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1.
Biomed Pharmacother ; 131: 110643, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32846329

RESUMO

Coronavirus Disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus -2 (SARS-CoV-2) has been widely spread in the world with a high mortality. Cytokine storm syndrome (CSS) and acute lung injury caused by SARS-CoV-2 infection severely threaten the patients. With the purpose to find effective and low-toxic drugs to mitigate CSS, entecavir and imipenem were identified to reduce TNF-α using a LPS-induced macrophage model from the anti-infective drug library. Entecavir and imipenem efficiently suppressed the release of inflammatory cytokines by partly intervention of NF-κB activity. The acute lung injury was also alleviated and the survival time was prolonged in mice. In addition, entecavir and imipenem inhibited the release of TNF-α and IL-10 in human peripheral blood mononuclear cells (hPBMCs). Collectively, we proposed that entecavir and imipenem might be candidates for the treatment of CSS.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Síndrome da Liberação de Citocina/tratamento farmacológico , Guanina/análogos & derivados , Imipenem/farmacologia , Pneumonia Viral/tratamento farmacológico , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/virologia , Animais , COVID-19 , Infecções por Coronavirus/complicações , Síndrome da Liberação de Citocina/virologia , Citocinas/imunologia , Reposicionamento de Medicamentos , Guanina/farmacologia , Humanos , Interleucina-10/imunologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Lipopolissacarídeos , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pandemias , Pneumonia Viral/complicações , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Tratamento Farmacológico da COVID-19
2.
Asian J Androl ; 22(2): 200-207, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31210145

RESUMO

Fusion between the transmembrane protease serine 2 and v-ets erythroblastosis virus E26 oncogene homolog (TMPRSS2-ERG fusion) is a common genetic alteration in prostate cancer among Western populations and has been suggested as playing a role in tumorigenesis and progression of prostate cancer. However, the prevalence of TMPRSS2-ERG fusion differs among different ethnic groups, and contradictory results have been reported in Asian patients. We aim to evaluate the prevalence and significance of TMPRSS2-ERG fusion as a molecular subtyping and prognosis indicator of prostate cancer in Asians. We identified the fusion status in 669 samples from prostate biopsy and radical prostatectomy by fluorescence in situ hybridization and/or immunohistochemistry in China. We examined the association of TMPRSS2-ERG fusion with clinicopathological characteristics and biochemical recurrence by Chi-square test and Kaplan-Meier analysis. Finally, a systematic review was performed to investigate the positive rate of the fusion in Asian prostate cancer patients. McNemar's test was employed to compare the positive rates of TMPRSS2-ERG fusion detected using different methods. The positive rates of TMPRSS2-ERG fusion were 16% in our samples and 27% in Asian patients. In our samples, 9.4% and 19.3% of cases were recognized as fusion positive by fluorescence in situ hybridization and immunohistochemistry, respectively. No significant association between the fusion and clinical parameters was observed. TMPRSS2-ERG fusion is not a frequent genomic alteration among Asian prostate cancer patients and has limited significance in clinical practices in China. Besides ethnic difference, detection methods potentially influence the results showing a positive rate of TMPRSS2-ERG fusion.


Assuntos
Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/genética , Neoplasias da Próstata/genética , Idoso , China , Humanos , Masculino , Pessoa de Meia-Idade , Serina Endopeptidases/genética , Regulador Transcricional ERG/genética
3.
Asian J Androl ; 20(5): 438-441, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29735816

RESUMO

We summarized our experience in transurethral seminal vesiculoscopy (TSV) for recurrent hemospermia by introducing surgical techniques, intraoperative findings, and treatment outcomes. TSV was performed in 419 patients with an initial diagnosis of persistent hemospermia at Shanghai Changhai Hospital (Shanghai, China) from May 2007 to November 2015. TSV was successfully performed in 381 cases (90.9%). Hemospermia was alleviated or disappeared in 324 (85.0%) patients by 3 months after surgery. Common intraoperative manifestations were bleeding, obstruction or stenosis, mucosal lesions, and calculus. Endoscopic presentation of the ejaculatory duct orifice and the verumontanum was categorized into four types, including 8 (1.9%), 32 (7.6%), 341 (81.4%), and 38 (9.1%) cases in Types A, B, C, and D, respectively. TSV is an effective and safe procedure in the management of seminal tract disorders. This study may help other surgeons to become familiar with and improve this procedure. However, further multicentric clinical trials are warranted to validate these findings.


Assuntos
Ductos Ejaculatórios/cirurgia , Hemospermia/cirurgia , Glândulas Seminais/cirurgia , Uretra/cirurgia , Adulto , Ductos Ejaculatórios/diagnóstico por imagem , Endoscopia/métodos , Hemospermia/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Glândulas Seminais/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Uretra/diagnóstico por imagem
4.
Clin Cancer Res ; 24(18): 4612-4626, 2018 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-29691294

RESUMO

Purpose: Cancer stem-like cells (CSC) contribute to the progression and androgen deprivation therapy (ADT) resistance of prostate cancer. As CSCs depend on their specific niche, including tumor-associated macrophages (TAM), elucidating the network between CSCs and TAMs may help to effectively inhibit the progression and ADT resistance of prostate cancer.Experimental Design: The underlying intracellular mechanism that sustains the stem-like characteristics of CSCs in prostate cancer was assessed via RNA sequencing, co-immunoprecipitation, chromatin immunoprecipitation, and other assays. A coculture system and cytokine antibody arrays were used to examine the interaction network between CSCs and TAMs. In addition, an orthotopic prostate cancer model was established to evaluate the in vivo effects of the combined targeting of CSCs and their interaction with TAMs on ADT resistance.Results: Autophagy-related gene 7 (ATG7) facilitated the transcription of OCT4 via ß-catenin, which binds to the OCT4 promoter, promoting CSC characteristics in prostate cancer, including self-renewal, tumor initiation, and drug resistance. In addition, CSCs remodeled their specific niche by educating monocytes/macrophages toward TAMs, and the CSC-educated TAMs reciprocally promoted the stem-like properties of CSCs, progression and ADT resistance of prostate cancer via IL6/STAT3. Furthermore, the combined targeting of CSCs and their interaction with TAMs by inhibiting ATG7/OCT4 and IL6 receptor effectively ameliorated ADT resistance in an orthotopic prostate cancer model.Conclusions: Targeting CSCs and their niche may prove to be a more powerful strategy than targeting CSCs alone, providing a rational approach to ameliorating ADT resistance in prostate cancer. Clin Cancer Res; 24(18); 4612-26. ©2018 AACR.


Assuntos
Antagonistas de Androgênios/administração & dosagem , Resistencia a Medicamentos Antineoplásicos/genética , Células-Tronco Neoplásicas/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Adulto , Idoso , Antagonistas de Androgênios/efeitos adversos , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Macrófagos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Células-Tronco Neoplásicas/patologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia
5.
Clin Cancer Res ; 24(3): 708-723, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29191973

RESUMO

Purpose: Androgen deprivation therapy (ADT), including enzalutamide, induces resistance in prostate cancer; ADT resistance is associated with neuroendocrine differentiation (NED) and tumor-associated macrophages (TAM). This study aimed to investigate the association between enzalutamide-induced NED and TAMs and its mechanism.Experimental Design: The association between enzalutamide-induced NED and TAMs was investigated by IHC using prostate cancer tissues, enzalutamide-resistant mouse xenografts, and a coculture system. The underlying mechanisms were assessed using in vitro cytokine antibody arrays, ELISAs, chromatin immunoprecipitation, and other methods. An orthotopic prostate cancer mouse model was established to evaluate the in vivo effects of combined IL6 receptor (IL6R) and high mobility group box 1 (HMGB1) inhibition on enzalutamide resistance.Results: High CD163 expression was observed in ADT-treated prostate cancer or castration-resistant prostate cancer (CRPC) tissues with high levels of neuron-specific enolase (NSE) and chromogranin A (CHGA) and in enzalutamide-resistant xenografts, indicating the crucial roles of NED and TAMs in enzalutamide resistance. Specifically, enzalutamide-induced HMGB1 expression facilitated TAM recruitment and polarization and drove NED via ß-catenin stabilization. HMGB1-activated TAMs secreted IL6 to augment enzalutamide-induced NED and directly promote HMGB1 transcription via STAT3. Finally, inhibition of the IL6/STAT3 pathway by tocilizumab combined with HMGB1 knockdown inhibited enzalutamide-induced resistance in an orthotopic prostate cancer mouse model.Conclusions: Enzalutamide elevates HMGB1 levels, which recruits and activates TAMs. Moreover, IL6 secreted by HMGB1-activated TAMs facilitates the enzalutamide-induced NED of prostate cancer, forming a positive feedback loop between NED in prostate cancer and TAMs. The combined inhibition of IL6R and HMGB1 may serve as a new treatment for enzalutamide resistance in patients with advanced or metastatic prostate cancer. Clin Cancer Res; 24(3); 708-23. ©2017 AACR.


Assuntos
Comunicação Celular/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Células Neuroendócrinas/efeitos dos fármacos , Células Neuroendócrinas/metabolismo , Feniltioidantoína/análogos & derivados , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Animais , Antineoplásicos/farmacologia , Benzamidas , Biomarcadores , Linhagem Celular Tumoral , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos , Proteína HMGB1/genética , Proteína HMGB1/metabolismo , Humanos , Imuno-Histoquímica , Macrófagos/imunologia , Masculino , Camundongos , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Nitrilas , Feniltioidantoína/farmacologia , Neoplasias da Próstata/imunologia , Fator de Transcrição STAT3/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
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