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1.
ACS Appl Mater Interfaces ; 13(33): 39003-39017, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34433253

RESUMO

Improving tumor immunogenicity is critical for increasing the responsiveness of triple-negative breast cancer (TNBC) to anti-PD-(L)1 treatment. Here, we verified that chidamide (CHI), an epigenetic modulator, could elicit immunogenic cell death within TNBC to enhance cancer immunogenicity and elicit an antitumor immune response. Additionally, CHI increased the expression level of PD-L1, MHC I, and MHC II on cancer cells, which contributed to T-cell recognition and PD-1/PD-L1 blockade therapy response. The synergistic antitumor efficacy of CHI and PD-L1 blockade therapy was further explored through liposomes co-delivering CHI and BMS-202 (a small-molecule PD-L1 inhibitor). The liposomes possessed good biocompatibility, security, and controllable drug release and endowed therapeutics drugs with favorable tumor accumulation. Furthermore, the drug-loaded liposomes could obviously boost the antitumor immunity of TNBC through CHI-enhanced tumor immunogenicity and BMS-202-mediated PD-L1 blockade, thereby effectively inhibiting the growth of primary and metastatic tumors with an inhibitory rate of metastasis of up to 96%. In summary, this work provided a referable and optional approach for clinical antitumor therapy based on the combination of an epigenetic modulator and PD-1/PD-L1 blockade therapy.


Assuntos
Acetamidas/química , Aminopiridinas/química , Antineoplásicos/farmacologia , Benzamidas/química , Portadores de Fármacos/química , Inibidores de Checkpoint Imunológico/química , Piridinas/química , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/imunologia , Acetamidas/farmacologia , Aminopiridinas/farmacologia , Animais , Benzamidas/farmacologia , Materiais Biocompatíveis/química , Linhagem Celular Tumoral , Terapia Combinada/métodos , Liberação Controlada de Fármacos , Epigênese Genética/efeitos dos fármacos , Feminino , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Imunoterapia/métodos , Lipossomos/química , Camundongos , Camundongos Endogâmicos BALB C , Piridinas/farmacologia , Bibliotecas de Moléculas Pequenas/química , Distribuição Tecidual , Resultado do Tratamento
2.
Clin Immunol ; 230: 108823, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34400321

RESUMO

Chronic graft-versus-host disease (cGVHD) is an immune-mediated disorder characterized by chronic inflammation and fibrosis. Rho-associated coiled-coil-containing protein kinases (ROCKs) are key coordinators of tissue response to injury, regulating multiple functions, such as gene expression and cell migration, proliferation and survival. Relevant to cGVHD and autoimmunity, only the ROCK2 isoform drives a pro-inflammatory type 17 helper T (Th17) cell response. Moreover, ROCK2 inhibition shifts the Th17/regulatory T (Treg) cell balance toward Treg cells and restores immune homeostasis in animal models of autoimmunity and cGVHD. Furthermore, the selective inhibition of ROCK2 by belumosudil reduces fibrosis by downregulating both transforming growth factor-ß signaling and profibrotic gene expression, thereby impeding the creation of focal adhesions. Consistent with its anti-inflammatory and antifibrotic activities, belumosudil has demonstrated efficacy in clinical studies, resulting in an overall response rate of >70% in patients with cGVHD who failed 2 to 5 prior lines of systemic therapy. In summary, selective ROCK2 inhibition has emerged as a promising novel therapeutic approach for treating cGVHD and other immunologic diseases with unique mechanisms of action, targeting both immune imbalance and detrimental fibrotic responses.


Assuntos
Doença Enxerto-Hospedeiro/enzimologia , Quinases Associadas a rho/imunologia , Acetamidas/farmacologia , Animais , Doença Crônica , Modelos Animais de Doenças , Fibrose , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/terapia , Humanos , Imunomodulação , Modelos Imunológicos , Inibidores de Proteínas Quinases/farmacologia , Linfócitos T Reguladores/imunologia , Quinases Associadas a rho/antagonistas & inibidores
3.
Life Sci ; 284: 119904, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34453945

RESUMO

AIM: Alcohol abuse is a significant causative factor of death worldwide. The Notch1 signaling pathway is involved in alcohol tolerance, withdrawal and dependence. Agomelatine is a known antidepressant acting as a melatonin receptor (MT1/2) agonist and a 5-hydroxytryptamine receptor-2C antagonist. However, its effects on alcohol cravings and alcohol withdrawal symptoms have not been investigated. In this study, we assessed the possibility of using agomelatine for the treatment of these symptoms in a rat model of alcoholism and the possible role of Notch1 signaling. MAIN METHODS: We induced alcoholism in rats using a free-choice drinking model for 60 days. From day 61, free-choice was continued until day 82 for the craving model, whereas only water was offered in the withdrawal model. Meanwhile, the treated groups for both models received agomelatine (50 mg/kg/day) orally from day 61 to 82, followed by behavioral, histopathological and biochemical assessment. KEY FINDINGS: Agomelatine treatment caused significant decrease in alcohol consumption with a positive effect on anxiety-like behavior in the open field, memory in the Morris water maze and immobility in the forced swim test. Moreover, agomelatine induced the expression of Notch1 pathway markers, including Notch1, NICD, CREB, CCNE-2, Hes-1, both total and phosphorylated ERK1/2, MMP9, Per2and RGS-2 in the hippocampal formation. By contrast, NMDAR expression was reduced. Furthermore, agomelatine normalized the serum levels of BDNF, cortisol, dopamine and glutamate which were disrupted by alcohol consumption. SIGNIFICANCE: Based on these findings, agomelatine reversed alcohol cravings and withdrawal symptoms associated with alcohol dependence by modulating the Notch1 signaling pathway.


Assuntos
Acetamidas/uso terapêutico , Bebidas Alcoólicas/efeitos adversos , Fissura , Receptor Notch1/metabolismo , Transdução de Sinais , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Síndrome de Abstinência a Substâncias/metabolismo , Acetamidas/farmacologia , Animais , Ansiedade/patologia , Comportamento Animal/efeitos dos fármacos , Biomarcadores/metabolismo , Ritmo Circadiano/efeitos dos fármacos , Hipocampo/metabolismo , Hidrocortisona/sangue , Masculino , Teste do Labirinto Aquático de Morris , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Neurotransmissores/sangue , Teste de Campo Aberto , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos
4.
Int J Mol Sci ; 22(13)2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34281197

RESUMO

Psoriasis, a long-lasting and multifactorial skin disease, is related to comorbidities such as metabolic disease, depression, and psoriatic arthritis. Psoriasis occurs due to a variety of factors including keratinocyte hyperproliferation, inflammation, and abnormal differentiation. Proinflammatory cytokines upregulated by increased activation of keratinocytes and immune cells in the skin trigger progression of psoriasis. This study aimed to investigate the effects of anoctamin1 (ANO1) on psoriasis development in vitro and in vivo. We analyzed the proliferation of HaCaT keratinocytes and ANO1-related ERK and AKT signaling pathways after ANO1 inhibitor (T16Ainh-A01 and Ani9) treatment and knock-down of ANO1. Furthermore, after applying imiquimod (IMQ) cream or coapplying IMQ cream and T16Ainh-A01 on mouse ears, we not only observed psoriatic symptoms, including ear thickening, but also quantified the effects of treatment on ERK and AKT signaling-involved proteins and proinflammatory cytokines. Inhibition of ANO1 attenuated the proliferation of HaCaT cells and induced reduction of pERK1/2. Coapplication of IMQ and T16Ainh-A01 on ears of mice reduced not only symptoms of IMQ-induced psoriasis such as thickening and erythema, but also expression of ANO1 and pERK1/2 compared to that of application of IMQ alone. In addition, the expression levels of IL-17A, IL-17F, IL-22, IL-23, IL-6, IL-1ß, and TNF-α increased after applying IMQ and were significantly reduced by coapplying IMQ and T16Ainh-A01. These results aid in understanding the underlying mechanisms of ANO1 in epidermal layer keratinocyte hyperproliferation and suggest the potential of ANO1 as a target to treat psoriasis.


Assuntos
Anoctamina-1/farmacologia , Queratinócitos/efeitos dos fármacos , Psoríase/induzido quimicamente , Acetamidas/farmacologia , Animais , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Células HaCaT , Humanos , Hidrazonas/farmacologia , Imiquimode/efeitos adversos , Imiquimode/farmacologia , Inflamação/metabolismo , Inflamação/patologia , Interleucinas/metabolismo , Queratinócitos/metabolismo , Queratinócitos/patologia , Sistema de Sinalização das MAP Quinases , Camundongos , Camundongos Endogâmicos BALB C , Psoríase/metabolismo , Psoríase/patologia , Pirimidinas/farmacologia , Tiazóis/farmacologia
5.
J Med Chem ; 64(12): 8127-8141, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34081857

RESUMO

Klisyri (KX01) is a dual tubulin/Src protein inhibitor that has shown potential therapeutic effects in several tumor models. However, a phase II clinical trial in patients with bone-metastatic castration-resistant prostate cancer was halted because of lack of efficacy. We previously reported that KX01 binds to the colchicine site of ß-tubulin and its morpholine group lies close to α-tubulin's surface. Thus, we hypothesized that enhancing the interaction of KX01 with α-tubulin could increase tubulin inhibition and synthesized a series of KX01 derivatives directed by docking studies. Among these derivatives, 8a exhibited more than 10-fold antiproliferation activity in several tumor cells than KX01 and significantly improved in vivo antitumor effects. The X-ray crystal structure suggested that 8a both bound to the colchicine site and extended into the interior of α-tubulin to form potent interactions, presenting a novel binding mode. A potential clinical candidate for cancer therapy was identified in this study.


Assuntos
Acetamidas/farmacologia , Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Moduladores de Tubulina/farmacologia , Quinases da Família src/antagonistas & inibidores , Acetamidas/síntese química , Acetamidas/metabolismo , Acetamidas/farmacocinética , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Bovinos , Linhagem Celular Tumoral , Galinhas , Cristalografia por Raios X , Desenho de Fármacos , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacocinética , Piridinas/síntese química , Piridinas/metabolismo , Piridinas/farmacocinética , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/metabolismo , Moduladores de Tubulina/farmacocinética
6.
Molecules ; 26(10)2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34065194

RESUMO

Diabetes mellitus (DM) is a chronic disorder and has affected a large number of people worldwide. Insufficient insulin production causes an increase in blood glucose level that results in DM. To lower the blood glucose level, various drugs are employed that block the activity of the α-glucosidase enzyme, which is considered responsible for the breakdown of polysaccharides into monosaccharides leading to an increase in the intestinal blood glucose level. We have synthesized novel 2-(3-(benzoyl/4-bromobenzoyl)-4-hydroxy-1,1-dioxido-2H-benzo[e][1,2]thiazin-2-yl)-N-arylacetamides and have screened them for their in silico and in vitro α-glucosidase inhibition activity. The derivatives 11c, 12a, 12d, 12e, and 12g emerged as potent inhibitors of the α-glucosidase enzyme. These compounds exhibited good docking scores and excellent binding interactions with the selected residues (Asp203, Asp542, Asp327, His600, Arg526) during in silico screening. Similarly, these compounds also showed good in vitro α-glucosidase inhibitions with IC50 values of 30.65, 18.25, 20.76, 35.14, and 24.24 µM, respectively, which were better than the standard drug, acarbose (IC50 = 58.8 µM). Furthermore, a good agreement was observed between in silico and in vitro modes of study.


Assuntos
Acetamidas/síntese química , Acetamidas/farmacologia , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/farmacologia , Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacologia , Tiazinas/química , Tiazinas/farmacologia , Acetamidas/química , Acetamidas/uso terapêutico , Simulação por Computador , Diabetes Mellitus/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/uso terapêutico , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/uso terapêutico , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Tiazinas/síntese química
7.
Toxicol Appl Pharmacol ; 425: 115601, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34081941

RESUMO

Obesity is recognized as a risk for the development of chronic kidney disease. Excessive fat accumulation in obesity is associated with the overproduction of reactive oxygen species with the underproduction of antioxidant mechanisms generating oxidative stress together with chronic low-grade inflammation which subsequently leads to the development of several obesity-related complications. It has been suggested that the abnormal lipid accumulation can induce endoplasmic reticulum (ER) stress and cellular apoptosis in several tissue types. Agomelatine is a relatively new antidepressant which is a synthetic agonist of melatonin. Previous study reported the antioxidant and anti-inflammatory effects of agomelatine. In this study, we investigated the therapeutic effects of agomelatine in obesity-related renal injury. Male Wistar rats were fed with normal diet or high-fat diet (HF) for 16 weeks. After that, vehicle or agomelatine or vildagliptin was orally administered to HF rats for 4 weeks. Our results indicated that HF rats demonstrated insulin resistance which was accompanied by an impairment of renal function and renal organic anion transporter 3 (Oat3) function as well as renal oxidative stress, ER stress, and apoptosis. Interestingly, agomelatine treatment not only improved the metabolic parameters, renal function and renal Oat3 function but also attenuated renal oxidative stress, ER stress and subsequent apoptosis. Therefore, agomelatine exerted renoprotective effects in obese insulin-resistant condition. These results suggested that agomelatine could be used as a drug to improve metabolic disturbance and prevent kidney dysfunction in obese condition.


Assuntos
Acetamidas/farmacologia , Apoptose/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Nefropatias/etiologia , Obesidade/complicações , Animais , Dieta Hiperlipídica/efeitos adversos , Regulação da Expressão Gênica/efeitos dos fármacos , Resistência à Insulina , Nefropatias/prevenção & controle , Masculino , Obesidade/induzido quimicamente , Distribuição Aleatória , Ratos , Ratos Wistar
8.
Cell Metab ; 33(8): 1577-1591.e7, 2021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34081913

RESUMO

Recent clinical data have suggested a correlation between coronavirus disease 2019 (COVID-19) and diabetes. Here, we describe the detection of SARS-CoV-2 viral antigen in pancreatic beta cells in autopsy samples from individuals with COVID-19. Single-cell RNA sequencing and immunostaining from ex vivo infections confirmed that multiple types of pancreatic islet cells were susceptible to SARS-CoV-2, eliciting a cellular stress response and the induction of chemokines. Upon SARS-CoV-2 infection, beta cells showed a lower expression of insulin and a higher expression of alpha and acinar cell markers, including glucagon and trypsin1, respectively, suggesting cellular transdifferentiation. Trajectory analysis indicated that SARS-CoV-2 induced eIF2-pathway-mediated beta cell transdifferentiation, a phenotype that could be reversed with trans-integrated stress response inhibitor (trans-ISRIB). Altogether, this study demonstrates an example of SARS-CoV-2 infection causing cell fate change, which provides further insight into the pathomechanisms of COVID-19.


Assuntos
COVID-19/virologia , Transdiferenciação Celular , Células Secretoras de Insulina/virologia , SARS-CoV-2/patogenicidade , Acetamidas/farmacologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , COVID-19/mortalidade , Transdiferenciação Celular/efeitos dos fármacos , Chlorocebus aethiops , Cicloexilaminas/farmacologia , Citocinas/metabolismo , Fator de Iniciação 2 em Eucariotos/metabolismo , Feminino , Glucagon , Interações Hospedeiro-Patógeno , Humanos , Insulina/metabolismo , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Transdução de Sinais , Técnicas de Cultura de Tecidos , Tripsina/metabolismo , Células Vero , Adulto Jovem
9.
Eur J Med Chem ; 223: 113622, 2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34147744

RESUMO

The emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the global pandemic coronavirus disease (COVID-19), but no specific antiviral drug has been proven effective for controlling this pandemic to date. In this study, several 2-((indol-3-yl)thio)-N-benzyl-acetamides were identified as SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) inhibitors. After a two-round optimization, a new series of 2-((indol-3-yl)thio)-N-benzyl-acetamides was designed, synthesized, and evaluated for SARS-CoV-2 RdRp inhibitory effect. Compounds 6b2, 6b5, 6c9, 6d2, and 6d5 were identified as potent inhibitors with IC50 values of 3.35 ± 0.21 µM, 4.55 ± 0.2 µM, 1.65 ± 0.05 µM, 3.76 ± 0.79 µM, and 1.11 ± 0.05 µM, respectively; the IC50 of remdesivir (control) was measured as 1.19 ± 0.36 µM. All of the compounds inhibited RNA synthesis by SARS-CoV-2 RdRp. The most potent compound 6d5, which showed a stronger inhibitory activity against the human coronavirus HCoV-OC43 than remdesivir, is a promising candidate for further investigation.


Assuntos
Acetamidas/síntese química , Antivirais/síntese química , COVID-19/tratamento farmacológico , Inibidores Enzimáticos/síntese química , RNA Viral/antagonistas & inibidores , RNA Polimerase Dependente de RNA/antagonistas & inibidores , SARS-CoV-2/efeitos dos fármacos , Acetamidas/farmacologia , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/farmacologia , Monofosfato de Adenosina/normas , Alanina/análogos & derivados , Alanina/farmacologia , Alanina/normas , Antivirais/farmacologia , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/farmacologia , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , SARS-CoV-2/genética , Relação Estrutura-Atividade
10.
Cryo Letters ; 42(1): 39-43, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33973991

RESUMO

BACKGROUND: Sperm cryopreservation of cockerels is a major challenge, and so far there is no adequate information to enable commercial use of frozen semen. OBJECTIVE: To test the toxicity of dimethylacetamide (DMA). MATERIALS AND METHODS: DMA was added at 3%, 6%, 9% and 12% to the freezing diluent, and maintained for equilibration with the semen sample for 1 min, 3 min, 5 min, 7 min and 9 min prior to freezing. Thawed semen was evaluated for kinetic characteristics by computer-assisted semen analysis (CASA) and for structural and functional properties by flow cytometry (plasma membrane rupture, mitochondrial functionality and plasma membrane functionality). RESULTS AND CONCLUSION: The addition of 6% DMA for 3-min equilibration resulted in the highest total and progressive motility, 42.0% and 36.9%, respectively. The point of intersection between a good protection and low plasma membrane rupture was obtained with the addition of 6% of DMA for 3-min equilibration with the rooster semen.


Assuntos
Acetamidas/farmacologia , Galinhas , Criopreservação/veterinária , Preservação do Sêmen/veterinária , Animais , Crioprotetores/farmacologia , Congelamento , Masculino , Sêmen , Análise do Sêmen , Motilidade Espermática , Espermatozoides
11.
Aging (Albany NY) ; 13(10): 13548-13559, 2021 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-33839700

RESUMO

BACKGROUND AND PURPOSE: Ischemic/reperfusions are regarded as the clinical consensus for stroke treatment, which results in secondary injury of brain tissues. Increased blood-brain barrier (BBB) permeability and infiltration of inflammatory cells are responsible for the ischemic/reperfusion injury. In the present study, we aimed to investigate the effects of Agomelatine on brain ischemic/reperfusions injury and the underlying mechanism. METHODS: MCAO model was established in mice. The expressions of CD68 and claudin-5 in the cerebral cortex were determined using an immunofluorescence assay. Brain permeability was evaluated using Evans blue staining assay. A two-chamber and two-cell trans-well assay was used to detect the migration ability of macrophages through endothelial cells. The expression levels of claudin-5 and MCP-1 in the endothelial cells were determined using qRT-PCR and ELISA. RESULTS: CD68 was found to be up-regulated in the cerebral cortex of MCAO mice but was down-regulated by treatment with Agomelatine. The expression level of down-regulated claudin-5 in the cerebral cortex of MCAO mice was significantly suppressed by Agomelatine. Deeper staining of Evans blue was found in the MCAO group, which was however faded significantly in the Agomelatine treated MCAO mice. The migrated macrophages were significantly increased by hypoxia incubation but were greatly suppressed by the introduction of Agomelatine. The down-regulated claudin-5 by hypoxic incubation in endothelial cells was up-regulated by treatment with Agomelatine. Furthermore, the increased expression of MCP-1 in endothelial cells under hypoxic conditions was significantly inhibited by Agomelatine. CONCLUSION: Agomelatine prevents macrophage infiltration and brain endothelial cell damage in a stroke mouse model.


Assuntos
Acetamidas/farmacologia , Encéfalo/patologia , Células Endoteliais/patologia , Macrófagos/patologia , Acidente Vascular Cerebral/patologia , Acetamidas/química , Acetamidas/uso terapêutico , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/patologia , Hipóxia Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Claudina-5/genética , Claudina-5/metabolismo , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Infarto da Artéria Cerebral Média/patologia , Macrófagos/efeitos dos fármacos , Camundongos , Permeabilidade , Acidente Vascular Cerebral/tratamento farmacológico , Proteínas de Junções Íntimas/metabolismo
12.
FEBS J ; 288(19): 5737-5754, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33837631

RESUMO

Mitochondrial dysfunction mediated by CCCP (carbonyl cyanide m-chlorophenyl hydrazone), an inhibitor of mitochondrial oxidative phosphorylation, evokes the integrated stress response (ISR), which is analyzed here by eIF2α phosphorylation and expression profiles of ATF4 and CHOP proteins. Our findings suggest that the CCCP-induced ISR pathway is mediated by activation of HRI kinase, but not by GCN2, PERK, or PKR. Also, CCCP activates AMPK, a cellular energy sensor, and AKT, a regulator implicated in cell survival, and suppresses phosphorylation of mTORC1 substrates eIF4E-BP1 and S6K. CCCP also downregulates translation and promotes autophagy, leading to noncaspase-mediated cell death in HepG2 cells. All these events are neutralized by NAC, an anti-ROS, suggesting that CCCP-induced mitochondrial dysfunction promotes oxidative stress. ISRIB, an inhibitor of the ISR pathway, mitigates CCCP-induced expression of ATF4 and CHOP, activation of AKT, and autophagy, similar to NAC. However, it fails to reverse CCCP-induced AMPK activation, suggesting that CCCP-induced autophagy is dependent on ISR and independent of AMPK activation. ISRIB restores partly, inhibition in eIF4E-BP1 phosphorylation, promotes eIF2α phosphorylation, albeit slowly, and mitigates suppression of translation accordingly, in CCCP-treated cells. These findings are consistent with the idea that CCCP-induced oxidative stress leading to eIF2α phosphorylation and ATF4 expression, which is known to stimulate genes involved in autophagy, play a pro-survival role together with AKT activation and regulate mTOR-mediated eIF4E-BP1 phosphorylation.


Assuntos
Fator 4 Ativador da Transcrição/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas de Ciclo Celular/genética , Fator de Iniciação 2 em Eucariotos/genética , Mitocôndrias/genética , Proteínas Quinases/genética , Acetamidas/farmacologia , Autofagia/genética , Carbonil Cianeto m-Clorofenil Hidrazona/farmacologia , Cicloexilaminas/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Humanos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Fosforilação Oxidativa/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Estresse Fisiológico/efeitos dos fármacos , Fator de Transcrição CHOP/genética
13.
Biomed Res Int ; 2021: 6664591, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33791372

RESUMO

Depression is a common and disabling mental disorder with high recurrence rate. Searching for more effective treatments for depression is a long-standing primary objective in neuroscience. Agomelatine (AGO) was reported as an antidepressant with unique pharmacological effects. However, its effects and the underlying mechanism are still unclear. In this study, we sought to evaluate the antidepressant effects of AGO on the chronic restraint stress (CRS) mouse model and preliminarily investigate its effects on the gut microbial metabolites. The CRS model mice were established in 28 days with AGO (60 mg/kg/day, by oral) or fluoxetine (15 mg/kg/day, by oral) administration. The number of behavioral tests was conducted to evaluate the effect of AGO on depression-like behavior alleviation. Meanwhile, the expression of the BDNF/TrkB/pERK signaling pathway, apoptosis, autophagy, and inflammatory protein markers were assessed using western blot and immunofluorescence. Our findings show that AGO can attenuate the depressive-like behavior that significantly appeared in both sucrose preference and forced swimming tests. Additionally, a noticeable upregulation of autophagy including Beclin1 and LC3II, microglial activity marker Iba-1, and BDNF/TrkB/pERK signaling pathways are indicated. An obvious decreased expression of NF-κB, iNOS, and nNOS as well as apoptosis including Bax is observed in AGO administration mice. On the other hand, we found that AGO impacted the rebalancing of short-chain fatty acids (SCFAs) in mouse feces. Altogether, these findings suggest that AGO can exert antidepressant effects in a different molecular mechanism.


Assuntos
Acetamidas/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Depressão , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Estresse Psicológico , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Depressão/tratamento farmacológico , Depressão/metabolismo , Depressão/patologia , Modelos Animais de Doenças , Masculino , Glicoproteínas de Membrana/metabolismo , Camundongos , Proteínas Tirosina Quinases/metabolismo , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/metabolismo , Estresse Psicológico/patologia , Proteína X Associada a bcl-2/metabolismo
14.
Mycoses ; 64(7): 748-752, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33755988

RESUMO

BACKGROUND: Invasive fusariosis is associated with marked morbidity and mortality in immunocompromised hosts, and clinical outcomes are poor with conventional therapy. Olorofim (F901318) is an investigational antifungal in the orotomide class that selectively targets fungal dihydroorotate dehydrogenase (DHODH) causing inhibition of pyrimidine biosynthesis. OBJECTIVE: We evaluated the in vitro activity of olorofim against 61 clinical isolates of the Fusarium oxysporum and F solani species complexes (FOSC and FSSC, respectively), the most prevalent causes of invasive fusariosis. METHODS: Clinical isolates of FOSC (n = 45) and FSSC (n = 16) were identified using DNA sequence analysis of the translation elongation factor 1-alpha (TEF1α) and RNA polymerase II second largest subunit (RPB2). Antifungal susceptibility testing was performed by CLSI M38 broth microdilution for olorofim, amphotericin B, isavuconazole, posaconazole, voriconazole and micafungin. RESULTS: Olorofim demonstrated good in vitro activity against both FOSC and FSSC. Against the 45 FOSC isolates, olorofim MICs ranged between 0.03-0.5 mg/L and 0.06->4 mg/L at the 50% and 100% inhibition endpoints, respectively. Against FSSC isolates, olorofim MIC ranged between 0.25-1 mg/L and 1->4 mg/L at 50% and 100% inhibition, respectively. While amphotericin B also demonstrated similar in vitro activity (MIC ranges 1-4 and 0.25-4 mg/L against FOSC and FSSC, respectively), neither the triazoles nor micafungin demonstrated consistent in vitro activity against Fusarium isolates at clinically relevant concentrations. CONCLUSIONS: The investigational agent olorofim demonstrated good in vitro activity against FOSC and FSSC clinical isolates. Further studies are warranted to determine how well this in vitro activity translates into in vivo efficacy.


Assuntos
Acetamidas/farmacologia , Fusarium , Piperazinas/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Antifúngicos/farmacologia , Fusariose/tratamento farmacológico , Fusariose/microbiologia , Fusarium/efeitos dos fármacos , Fusarium/isolamento & purificação , Humanos , Testes de Sensibilidade Microbiana
15.
Mol Biol Rep ; 48(3): 2133-2142, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33650080

RESUMO

P2X7R activation contributes to the pathogenesis of pulmonary hypertension. However, the molecular mechanism through which P2X7R participates in pulmonary vascular remodeling is largely unknown. The rats and pulmonary artery smooth muscle cells (PASMCs) were maintained under hypoxia. P2X7R expression was determined by real-time PCR and western blotting. The pathological changes of lung tissue were evaluated via HE staining after treatment with a P2X7R antagonist, A740003. After treatment with A740003 or silencing P2X7R, proliferating cell nuclear antigen (PCNA), phenotype markers and phospho-c-Jun N-terminal kinase (JNK)/JNK expression were tested by western blotting. P2X7R expression in hypoxia group was significantly higher than that in normoxia group in vivo and in vitro. The pathological changes of lung tissue induced by hypoxia were significantly relieved by treatment with a P2X7R antagonist, A740003. Hypoxia stimulated the proliferation and synthetic phenotype of PASMCs, which were aggravated by a P2X7R agonist treatment and alleviated by a P2X7R antagonist or silencing P2X7R mRNA treatment. Silencing P2X7R mRNA significantly decreased the hypoxia-induced upregulation of phospho-JNK/JNK in PASMCs. The phenotype switching of PASMCs in hypoxia was reversed by treatment with JNK inhibitor. The findings indicate that P2X7R may be involved in the hypoxia-induced proliferation and phenotype switching of PASMCs via JNK signaling pathway, which suggests a new therapeutic strategy targeting P2X7R in vascular remodeling of pulmonary arterial hypertension.


Assuntos
Hipóxia/patologia , Miócitos de Músculo Liso/patologia , Artéria Pulmonar/patologia , Receptores Purinérgicos P2X7/metabolismo , Acetamidas/farmacologia , Animais , Hipóxia Celular/efeitos dos fármacos , Hipóxia Celular/genética , Proliferação de Células/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Hipóxia/genética , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Masculino , Contração Muscular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Fenótipo , Quinolinas/farmacologia , Ratos Wistar , Receptores Purinérgicos P2X7/genética
16.
Eur J Med Chem ; 216: 113265, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33652352

RESUMO

Tropomyosin receptor kinase (TRK) represents an attractive oncology target for cancer therapy related to its critical role in cancer formation and progression. NTRK fusions are found to occur in 3.3% of lung cancers, 2.2% of colorectal cancers, 16.7% of thyroid cancers, 2.5% of glioblastomas, and 7.1% of pediatric gliomas. In this paper, we described the discovery of the type-II pan-TRK inhibitor 4c through the structure-based drug design strategy from the original hits 1b and 2b. Compound 4c exhibited excellent in vitro TRKA, TRKB, and TRKC kinase inhibitory activity and anti-proliferative activity against human colorectal carcinoma derived cell line KM12. In the NCI-60 human cancer cell lines screen, compound 4g demonstrated nearly 80% of growth inhibition for KM12, while only minimal inhibitory activity was observed for the remaining 59 cancer cell lines. Western blot analysis demonstrated that 4c and its urea cousin 4k suppressed the TPM3-TRKA autophosphorylation at the concentrations of 100 nM and 10 nM, respectively. The work presented that 2-(4-(thieno[3,2-d]pyrimidin-4-ylamino)phenyl)acetamides could serve as a novel scaffold for the discovery and development of type-II pan-TRK inhibitors for the treatment of TRK driven cancers.


Assuntos
Acetamidas/química , Desenho de Fármacos , Inibidores de Proteínas Quinases/síntese química , Receptor trkA/antagonistas & inibidores , Receptor trkB/antagonistas & inibidores , Acetamidas/metabolismo , Acetamidas/farmacologia , Sítios de Ligação , Barreira Hematoencefálica/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/química , Pirimidinas/química , Receptor trkA/metabolismo , Receptor trkB/metabolismo , Relação Estrutura-Atividade
17.
Bioorg Med Chem ; 35: 116056, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33607488

RESUMO

A structure-activity relationship (SAR) study towards novel ACC1-selective inhibitors was carried out by modifying the molecular length of the linker in biaryl derivative 1 g, an ACC1/2 dual inhibitor. Ultimately, this leads us to discover novel phenoxybenzyloxy derivative 1i as a potent ACC1-selective inhibitor. Further chemical modification of this scaffold to improve cellular potency as well as physicochemical and pharmacokinetic (PK) properties produced N-2-(pyridin-2-ylethyl)acetamide derivative 1n, which showed highly potent ACC1-selective inhibition as well as sufficient PK profile for further in vivo evaluations. Oral administration of 1n significantly reduced the concentration of malonyl-CoA in HCT-116 xenograft tumors at doses of 100 mg/kg. Accordingly, our novel series of potent ACC1-selective inhibitors represents a set of useful orally-available research tools, as well as potential therapeutic agents for cancer and fatty acid-related diseases.


Assuntos
Acetamidas/farmacologia , Acetil-CoA Carboxilase/antagonistas & inibidores , Compostos de Benzil/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Acetamidas/síntese química , Acetamidas/química , Acetil-CoA Carboxilase/metabolismo , Animais , Compostos de Benzil/síntese química , Compostos de Benzil/química , Células Cultivadas , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Relação Estrutura-Atividade
18.
Chem Biodivers ; 18(4): e2000907, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33576162

RESUMO

A new class of 2-aryloxy-N-phenylacetamide and N'-(2-aryloxyoxyacetyl) benzohydrazide derivatives with different active moieties were synthesized and screened for their antibacterial activity. Structural characterization of synthesized compounds was performed using HR-MS, 1 H-NMR, and 13 C-NMR spectral data. Amongst the synthesized compounds, 4-{2-[2-(2-chloroacetamido)phenoxy]acetamido}-3-nitrobenzoic acid (3h) and 2-chloro-N-(2-{2-[2-(2-chlorobenzoyl)hydrazinyl]-2-oxoethoxy}phenyl)acetamide (3o) have shown good antibacterial activity against a selected panel of bacteria. Besides, compounds also exhibited bactericidal activity against P. aeruginosa (3h, 0.69 µg/mL) and S. aureus (3o, 0.62 µg/mL) as evident by MBC and time-kill kinetics studies. In silico molecular docking and ADMET properties of newly synthesized compounds revealed that compounds could be considered as promising antibacterial agents.


Assuntos
Acetamidas/farmacologia , Antibacterianos/farmacologia , Hidrazinas/farmacologia , Simulação de Acoplamento Molecular , Pseudomonas aeruginosa/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Acetamidas/síntese química , Acetamidas/química , Antibacterianos/síntese química , Antibacterianos/química , Hidrazinas/síntese química , Hidrazinas/química , Cinética , Testes de Sensibilidade Microbiana , Estrutura Molecular
20.
J Med Chem ; 64(4): 1835-1843, 2021 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-33591756

RESUMO

Acute myeloid leukemia (AML) is marked by significant unmet clinical need due to both poor survival and high relapse rates where long-term disease control for most patients with relapsed or refractory AML remain dismal. Inspired to bring novel therapeutic options to these patients, we envisioned protein degradation as a potential therapeutic approach for the treatment of AML. Following this course, we discovered and pioneered a novel mechanism of action which culminated in the discovery of CC-90009. CC-90009 represents a novel protein degrader and the first cereblon E3 ligase modulating drug to enter clinical development that specifically targets GSPT1 (G1 to S phase transition 1) for proteasomal degradation. This manuscript briefly summarizes the mechanism of action, scientific rationale, medicinal chemistry, pharmacokinetic properties, and efficacy data for CC-90009, which is currently in phase 1 clinical development.


Assuntos
Acetamidas/uso terapêutico , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Antineoplásicos/uso terapêutico , Isoindóis/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Fatores de Terminação de Peptídeos/antagonistas & inibidores , Piperidonas/uso terapêutico , Ubiquitina-Proteína Ligases/metabolismo , Acetamidas/química , Acetamidas/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Isoindóis/química , Isoindóis/farmacologia , Macaca fascicularis , Masculino , Camundongos , Estrutura Molecular , Fatores de Terminação de Peptídeos/química , Fatores de Terminação de Peptídeos/metabolismo , Piperidonas/química , Piperidonas/farmacologia , Proteólise/efeitos dos fármacos , Relação Estrutura-Atividade
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