only one effective drug, praziquantel (PZQ) and, due to mass treatment, the increasing risk of selecting for schistosome strains that are resistant to PZQ has alerted investigators to the urgent need to develop novel therapeutic strategies. The histone-modifying enzymes (HMEs) represent promising targets for the development of epigenetic drugs against Schistosoma mansoni. In the present study, we targeted the S. mansoni lysine-specific demethylase 1 (SmLSD1), a transcriptional corepressor, using a novel and selective synthetic inhibitor, MC3935, which was used to treat schistosomula and adult worms in vitro. By using cell viability assays and optical and electron microscopy, we showed that treatment with MC3935 affected parasite motility, egg-laying, tegument, and cellular organelle structures, culminating in the death of schistosomula and adult worms. In silico molecular modeling and docking analysis suggested that MC3935 binds to the catalytic pocket of SmLSD1. Western blot analysis revealed that MC3935 inhibited SmLSD1 demethylation activity of H3K4me1/2. Knockdown of SmLSD1 by RNAi recapitulated MC3935 phenotypes in adult worms. RNA-Seq analysis of MC3935-treated parasites revealed significant differences in gene expression related to critical biological processes. Collectively, our findings show that SmLSD1 is a promising drug target for the treatment of schistosomiasis and strongly support the further development and in vivo testing of selective schistosome LSD1 inhibitors.

4.
Cancer Cell Int ; 18: 71, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29760584

RESUMO

BACKGROUND: Castrate resistant prostate cancer (CRPC) is often driven by constitutively active forms of the androgen receptor such as the V7 splice variant (AR-V7) and commonly becomes resistant to established hormonal therapy strategies such as enzalutamide as a result. The lysine demethylase LSD1 is a co-activator of the wild type androgen receptor and a potential therapeutic target in hormone sensitive prostate cancer. We evaluated whether LSD1 could also be therapeutically targeted in CRPC models driven by AR-V7. METHODS: We utilised cell line models of castrate resistant prostate cancer through over expression of AR-V7 to test the impact of chemical LSD1 inhibition on AR activation. We validated findings through depletion of LSD1 expression and in prostate cancer cell lines that express AR-V7. RESULTS: Chemical inhibition of LSD1 resulted in reduced activation of the androgen receptor through both the wild type and its AR-V7 splice variant forms. This was confirmed and validated in luciferase reporter assays, in LNCaP and 22Rv1 prostate cancer cell lines and in LSD1 depletion experiments. CONCLUSION: LSD1 contributes to activation of both the wild type and V7 splice variant forms of the androgen receptor and can be therapeutically targeted in models of CRPC. Further development of this approach is warranted.

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