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1.
Int J Mol Sci ; 22(13)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34209188

RESUMO

Coronavirus disease (COVID)-19 is the leading global health threat to date caused by a severe acute respiratory syndrome coronavirus (SARS-CoV-2). Recent clinical trials reported that the use of Bruton's tyrosine kinase (BTK) inhibitors to treat COVID-19 patients could reduce dyspnea and hypoxia, thromboinflammation, hypercoagulability and improve oxygenation. However, the mechanism of action remains unclear. Thus, this study employs structure-based virtual screening (SBVS) to repurpose BTK inhibitors acalabrutinib, dasatinib, evobrutinib, fostamatinib, ibrutinib, inositol 1,3,4,5-tetrakisphosphate, spebrutinib, XL418 and zanubrutinib against SARS-CoV-2. Molecular docking is conducted with BTK inhibitors against structural and nonstructural proteins of SARS-CoV-2 and host targets (ACE2, TMPRSS2 and BTK). Molecular mechanics-generalized Born surface area (MM/GBSA) calculations and molecular dynamics (MD) simulations are then carried out on the selected complexes with high binding energy. Ibrutinib and zanubrutinib are found to be the most potent of the drugs screened based on the results of computational studies. Results further show that ibrutinib and zanubrutinib could exploit different mechanisms at the viral entry and replication stage and could be repurposed as potential inhibitors of SARS-CoV-2 pathogenesis.


Assuntos
Adenina/análogos & derivados , Reposicionamento de Medicamentos , Simulação de Dinâmica Molecular , Piperidinas/química , Inibidores de Proteínas Quinases/química , Pirazóis/química , Pirimidinas/química , Adenina/química , Adenina/metabolismo , Adenina/uso terapêutico , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Tirosina Quinase da Agamaglobulinemia/metabolismo , Enzima de Conversão de Angiotensina 2/antagonistas & inibidores , Enzima de Conversão de Angiotensina 2/metabolismo , Sítios de Ligação , COVID-19/tratamento farmacológico , COVID-19/patologia , COVID-19/virologia , Humanos , Simulação de Acoplamento Molecular , Piperidinas/metabolismo , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/metabolismo , Pirazóis/uso terapêutico , Pirimidinas/metabolismo , Pirimidinas/uso terapêutico , SARS-CoV-2/isolamento & purificação , SARS-CoV-2/metabolismo , Serina Endopeptidases/química , Serina Endopeptidases/metabolismo , Termodinâmica , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/metabolismo
2.
Int J Mol Sci ; 22(13)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: covidwho-1288906

RESUMO

Coronavirus disease (COVID)-19 is the leading global health threat to date caused by a severe acute respiratory syndrome coronavirus (SARS-CoV-2). Recent clinical trials reported that the use of Bruton's tyrosine kinase (BTK) inhibitors to treat COVID-19 patients could reduce dyspnea and hypoxia, thromboinflammation, hypercoagulability and improve oxygenation. However, the mechanism of action remains unclear. Thus, this study employs structure-based virtual screening (SBVS) to repurpose BTK inhibitors acalabrutinib, dasatinib, evobrutinib, fostamatinib, ibrutinib, inositol 1,3,4,5-tetrakisphosphate, spebrutinib, XL418 and zanubrutinib against SARS-CoV-2. Molecular docking is conducted with BTK inhibitors against structural and nonstructural proteins of SARS-CoV-2 and host targets (ACE2, TMPRSS2 and BTK). Molecular mechanics-generalized Born surface area (MM/GBSA) calculations and molecular dynamics (MD) simulations are then carried out on the selected complexes with high binding energy. Ibrutinib and zanubrutinib are found to be the most potent of the drugs screened based on the results of computational studies. Results further show that ibrutinib and zanubrutinib could exploit different mechanisms at the viral entry and replication stage and could be repurposed as potential inhibitors of SARS-CoV-2 pathogenesis.


Assuntos
Adenina/análogos & derivados , Reposicionamento de Medicamentos , Simulação de Dinâmica Molecular , Piperidinas/química , Inibidores de Proteínas Quinases/química , Pirazóis/química , Pirimidinas/química , Adenina/química , Adenina/metabolismo , Adenina/uso terapêutico , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Tirosina Quinase da Agamaglobulinemia/metabolismo , Enzima de Conversão de Angiotensina 2/antagonistas & inibidores , Enzima de Conversão de Angiotensina 2/metabolismo , Sítios de Ligação , COVID-19/tratamento farmacológico , COVID-19/patologia , COVID-19/virologia , Humanos , Simulação de Acoplamento Molecular , Piperidinas/metabolismo , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/metabolismo , Pirazóis/uso terapêutico , Pirimidinas/metabolismo , Pirimidinas/uso terapêutico , SARS-CoV-2/isolamento & purificação , SARS-CoV-2/metabolismo , Serina Endopeptidases/química , Serina Endopeptidases/metabolismo , Termodinâmica , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/metabolismo
3.
Gan To Kagaku Ryoho ; 48(7): 921-926, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34267029

RESUMO

In Japan, ibrutinib has been approved as both a front-line and later-line treatment for chronic leukemia/small lymphocytic lymphoma(CLL/SLL). However, little is known about the actual outcomes and adverse events(AEs)associated with the use of ibrutinib in Japanese patients. OBJECTIVE: The outcomes and AEs of patients treated with ibrutinib in a real-world setting were investigated. METHODS: A retrospective cohort study of all patients with CLL/SLL who were treated with ibrutinib at a single institution was conducted. RESULT: In total, 10 patients, including 5 treatment-naïve patients(50%), were enrolled. The median follow-up period was 9.8 months(range, 0.2-21.6 months), and the estimated overall response rate (ORR: complete remission plus partial remission)was 60%. The median overall survival and progression-free survival outcomes were not reached. During the follow-up period, 4 patients(40%)had at least one AE and 1 patient(10%)had at least one grade≥3 AE. Ibrutinib was discontinued in 4 patients(40%)because of AEs in 2 patients(20%), the progression of CLL in 1 patient(10%), and financial reasons in 1 patient(10%). Richter's transformation did not occur in any of the cases. CONCLUSION: The ORR was lower(60%)than that observed in clinical trials. The frequency and severity of AEs were both relatively low, although the discontinuation rate was high(40%). Patient education and medication adherence were considered important.


Assuntos
Leucemia Linfocítica Crônica de Células B , Adenina/análogos & derivados , Humanos , Japão , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Piperidinas , Pirazóis/efeitos adversos , Estudos Retrospectivos , Resultado do Tratamento
5.
Sci Adv ; 7(25)2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34134991

RESUMO

Infection by highly pathogenic coronaviruses results in substantial apoptosis. However, the physiological relevance of apoptosis in the pathogenesis of coronavirus infections is unknown. Here, with a combination of in vitro, ex vivo, and in vivo models, we demonstrated that protein kinase R-like endoplasmic reticulum kinase (PERK) signaling mediated the proapoptotic signals in Middle East respiratory syndrome coronavirus (MERS-CoV) infection, which converged in the intrinsic apoptosis pathway. Inhibiting PERK signaling or intrinsic apoptosis both alleviated MERS pathogenesis in vivo. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and SARS-CoV induced apoptosis through distinct mechanisms but inhibition of intrinsic apoptosis similarly limited SARS-CoV-2- and SARS-CoV-induced apoptosis in vitro and markedly ameliorated the lung damage of SARS-CoV-2-inoculated human angiotensin-converting enzyme 2 (hACE2) mice. Collectively, our study provides the first evidence that virus-induced apoptosis is an important disease determinant of highly pathogenic coronaviruses and demonstrates that this process can be targeted to attenuate disease severity.


Assuntos
Antivirais/farmacologia , Apoptose/efeitos dos fármacos , COVID-19/tratamento farmacológico , Infecções por Coronavirus/tratamento farmacológico , eIF-2 Quinase/metabolismo , Adenina/análogos & derivados , Adenina/farmacologia , Enzima de Conversão de Angiotensina 2/genética , Animais , Apoptose/fisiologia , COVID-19/etiologia , COVID-19/patologia , Linhagem Celular , Infecções por Coronavirus/etiologia , Infecções por Coronavirus/patologia , Dipeptidil Peptidase 4/genética , Células Epiteliais/virologia , Feminino , Humanos , Indóis/farmacologia , Pulmão/virologia , Masculino , Camundongos Transgênicos , eIF-2 Quinase/antagonistas & inibidores , eIF-2 Quinase/genética
6.
BMC Infect Dis ; 21(1): 567, 2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34126939

RESUMO

BACKGROUND & AIMS: There is limited evidence on the efficacy and safety of nucleos(t) ide analogues (NAs) in the treatment of HBV-ACLF. Our objective was to evaluate the outcomes among TAF, TDF and ETV, three first-line antivirals against chronic hepatitis B, in patients with HBV-ACLF. METHODS: Patients with HBV-related ACLF were recruited and received daily TAF (25 mg/d), TDF (300 mg/d) and ETV (0.5 mg/d). They were prospectively followed-up. The primary endpoint was overall survival at week 12 and week 48, the secondary endpoints were virological response and biochemical response. RESULTS: Forty gender and age matched eligible subjects were recruited and divided into three groups: TAF group, TDF group and ETV group. By week 48, 8 (80%) patients in TAF group, 6 (60%) patients in TDF group and 17 (85%) patients in ETV group survived without liver transplantation (P = 0.251). After 4 weeks of NAs treatment, all three groups showed paralleling reduction of HBV DNA levels. All three groups presented similar biochemical responses at week 4, patients treated with TAF showed a priority in total bilirubin reduction, albumin and cholesterol maintenance. Additionally, although there was no significant difference in changes of serum urea, serum creatinine, serum cystatin C and estimated GFR among the three groups by treatment week 4, TDF showed unfavorable renal safety even in short -term treatment. The treatment using NAs was well-tolerated and there was no serious drug-related adverse event reported. CONCLUSIONS: TAF, TDF and ETV are of similar efficacy and safety in short-term and long-term treatment of HBV-ACLF. TRIAL REGISTRATION: This study is ongoing and is registered with ClinicalTrials.gov , NCT03640728 (05/02/2019).


Assuntos
Insuficiência Hepática Crônica Agudizada/tratamento farmacológico , Antivirais/uso terapêutico , Hepatite B Crônica/tratamento farmacológico , Adenina/análogos & derivados , Adenina/uso terapêutico , Adulto , Guanina/análogos & derivados , Guanina/uso terapêutico , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/genética , Humanos , Masculino , Pessoa de Meia-Idade , Tenofovir/uso terapêutico , Resultado do Tratamento
9.
Aging (Albany NY) ; 13(12): 16381-16403, 2021 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-34175838

RESUMO

Cardiac senescence is associated with cardiomyopathy which is a degenerative disease in the aging process of the elderly. The present study investigates using multiple experimental approaches whether the natural flavone acacetin could attenuate myocardial senescence in C57/BL6 mice and H9C2 rat cardiac cells induced by D-galactose. We found that the impaired heart function in D-galactose-induced accelerated aging mice was improved by oral acacetin treatment in a dose-dependent manner. Acacetin significantly countered the increased serum advanced glycation end products, the myocardial telomere length shortening, the increased cellular senescence marker proteins p21 and p53, and the reduced mitophagy signaling proteins PINK1/Parkin and Sirt6 expression in aging mice. In H9C2 rat cardiac cells, acacetin alleviated cell senescence induced by D-galactose in a concentration-dependent manner. Acacetin decreased p21 and p53 expression, up-regulated PINK1/Parkin, LC3II/LC3I ratio, pLKB1, pAMPK and Sirt6, and reversed the depolarized mitochondrial membrane potential in aging cardiac cells. Mitophagy inhibition with 3-methyladenine or silencing Sirt6 abolished the protective effects of acacetin against cardiac senescence. Further analysis revealed that acacetin effect on Sirt6 was mediated by Sirt1 activation and increase of NAD+/NADH ratio. These results demonstrate that acacetin significantly inhibits in vivo and in vitro cardiac senescence induced by D-galactose via Sirt1-mediated activation of Sirt6/AMPK signaling pathway, thereby enhancing mitophagy and preserving mitochondrial function, which suggests that acacetin may be a drug candidate for treating cardiovascular disorders related to aging.


Assuntos
Envelhecimento/patologia , Flavonas/farmacologia , Mitofagia/efeitos dos fármacos , Miocárdio/patologia , Acetilação , Adenina/análogos & derivados , Adenina/farmacologia , Adenilato Quinase/metabolismo , Envelhecimento/efeitos dos fármacos , Animais , Biomarcadores/metabolismo , Cardiotônicos/farmacologia , Regulação para Baixo/efeitos dos fármacos , Galactose , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Modelos Animais , NAD/metabolismo , Nicotinamida Fosforribosiltransferase/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Quinases/metabolismo , Sirtuínas/metabolismo
10.
Sci Adv ; 7(25)2021 06.
Artigo em Inglês | MEDLINE | ID: covidwho-1276873

RESUMO

Infection by highly pathogenic coronaviruses results in substantial apoptosis. However, the physiological relevance of apoptosis in the pathogenesis of coronavirus infections is unknown. Here, with a combination of in vitro, ex vivo, and in vivo models, we demonstrated that protein kinase R-like endoplasmic reticulum kinase (PERK) signaling mediated the proapoptotic signals in Middle East respiratory syndrome coronavirus (MERS-CoV) infection, which converged in the intrinsic apoptosis pathway. Inhibiting PERK signaling or intrinsic apoptosis both alleviated MERS pathogenesis in vivo. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and SARS-CoV induced apoptosis through distinct mechanisms but inhibition of intrinsic apoptosis similarly limited SARS-CoV-2- and SARS-CoV-induced apoptosis in vitro and markedly ameliorated the lung damage of SARS-CoV-2-inoculated human angiotensin-converting enzyme 2 (hACE2) mice. Collectively, our study provides the first evidence that virus-induced apoptosis is an important disease determinant of highly pathogenic coronaviruses and demonstrates that this process can be targeted to attenuate disease severity.


Assuntos
Antivirais/farmacologia , Apoptose/efeitos dos fármacos , COVID-19/tratamento farmacológico , Infecções por Coronavirus/tratamento farmacológico , eIF-2 Quinase/metabolismo , Adenina/análogos & derivados , Adenina/farmacologia , Enzima de Conversão de Angiotensina 2/genética , Animais , Apoptose/fisiologia , COVID-19/etiologia , COVID-19/patologia , Linhagem Celular , Infecções por Coronavirus/etiologia , Infecções por Coronavirus/patologia , Dipeptidil Peptidase 4/genética , Células Epiteliais/virologia , Feminino , Humanos , Indóis/farmacologia , Pulmão/virologia , Masculino , Camundongos Transgênicos , eIF-2 Quinase/antagonistas & inibidores , eIF-2 Quinase/genética
11.
Liver Int ; 41 Suppl 1: 9-14, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34155802

RESUMO

Chronic hepatitis B virus (HBV) infection remains an important global health problem, and may be difficult to manage in clinical practice. Nucleos(t)ide analogues (NAs) with a high barrier to resistance (entecavir [ETV], tenofovir disoproxil fumarate [TDF] and tenofovir alafenamide [TAF]) are the most frequently used HBV treatments because of their long-term effectiveness and tolerability. ETV may be less effective in patients with lamivudine-resistant strains, and TDF is associated with impaired renal function and reductions in bone mineral density. TAF, a new tenofovir prodrug, has been developed to overcome the less favourable safety profile of TDF. TAF is more stable in plasma, and higher tenofovir levels are achieved within cells at lower doses than with TDF. Several registration and real-life studies, performed up to week 144 of treatment, have shown that TAF is at least as effective as TDF, with higher rates of ALT normalization and significantly fewer kidney disturbances and changes in bone mineral density. No emergence of drug resistance has been found with TAF use. The main limitation to prescribing TAF is its price. The European Association for the Study of the Liver has suggested selecting TAF or ETV instead of TDF in patients >65 years old and in those with a risk of osteoporosis or renal abnormalities, and to prescribe TAF rather than ETV in patients previously exposed to NAs.


Assuntos
Hepatite B Crônica , Adenina/efeitos adversos , Adenina/análogos & derivados , Idoso , Antivirais/efeitos adversos , Hepatite B Crônica/tratamento farmacológico , Humanos , Tenofovir/efeitos adversos , Resultado do Tratamento
12.
Ann Hematol ; 100(7): 1733-1742, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34018029

RESUMO

Anti-CD20 antibody treatments, such as obinutuzumab, have been associated with infusion-related reactions (IRRs). In the phase 3 iLLUMINATE study of ibrutinib-obinutuzumab versus chlorambucil-obinutuzumab in first-line chronic lymphocytic leukemia/small lymphocytic lymphoma, IRRs were substantially reduced with ibrutinib-obinutuzumab versus chlorambucil-obinutuzumab. We prospectively analyzed inflammatory cytokines to evaluate the impact of ibrutinib on circulating cytokine levels following obinutuzumab infusion. In iLLUMINATE, ibrutinib or chlorambucil was given approximately 30-120 min before the first obinutuzumab infusion. Cytokines evaluated were IFNγ, IL-6, IL-8, IL-10, IL-18, MCP-1, MIP-1α, MIP-1ß, and TNFα. Changes in peak cytokine levels from baseline (immediately before obinutuzumab) to post-obinutuzumab infusion were compared between arms and between patients with versus without IRRs using Wilcoxon rank sum test. Of 228 treated patients, 95 on ibrutinib-obinutuzumab (15 with IRRs, 80 without) and 88 on chlorambucil-obinutuzumab (45 with IRRs, 43 without) with cytokine data were included. Irrespective of IRR occurrence, median increase in cytokines was lower with ibrutinib-obinutuzumab versus chlorambucil-obinutuzumab for all cytokines (P < 0.01) except MIP-1ß. Across treatment arms, post-obinutuzumab median increase in all cytokines except MIP-1ß was greater in patients with versus without IRRs (P < 0.001). IL-6 and IL-8 elevations were associated with IRRs in both treatment arms. Among patients with IRRs, those receiving ibrutinib-obinutuzumab had lower post-obinutuzumab increases in IL-6, IL-8, IL-10, and MCP-1 (P < 0.04) than patients receiving chlorambucil-obinutuzumab. For patients in the ibrutinib-treatment arm, we observed a reduction in both the rate of clinically apparent IRRs and the levels of IRR-related cytokines and chemokines. This observation supports an immunomodulatory mechanism of action for ibrutinib. Clinical Trial Registration: NCT02264574.


Assuntos
Adenina/análogos & derivados , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Citocinas/sangue , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Piperidinas/administração & dosagem , Pré-Medicação , Adenina/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Clorambucila/administração & dosagem , Feminino , Humanos , Infusões Intravenosas , Leucemia Linfocítica Crônica de Células B/sangue , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
13.
Cancer Sci ; 112(7): 2642-2651, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33932067

RESUMO

The efficacy and side effects of the second-time humanized CD19 chimeric antigen receptor (CD19-CAR) T-cell therapy after unsuccessful first-time anti-CD19-CAR T-cell therapy and subsequent ibrutinib salvage treatment were observed in patients with refractory B-cell lymphoma. In our study, 3 patients with refractory mantle cell lymphoma (MCL) and 4 patients with refractory follicular lymphoma (FL) reached stable disease (SD), partial remission (PR), or progression of disease (PD) after first-time humanized anti-CD19-CAR T-cell therapy. They received ibrutinib as a salvage treatment and kept an SD in the following 7-16 mo, but their disease progressed again during ibrutinib salvage treatment. All 7 patients received a second-time humanized anti-CD19-CAR T-cell therapy, which was the same as their first-time anti-CD19-CAR T-cell therapy. In total, 3 MCL patients and 3 FL patients reached complete response (CR) with the second-time anti-CD19-CAR T-cell therapy combined with ibrutinib, whereas 1 FL patient reached PR. There were no differences in the transduction efficiency and proliferation between the 2 instances of anti-CD19-CAR T-cell therapy. However, the second-time anti-CD19-CAR T-cell therapy led to higher peaks of anti-CD19-CAR T cells and anti-CD19-CAR gene copies, but also to higher grades of cytokine release syndrome (CRS) and more serious hematological toxicity. The successful outcome of the second-time anti-CD19-CAR T-cell therapy might suggest that the previous ibrutinib treatment improved the activities of anti-CD19-CAR T cells.


Assuntos
Adenina/análogos & derivados , Imunoterapia Adotiva/métodos , Linfoma Folicular/terapia , Linfoma de Célula do Manto/terapia , Piperidinas/uso terapêutico , Receptores de Antígenos Quiméricos , Terapia de Salvação , Adenina/uso terapêutico , Adulto , Idoso , Terapia Combinada/métodos , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Imunoterapia Adotiva/efeitos adversos , Interleucina-6/sangue , Interleucina-8/sangue , Linfoma de Células B/sangue , Linfoma de Células B/terapia , Linfoma Folicular/sangue , Linfoma Difuso de Grandes Células B/sangue , Linfoma Difuso de Grandes Células B/terapia , Linfoma de Célula do Manto/sangue , Masculino , Pessoa de Meia-Idade , Receptores de Antígenos Quiméricos/genética , Receptores de Interleucina-2/sangue , Indução de Remissão/métodos , Retratamento , Resultado do Tratamento
15.
Biomed Res Int ; 2021: 6625952, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33880372

RESUMO

The liver is the primary target organ for perfluorooctane sulphonate (PFOS), a recently discovered persistent organic pollutant. However, the mechanisms mediating hepatotoxicity remain unclear. Herein, we explored the relationship between reactive oxygen species (ROS) and autophagy and apoptosis induced by PFOS in L-02 cells, which are incubated with different concentrations of PFOS (0, 50, 100, 150, 200, or 250 µmol/L) for 24 or 48 hrs at 37°C. The results indicated that PFOS exposure decreased cell activities, enhanced ROS levels in a concentration-dependent manner, decreased mitochondrial membrane potential (MMP), and induced autophagy and apoptosis. Compared with the control, 200 µmol/L PFOS increased ROS levels; enhanced the expression of Bax, cleaved-caspase-3, and LC3-II; induced autophagy; decreased MMP; and lowered Bcl-2, p62, and Bcl-2/Bax ratio. The antioxidant N-acetyl cysteine (NAC) protected MMP against PFOS-induced changes and diminished apoptosis and autophagy. Compared with 200 µmol/L PFOS treatment, NAC pretreatment reversed the increase in ROS, Bax, and cleaved-caspase-3 protein caused by PFOS, lowered the apoptosis rate increased by PFOS, and increased the levels of MMP and Bcl-2/Bax ratio decreased by PFOS. The autophagy inhibitor 3-methyladenine and chloroquine decreased apoptosis and cleaved-caspase-3 protein level and increased the Bcl-2/Bax ratio. In summary, our results suggest that ROS-triggered autophagy is involved in PFOS-induced apoptosis in L-02 cells.


Assuntos
Ácidos Alcanossulfônicos/farmacologia , Apoptose , Autofagia , Embrião de Mamíferos/patologia , Fluorcarbonetos/farmacologia , Fígado/embriologia , Fígado/patologia , Espécies Reativas de Oxigênio/metabolismo , Acetilcisteína/farmacologia , Adenina/análogos & derivados , Adenina/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Cadaverina/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Microambiente Celular/efeitos dos fármacos , Humanos , Fígado/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Proteínas/metabolismo , Vacúolos/efeitos dos fármacos , Vacúolos/metabolismo
16.
Mol Pharmacol ; 99(5): 319-327, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33824185

RESUMO

Children have difficulty swallowing capsules. Yet, when presented with liquid formulations, children often reject oral medications due to their intense bitterness. Presently, effective strategies to identify methods, reagents, and tools to block bitterness remain elusive. For a specific bitter-tasting drug, identification of the responsible bitter receptors and discovery of antagonists for those receptors can provide a method to block perceived bitterness. We have identified a compound (6-methylflavone) that can block responses to an intensely bitter-tasting anti-human immunodeficiency virus (HIV) drug, tenofovir alafenamide (TAF), using a primary human taste bud epithelial cell culture as a screening platform. Specifically, TAS2R39 and TAS2R1 are the main type 2 taste receptors responding to TAF observed via heterologously expressing specific TAS2R receptors into HEK293 cells. In this assay, 6-methylflavone blocked the responses of TAS2R39 to TAF. In human sensory testing, 8 of 16 subjects showed reduction in perceived bitterness of TAF after pretreating (or "prerinsing") with 6-methylflavone and mixing 6-methylflavone with TAF. Bitterness was completely and reliably blocked in two of these subjects. These data demonstrate that a combined approach of human taste cell culture-based screening, receptor-specific assays, and human psychophysical testing can successfully discover molecules for blocking perceived bitterness of pharmaceuticals, such as the HIV therapeutic TAF. Our hope is to use bitter taste blockers to increase medical compliance with these vital medicines. SIGNIFICANCE STATEMENT: Identification of a small molecule that inhibits bitter taste from tenofovir alafenamide may increase the compliance in treating children with human immunodeficiency virus infections.


Assuntos
Adenina/análogos & derivados , Aromatizantes/administração & dosagem , Aromatizantes/química , Papilas Gustativas/efeitos dos fármacos , Paladar/efeitos dos fármacos , Adenina/efeitos adversos , Adenina/química , Adulto , Antivirais/efeitos adversos , Antivirais/química , Linhagem Celular , Feminino , Flavonas/administração & dosagem , Flavonas/química , Células HEK293 , Humanos , Masculino , Receptores de Superfície Celular/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Papilas Gustativas/metabolismo
17.
Biochem Biophys Res Commun ; 555: 182-189, 2021 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-33823364

RESUMO

Autophagy and apoptosis, as major modes of cell death, play critical roles in cellular homeostasis. Our previous study demonstrated that the cross-talk between autophagy and apoptosis regulated cadmium-induced testicular injury and self-recovery, influencing male fertility. However, the underlying mechanism remains blurry. Herein, our subfertility rat model indicated that cadmium-induced autophagy and apoptosis were ameliorated by the activation of SIRT3 and blunted by the inhibition of SIRT3 in rat testis. Further, generating SIRT3 overexpression and knockdown models in TM3 mouse Leydig cells, we found that melatonin (SIRT3 activator) and overexpression of SIRT3 rescued cadmium-induced autophagy and apoptosis in TM3 cells. Knockdown of SIRT3 induced autophagy and apoptosis, which failed to be reversed by melatonin in TM3 cells. Taken together, SIRT3 functions as a pivotal protective factor in testicular Leydig cells injury, and melatonin regulates the cross-talk between autophagy and apoptosis by SIRT3, ameliorating cadmium-induced testicular injury.


Assuntos
Apoptose/fisiologia , Autofagia/fisiologia , Células Intersticiais do Testículo/metabolismo , Melatonina/metabolismo , Sirtuína 3/metabolismo , Adenina/análogos & derivados , Adenina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Cádmio/toxicidade , Células Cultivadas , Técnicas de Silenciamento de Genes , Células Intersticiais do Testículo/efeitos dos fármacos , Masculino , Melatonina/farmacologia , Camundongos , Ratos Sprague-Dawley , Sirtuína 3/genética , Sirtuínas/metabolismo , Testículo/citologia , Testículo/efeitos dos fármacos , Testículo/metabolismo
18.
Biochem Biophys Res Commun ; 555: 196-201, 2021 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-33831782

RESUMO

The nucleotide-binding domain leucine-rich repeat containing protein 3 (NLRP3) inflammasome is a critical inflammatory mechanism identified in platelets, which controls platelet activation and aggregation. We have recently shown that the platelet NLRP3 inflammasome is upregulated in sickle cell disease (SCD), which is mediated by Bruton tyrosine kinase (BTK). Here, we investigated the effect of pharmacological inhibition of NLRP3 and BTK on platelet aggregation and the formation of in vitro thrombi in Townes SCD mice. Mice were injected for 4 weeks with the NLRP3 inhibitor MCC950, the BTK inhibitor ibrutinib or vehicle control. NLRP3 activity, as monitored by caspase-1 activation, was upregulated in platelets from SCD mice, which was dependent on BTK. Large areas of platelet aggregates detected in the liver of SCD mice were decreased when mice were treated with MCC950 or ibrutinib. Moreover, platelet aggregation and in vitro thrombus formation were upregulated in SCD mice and were inhibited when mice were subjected to pharmacological inhibition of NLRP3 and BTK. Targeting the NLRP3 inflammasome might be a novel approach for antiplatelet therapy in SCD.


Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Anemia Falciforme/fisiopatologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Agregação Plaquetária/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Adenina/análogos & derivados , Adenina/farmacologia , Tirosina Quinase da Agamaglobulinemia/metabolismo , Animais , Plaquetas/efeitos dos fármacos , Plaquetas/patologia , Modelos Animais de Doenças , Feminino , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Inflamassomos , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Camundongos Transgênicos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Piperidinas/farmacologia , Agregação Plaquetária/fisiologia , Sulfonas/farmacologia , Trombose/tratamento farmacológico , Trombose/etiologia
19.
Lancet ; 397(10281): 1276-1292, 2021 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-33812487

RESUMO

BACKGROUND: Antiretroviral therapy (ART) during pregnancy is important for both maternal health and prevention of perinatal HIV-1 transmission; however adequate data on the safety and efficacy of different ART regimens that are likely to be used by pregnant women are scarce. In this trial we compared the safety and efficacy of three antiretroviral regimens started in pregnancy: dolutegravir, emtricitabine, and tenofovir alafenamide fumarate; dolutegravir, emtricitabine, and tenofovir disoproxil fumarate; and efavirenz, emtricitabine, and tenofovir disoproxil fumarate. METHODS: This multicentre, open-label, randomised controlled, phase 3 trial was done at 22 clinical research sites in nine countries (Botswana, Brazil, India, South Africa, Tanzania, Thailand, Uganda, the USA, and Zimbabwe). Pregnant women (aged ≥18 years) with confirmed HIV-1 infection and at 14-28 weeks' gestation were eligible. Women who had previously taken antiretrovirals in the past were excluded (up to 14 days of ART during the current pregnancy was permitted), as were women known to be pregnant with multiple fetuses, or those with known fetal anomaly or a history of psychiatric illness. Participants were randomly assigned (1:1:1) using a central computerised randomisation system. Randomisation was done using permuted blocks (size six) stratified by gestational age (14-18, 19-23, and 24-28 weeks' gestation) and country. Participants were randomly assigned to receive either once-daily oral dolutegravir 50 mg, and once-daily oral fixed-dose combination emtricitabine 200 mg and tenofovir alafenamide fumarate 25 mg; once-daily oral dolutegravir 50 mg, and once-daily oral fixed-dose combination emtricitabine 200 mg and tenofovir disoproxil fumarate 300 mg; or once-daily oral fixed-dose combination of efavirenz 600 mg, emtricitabine 200 mg, and tenofovir disoproxil fumarate 300 mg. The primary efficacy outcome was the proportion of participants with viral suppression, defined as an HIV-1 RNA concentration of less than 200 copies per mL, at or within 14 days of delivery, assessed in all participants with an HIV-1 RNA result available from the delivery visit, with a prespecified non-inferiority margin of -10% in the combined dolutegravir-containing groups versus the efavirenz-containing group (superiority was tested in a pre-planned secondary analysis). Primary safety outcomes, compared pairwise among treatment groups, were the occurrence of a composite adverse pregnancy outcome (ie, either preterm delivery, the infant being born small for gestational age, stillbirth, or spontaneous abortion) in all participants with a pregnancy outcome, and the occurrence of grade 3 or higher maternal and infant adverse events in all randomised participants. This trial was registered with ClinicalTrials.gov, NCT03048422. FINDINGS: Between Jan 19, 2018, and Feb 8, 2019, we enrolled and randomly assigned 643 pregnant women: 217 to the dolutegravir, emtricitabine, and tenofovir alafenamide fumarate group, 215 to the dolutegravir, emtricitabine, and tenofovir disoproxil fumarate group, and 211 to the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group. At enrolment, median gestational age was 21·9 weeks (IQR 18·3-25·3), the median HIV-1 RNA concentration among participants was 902·5 copies per mL (152·0-5182·5; 181 [28%] of 643 participants had HIV-1 RNA concentrations of <200 copies per mL), and the median CD4 count was 466 cells per µL (308-624). HIV-1 RNA concentrations at delivery were available for 605 (94%) participants. Of these, 395 (98%) of 405 participants in the combined dolutegravir-containing groups had viral suppression at delivery compared with 182 (91%) of 200 participants in the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group (estimated difference 6·5% [95% CI 2·0 to 10·7], p=0·0052; excluding the non-inferiority margin of -10%). Significantly fewer participants in the dolutegravir, emtricitabine, and tenofovir alafenamide fumarate group (52 [24%] of 216) had a composite adverse pregnancy outcome than those in the dolutegravir, emtricitabine, and tenofovir disoproxil fumarate group (70 [33%] of 213; estimated difference -8·8% [95% CI -17·3 to -0·3], p=0·043) or the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group (69 [33%] of 211; -8·6% [-17·1 to -0·1], p=0·047). The proportion of participants or infants with grade 3 or higher adverse events did not differ among the three groups. The proportion of participants who had a preterm delivery was significantly lower in the dolutegravir, emtricitabine, and tenofovir alafenamide fumarate group (12 [6%] of 208) than in the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group (25 [12%] of 207; -6·3% [-11·8 to -0·9], p=0·023). Neonatal mortality was significantly higher in the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group (ten [5%] of 207 infants) than in the dolutegravir, emtricitabine, and tenofovir alafenamide fumarate group (two [1%] of 208; p=0·019) or the dolutegravir, emtricitabine, and tenofovir disoproxil fumarate group (three [2%] of 202; p=0·050). INTERPRETATION: When started in pregnancy, dolutegravir-containing regimens had superior virological efficacy at delivery compared with the efavirenz, emtricitabine, and tenofovir disoproxil fumarate regimen. The dolutegravir, emtricitabine, and tenofovir alafenamide fumarate regimen had the lowest frequency of composite adverse pregnancy outcomes and of neonatal deaths. FUNDING: National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Mental Health.


Assuntos
Adenina/análogos & derivados , Fármacos Anti-HIV/administração & dosagem , Emtricitabina/administração & dosagem , Infecções por HIV/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Oxazinas/administração & dosagem , Piperazinas/administração & dosagem , Piridonas/administração & dosagem , Tenofovir/administração & dosagem , Adenina/administração & dosagem , Adenina/efeitos adversos , Adulto , Fármacos Anti-HIV/efeitos adversos , Quimioterapia Combinada , Emtricitabina/efeitos adversos , Feminino , Idade Gestacional , Infecções por HIV/prevenção & controle , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Humanos , Recém-Nascido , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Oxazinas/efeitos adversos , Piperazinas/efeitos adversos , Gravidez , Complicações Infecciosas na Gravidez/tratamento farmacológico , Resultado da Gravidez , Piridonas/efeitos adversos , Tenofovir/efeitos adversos , Ultrassonografia Pré-Natal
20.
Cancer Sci ; 112(6): 2314-2324, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33792119

RESUMO

Mantle cell lymphoma (MCL) is a rare subtype of non-Hodgkin's lymphoma, which is characterized by overexpression of cyclin D1. Although novel drugs, such as ibrutinib, show promising clinical outcomes, relapsed MCL often acquires drug resistance. Therefore, alternative approaches for refractory and relapsed MCL are needed. Here, we examined whether a novel inhibitor of enhancer of zeste homologs 1 and 2 (EZH1/2), OR-S1 (a close analog of the clinical-stage compound valemetostat), had an antitumor effect on MCL cells. In an ibrutinib-resistant MCL patient-derived xenograft (PDX) mouse model, OR-S1 treatment by oral administration significantly inhibited MCL tumor growth, whereas ibrutinib did not. In vitro growth assays showed that compared with an established EZH2-specific inhibitor GSK126, OR-S1 had a marked antitumor effect on MCL cell lines. Furthermore, comprehensive gene expression analysis was performed using OR-S1-sensitive or insensitive MCL cell lines and showed that OR-S1 treatment modulated B-cell activation, differentiation, and cell cycle. In addition, we identified Cyclin Dependent Kinase Inhibitor 1C (CDKN1C, also known as p57, KIP2), which contributes to cell cycle arrest, as a direct target of EZH1/2 and showed that its expression influenced MCL cell proliferation. These results suggest that EZH1/2 may be a potential novel target for the treatment of aggressive ibrutinib-resistant MCL via CDKN1C-mediated cell cycle arrest.


Assuntos
Adenina/análogos & derivados , Antineoplásicos/farmacologia , Inibidor de Quinase Dependente de Ciclina p57/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Linfoma de Célula do Manto/tratamento farmacológico , Piperidinas/farmacologia , Complexo Repressor Polycomb 2/antagonistas & inibidores , Adenina/farmacologia , Adenina/uso terapêutico , Animais , Antineoplásicos/uso terapêutico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Inibidor de Quinase Dependente de Ciclina p57/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/patologia , Camundongos , Piperidinas/uso terapêutico , Sindecana-1/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
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