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1.
Bioorg Chem ; 147: 107396, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38705108

RESUMO

RN-9893, a TRPV4 antagonist identified by Renovis Inc., showcased notable inhibition of TRPV4 channels. This research involved synthesizing and evaluating three series of RN-9893 analogues for their TRPV4 inhibitory efficacy. Notably, compounds 1b and 1f displayed a 2.9 to 4.5-fold increase in inhibitory potency against TRPV4 (IC50 = 0.71 ± 0.21 µM and 0.46 ± 0.08 µM, respectively) in vitro, in comparison to RN-9893 (IC50 = 2.07 ± 0.90 µM). Both compounds also significantly outperformed RN-9893 in TRPV4 current inhibition rates (87.6 % and 83.2 % at 10 µM, against RN-9893's 49.4 %). For the first time, these RN-9893 analogues were profiled in an in vivo mouse model, where intraperitoneal injections of 1b or 1f at 10 mg/kg notably mitigated symptoms of acute lung injury induced by lipopolysaccharide (LPS). These outcomes indicate that compounds 1b and 1f are promising candidates for acute lung injury treatment.


Assuntos
Lesão Pulmonar Aguda , Benzenossulfonamidas , Sulfonamidas , Canais de Cátion TRPV , Relação Estrutura-Atividade , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/metabolismo , Lesão Pulmonar Aguda/tratamento farmacológico , Sulfonamidas/química , Sulfonamidas/farmacologia , Sulfonamidas/síntese química , Animais , Camundongos , Humanos , Estrutura Molecular , Relação Dose-Resposta a Droga , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Masculino , Camundongos Endogâmicos C57BL
2.
Cancer Lett ; 592: 216933, 2024 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-38705564

RESUMO

Acute myeloid leukemia (AML) patients carrying Fms-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutations often face a poor prognosis. While some FLT3 inhibitors have been used clinically, challenges such as short efficacy and poor specificity persist. Proteolytic targeting chimera (PROTAC), with its lower ligand affinity requirement for target proteins, offers higher and rapid targeting capability. Gilteritinib, used as the ligand for the target protein, was connected with different E3 ligase ligands to synthesize several series of PROTAC targeting FLT3-ITD. Through screening and structural optimization, the optimal lead compound PROTAC Z29 showed better specificity than Gilteritinib. Z29 induced FLT3 degradation through the proteasome pathway and inhibited tumor growth in subcutaneous xenograft mice. We verified Z29's minimal impact on platelets in a patient-derived xenografts (PDX) model compared to Gilteritinib. The combination of Z29 and Venetoclax showed better anti-tumor effects, lower platelet toxicity, and lower hepatic toxicity in FLT3-ITD+ models. The FLT3-selective PROTAC can mitigate the platelet toxicity of small molecule inhibitors, ensuring safety and efficacy in monotherapy and combination therapy with Venetoclax. It is a promising strategy for FLT3-ITD+ patients, especially those with platelet deficiency or liver damage.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes , Leucemia Mieloide Aguda , Mutação , Sulfonamidas , Ensaios Antitumorais Modelo de Xenoenxerto , Tirosina Quinase 3 Semelhante a fms , Tirosina Quinase 3 Semelhante a fms/genética , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Tirosina Quinase 3 Semelhante a fms/metabolismo , Humanos , Animais , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Sulfonamidas/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Camundongos , Linhagem Celular Tumoral , Pirazinas/farmacologia , Sinergismo Farmacológico , Compostos de Anilina/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proteólise/efeitos dos fármacos , Feminino , Inibidores de Proteínas Quinases/farmacologia
3.
Ecotoxicol Environ Saf ; 278: 116454, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38749199

RESUMO

AIM: We reveal the mechanism of action whereby ambient PM2.5 promotes kidney injury. METHODS: Using C57BL/6 mice, the effects of PM2.5 exposure on the acute kidney injury (AKI) were investigated, including renal function changes, expression of inflammatory cytokines, histopathological changes, as well as activation of nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3(NLRP3). The effects of PM2.5 on renal injury after NLRP3 inhibition were explored using NLRP3 inhibitor (MCC950) and NLRP3 knockout mice. The effects of PM2.5 on the inflammatory response of renal macrophages were investigated at the cellular level. RESULTS: PM2.5 exposure could promote kidney injury, NLRP3 activation and inflammatory response in mice. After using MCC950 and NLRP3 knockout mice, the effects of PM2.5 and the kidney injury could be inhibited. The cellular-level results also suggested that MCC950 could inhibit the effects of PM2.5. CONCLUSION: PM2.5 can promote the progression of AKI and aggravate tissue inflammation through NLRP3, which is an important environmental toxicological mechanism of PM2.5.


Assuntos
Injúria Renal Aguda , Inflamação , Macrófagos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR , Material Particulado , Animais , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Material Particulado/toxicidade , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/patologia , Camundongos , Macrófagos/efeitos dos fármacos , Inflamação/induzido quimicamente , Masculino , Sulfonamidas/toxicidade , Sulfonamidas/farmacologia , Indenos/toxicidade , Poluentes Atmosféricos/toxicidade , Furanos/toxicidade , Sulfonas/toxicidade
4.
J Med Chem ; 67(10): 7836-7858, 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38695063

RESUMO

The approval of venetoclax, a B-cell lymphoma-2 (Bcl-2) selective inhibitor, for the treatment of chronic lymphocytic leukemia demonstrated that the antiapoptotic protein Bcl-2 is a druggable target for B-cell malignancies. However, venetoclax's limited potency cannot produce a strong, durable clinical benefit in other Bcl-2-mediated malignancies (e.g., diffuse large B-cell lymphomas) and multiple recurrent Bcl-2 mutations (e.g., G101V) have been reported to mediate resistance to venetoclax after long-term treatment. Herein, we described novel Bcl-2 inhibitors with increased potency for both wild-type (WT) and mutant Bcl-2. Comprehensive structure optimization led to the clinical candidate BGB-11417 (compound 12e, sonrotoclax), which exhibits strong in vitro and in vivo inhibitory activity against both WT Bcl-2 and the G101V mutant, as well as excellent selectivity over Bcl-xL without obvious cytochrome P450 inhibition. Currently, BGB-11417 is undergoing phase II/III clinical assessments as monotherapy and combination treatment.


Assuntos
Antineoplásicos , Mutação , Proteínas Proto-Oncogênicas c-bcl-2 , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Humanos , Animais , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Relação Estrutura-Atividade , Camundongos , Linhagem Celular Tumoral , Sulfonamidas/farmacologia , Sulfonamidas/química , Ratos , Descoberta de Drogas
5.
Cytokine ; 179: 156620, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38701735

RESUMO

PURPOSE: The emergence of immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment, but these drugs can also cause severe immune-related adverse effects (irAEs), including myocarditis. Researchers have become interested in exploring ways to mitigate this side effect, and one promising avenue is the use of baricitinib, a Janus kinase inhibitor known to have anti-inflammatory properties. This study aimed to examine the potential mechanism by which baricitinib in ICIs-related myocarditis. METHODS: To establish an ICIs-related myocarditis model, BALB/c mice were administered murine cardiac troponin I (cTnI) peptide and anti-mouse programmed death 1 (PD-1) antibodies. Subsequently, baricitinib was administered to the mice via intragastric administration. Echocardiography, HE staining, and Masson staining were performed to evaluate myocardial functions, inflammation, and fibrosis. Immunofluorescence was used to detect macrophages in the cardiac tissue of the mice.In vitro experiments utilized raw264.7 cells to induce macrophage polarization using anti-PD-1 antibodies. Different concentrations of baricitinib were applied to assess cell viability, and the release of pro-inflammatory cytokines was measured. The activation of the JAK1/STAT3 signaling pathway was evaluated through western blot analysis. RESULTS: Baricitinib demonstrated its ability to improve cardiac function and reduce cardiac inflammation, as well as fibrosis induced by ICIs. Mechanistically, baricitinib treatment promoted the polarization of macrophages towards the M2 phenotype. In vitro and in vivo experiments showed that anti-PD-1 promoted the release of inflammatory factors. However, treatment with baricitinib significantly inhibited the phosphorylation of JAK1 and STAT3. Additionally, the use of RO8191 reversed the effects of baricitinib, further confirming our findings. CONCLUSION: Baricitinib demonstrated its potential as a protective agent against ICIs-related myocarditis by modulating macrophage polarization. These findings provide a solid theoretical foundation for the development of future treatments for ICIs-related myocarditis.


Assuntos
Azetidinas , Janus Quinase 1 , Macrófagos , Camundongos Endogâmicos BALB C , Miocardite , Purinas , Pirazóis , Fator de Transcrição STAT3 , Sulfonamidas , Animais , Masculino , Camundongos , Azetidinas/farmacologia , Inibidores de Checkpoint Imunológico/farmacologia , Janus Quinase 1/metabolismo , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Miocardite/induzido quimicamente , Miocardite/tratamento farmacológico , Miocardite/patologia , Miocardite/metabolismo , Purinas/farmacologia , Pirazóis/farmacologia , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Sulfonamidas/farmacologia , Troponina I/metabolismo
6.
Exp Cell Res ; 438(2): 114061, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38692345

RESUMO

Acute myocardial infarction (AMI) is a prevalent cardiovascular disease with high morbidity and mortality rates worldwide. Pyroptosis is an inflammatory form of programmed cell death that has been linked to various pathological conditions. However, its exact contribution to the onset and progression of heart injury in AMI has not yet fully elucidated. Herein, we established mouse AMI model by ligating the left anterior descending artery and performed transcriptome analysis during the early phase of AMI. Mouse HL-1 and human AC-16 cardiomyocytes were subjected to hypoxia to simulate ischemic injury in vitro. Our results revealed a significant activation of the inflammatory response at 3 h post-ligation, as confirmed by RNA sequencing. We identified the occurrence of NLRP3 inflammasome-mediated pyroptosis in the cardiac tissues of human cases with AMI, as well as in mouse models of AMI and hypoxia-induced cardiomyocytes, using immunohistochemistry staining and Western blotting assays. Concurrently, pharmacological inhibition of NLRP3 inflammasome-mediated pyroptosis with MCC950 and VX-765 effectively decreased hypoxia-induced cardiomyocytes injury, while mitigating myocardial oxidative stress, apoptosis and inflammation caused by hypoxia. Moreover, the circulating levels of gasdermin D (GSDMD), the pyroptosis executor, were remarkably elevated in the plasma of mice with early AMI and in the supernatant of hypoxia-exposed cardiomyocytes in a time-dependent manner using ELISA and Western blotting. Furthermore, the change in circulating GSDMD positively correlated with Creatine Kinase-MB (CK-MB) in the plasma of early-stage AMI mouse. In summary, these findings indicated a critical role for NLRP3 inflammasome-mediated pyroptosis in the progression of AMI, the administration of MCC950 and VX-765 may be attractive candidate therapeutic approaches for cardiac injury caused by acute hypoxia or even AMI. Additionally, the circulating GSDMD exhibits potential as a newly diagnostic biomarker for AMI.


Assuntos
Apoptose , Furanos , Inflamação , Camundongos Endogâmicos C57BL , Infarto do Miocárdio , Miócitos Cardíacos , Estresse Oxidativo , Piroptose , Sulfonamidas , Piroptose/efeitos dos fármacos , Animais , Camundongos , Apoptose/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Sulfonamidas/farmacologia , Humanos , Inflamação/metabolismo , Inflamação/patologia , Inflamação/tratamento farmacológico , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Masculino , Furanos/farmacologia , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Infarto do Miocárdio/tratamento farmacológico , Indenos/farmacologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , para-Aminobenzoatos/farmacologia , Inflamassomos/metabolismo , Inflamassomos/efeitos dos fármacos , Modelos Animais de Doenças , Miocárdio/metabolismo , Miocárdio/patologia , Hipóxia/metabolismo , Hipóxia/complicações , Dipeptídeos
7.
PLoS One ; 19(5): e0299424, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38781172

RESUMO

Mutations in the non-structural protein regions of hepatitis C virus (HCV) are a cause of a non-sustained virological response (SVR) to treatment with direct-acting antivirals (DAAs) for chronic hepatitis; however, there are non-SVR cases without these mutations. In this study, we examined immune cell profiles in peripheral blood before and after ombitasvir/paritaprevir/ritonavir treatment and screened for genes that could be used to predict the therapeutic effects of DAAs. Fluorescence-activated cell sorting analysis indicated that the median frequencies of programmed cell death-1-positive (PD-1+) effector regulatory T cells (eTregs), PD-1+CD8+ T cells, and PD-1+Helper T cells were decreased significantly in SVR cases, but without significant changes in non-SVR cases. The frequency of PD-1+ naïve Tregs was significantly higher in the SVR group than in the non-SVR group before and after treatment. Similar results were found in patients treated with other DAAs (e.g., daclatasvir plus asunaprevir) and supported an immune response after HCV therapy. RNA-sequencing analysis indicated a significant increase in the expression of genes associated with the immune response in the SVR group, while genes related to intracellular and extracellular signal transduction were highly expressed in the non-SVR group. Therefore, we searched for genes associated with PD-1+ eTregs and CD8+ T cells that were significantly different between the SVR and non-SVR groups and found that T-box transcription factor 21 was associated with the non-SVR state. These results indicate that PD-1-related signaling pathways are associated with a non-SVR mechanism after DAAs treatment separate from mutation-related drug resistance.


Assuntos
Antivirais , Linfócitos T CD8-Positivos , Carbamatos , Hepacivirus , Hepatite C Crônica , Receptor de Morte Celular Programada 1 , Sulfonamidas , Linfócitos T Reguladores , Humanos , Antivirais/uso terapêutico , Masculino , Hepacivirus/efeitos dos fármacos , Hepacivirus/imunologia , Hepacivirus/genética , Feminino , Pessoa de Meia-Idade , Carbamatos/uso terapêutico , Linfócitos T CD8-Positivos/imunologia , Linfócitos T Reguladores/imunologia , Sulfonamidas/uso terapêutico , Sulfonamidas/farmacologia , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/imunologia , Hepatite C Crônica/virologia , Hepatite C Crônica/sangue , Ciclopropanos/uso terapêutico , Valina/análogos & derivados , Prolina/análogos & derivados , Anilidas/uso terapêutico , Anilidas/farmacologia , Lactamas Macrocíclicas/uso terapêutico , Compostos Macrocíclicos/uso terapêutico , Compostos Macrocíclicos/farmacologia , Idoso , Ritonavir/uso terapêutico , Adulto , Quimioterapia Combinada , Linfócitos T Auxiliares-Indutores/imunologia , Imidazóis , Isoquinolinas , Pirrolidinas
8.
Genes (Basel) ; 15(5)2024 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-38790277

RESUMO

Acute myeloid leukemia is the second most frequent type of leukemia in adults. Due to a high risk of development of chemoresistance to first-line chemotherapy, the survival rate of patients in a 5-year period is below 30%. One of the reasons is that the AML population is heterogeneous, with cell populations partly composed of very primitive CD34+CD38- hematopoietic stem/progenitor cells, which are often resistant to chemotherapy. First-line treatment with cytarabine and idarubicin fails to inhibit the proliferation of CD34+CD38- cells. In this study, we investigated Metformin's effect with or without first-line conventional chemotherapy, or with other drugs like venetoclax and S63845, on primitive and undifferentiated CD34+ AML cells in order to explore the potential of Metformin or S63845 to serve as adjuvant therapy for AML. We found that first-line conventional chemotherapy treatment inhibited the growth of cells and arrested the cells in the S phase of the cell cycle; however, metformin affected the accumulation of cells in the G2/M phase. We observed that CD34+ KG1a cells respond better to lower doses of cytarabine or idarubicin in combination with metformin. Also, we determined that treatment with cytarabine, venetoclax, and S63845 downregulated the strong tendency of CD34+ KG1a cells to form cell aggregates in culture due to the downregulation of leukemic stem cell markers like CD34 and CD44, as well as adhesion markers. Also, we found that idarubicin slightly upregulated myeloid differentiation markers, CD11b and CD14. Treatment with cytarabine, idarubicin, venetoclax, metformin, and S63845 upregulated some cell surface markers like HLA-DR expression, and metformin upregulated CD9, CD31, and CD105 cell surface marker expression. In conclusion, we believe that metformin has the potential to be used as an adjuvant in the treatment of resistant-to-first-line-chemotherapy AML cells. Also, we believe that the results of our study will stimulate further research and the potential use of changes in the expression of cell surface markers in the development of new therapeutic strategies.


Assuntos
Antígenos CD34 , Citarabina , Resistencia a Medicamentos Antineoplásicos , Leucemia Mieloide Aguda , Metformina , Humanos , Metformina/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Antígenos CD34/metabolismo , Linhagem Celular Tumoral , Citarabina/farmacologia , Proliferação de Células/efeitos dos fármacos , Sulfonamidas/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Idarubicina/farmacologia
9.
J Agric Food Chem ; 72(20): 11369-11380, 2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38727083

RESUMO

In keeping with our investigation, a simple and practical synthesis of novel heterocyclic compounds with a sulfamoyl moiety that can be employed as insecticidal agents was reported. The compound 2-hydrazinyl-N-(4-sulfamoylphenyl)-2-thioxoacetamide 1 was coupled smoothly with triethylorthoformate or a variety of halo compounds, namely phenacyl chloride, chloroacetyl chloride, chloroacetaldehyde, chloroacetone, 1,3-dichloropropane, 1,2-dichloroethane, ethyl chloroformate, 2,3-dichloro-1,4-naphthoquinone, and chloroanil respectively, which afforded the 1,3,4-thiadiazole and 1,3,4-thiadiazine derivatives. The new products structure was determined using elemental and spectral analysis. Under laboratory conditions, the biological and toxicological effects of the synthetic compounds were also evaluated as insecticides against Spodoptera littoralis (Boisd.). Compounds 3 and 5 had LC50 values of 6.42 and 6.90 mg/L, respectively. The investigated compounds (from 2 to 11) had been undergoing molecular docking investigation for prediction of the optimal arrangement and strength of binding between the ligand (herein, the investigated compounds (from 2 to 11)) and a receptor (herein, the 2CH5) molecule. The binding affinity within docking score (S, kcal/mol) ranged between -8.23 (for compound 5), -8.12 (for compound 3) and -8.03 (for compound 9) to -6.01 (for compound 8). These compounds were shown to have a variety of binding interactions within the 2CH5 active site, as evidenced by protein-ligand docking configurations. This study gives evidence that those compounds have 2CH5-inhibitory capabilities and hence may be used for 2CH5-targeting development. Furthermore, the three top-ranked compounds (5, 3, and 9) and the standard buprofezin were subjected to density functional theory (DFT) analysis. The highest occupied molecular orbital-lowest unoccupied molecular orbital (HOMO-LUMO) energy difference (ΔE) of compounds 5, 3, and 9 was found to be comparable to that of buprofezin. These findings highlighted the potential and relevance of charge transfer at the molecular level.


Assuntos
Desenho de Fármacos , Inseticidas , Simulação de Acoplamento Molecular , Spodoptera , Tiadiazinas , Tiadiazóis , Animais , Inseticidas/química , Inseticidas/síntese química , Inseticidas/farmacologia , Spodoptera/efeitos dos fármacos , Tiadiazóis/química , Tiadiazóis/farmacologia , Tiadiazóis/síntese química , Tiadiazinas/química , Tiadiazinas/farmacologia , Tiadiazinas/síntese química , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia , Sulfonamidas/síntese química , Proteínas de Insetos/química , Benzenossulfonamidas , Estrutura Molecular , Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica II/metabolismo , Anidrase Carbônica II/química
10.
Stem Cell Res Ther ; 15(1): 145, 2024 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-38764093

RESUMO

BACKGROUND: Mesenchymal stem cells (MSCs) play important roles in tissue homeostasis by providing a supportive microenvironmental niche for the hematopoietic system. Cigarette smoking induces systemic abnormalities, including an impeded recovery process after hematopoietic stem cell transplantation. However, the role of cigarette smoking-mediated alterations in MSC niche function have not been investigated. METHODS: In the present study, we investigated whether exposure to cigarette smoking extract (CSE) disrupts the hematopoietic niche function of MSCs, and pathways impacted. To investigate the effects on bone marrow (BM)-derived MSCs and support of hematopoietic stem and progenitor cells (HSPCs), mice were repeatedly infused with the CSE named 3R4F, and hematopoietic stem and progenitor cells (HSPCs) supporting function was determined. The impact of 3R4F on MSCs at cellular level were screened by bulk-RNA sequencing and subsequently validated through qRT-PCR. Specific inhibitors were treated to verify the ROS or NLRP3-specific effects, and the cells were then transplanted into the animal model or subjected to coculture with HSPCs. RESULTS: Both direct ex vivo and systemic in vivo MSC exposure to 3R4F resulted in impaired engraftment in a humanized mouse model. Furthermore, transcriptomic profile analysis showed significantly upregulated signaling pathways related to reactive oxygen species (ROS), inflammation, and aging in 3R4F-treated MSCs. Notably, ingenuity pathway analysis revealed the activation of NLRP3 inflammasome signaling pathway in 3R4F-treated MSCs, and pretreatment with the NLRP3 inhibitor MCC950 rescued the HSPC-supporting ability of 3R4F-treated MSCs. CONCLUSION: In conclusion, these findings indicate that exposure to CSE reduces HSPCs supportive function of MSCs by inducing robust ROS production and subsequent NLRP3 activation.


Assuntos
Células-Tronco Hematopoéticas , Indenos , Células-Tronco Mesenquimais , Proteína 3 que Contém Domínio de Pirina da Família NLR , Espécies Reativas de Oxigênio , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , Animais , Espécies Reativas de Oxigênio/metabolismo , Camundongos , Indenos/farmacologia , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/citologia , Furanos/farmacologia , Sulfonas/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Camundongos Endogâmicos C57BL , Sulfonamidas/farmacologia , Fumar Cigarros/efeitos adversos , Humanos , Inflamassomos/metabolismo
11.
Bioorg Chem ; 147: 107409, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38714116

RESUMO

Sulfonamides have gained prominence as versatile agents in cancer therapy, effectively targeting a spectrum of cancer-associated enzymes. This review provides an extensive exploration of their multifaceted roles in cancer biology. Sulfonamides exhibit adaptability by acting as tyrosine kinase inhibitors, disrupting pivotal signaling pathways in cancer progression. Moreover, they disrupt pH regulation mechanisms in cancer cells as carbonic anhydrase inhibitors, inhibiting growth, and survival. Sulfonamides also serve as aromatase inhibitors, interfering with estrogen synthesis in hormone-driven cancers. Inhibition of matrix metalloproteinases presents an opportunity to impede cancer cell invasion and metastasis. Additionally, their emerging role as histone deacetylase inhibitors offers promising prospects in epigenetic-based cancer therapies. These diverse roles underscore sulfonamides as invaluable tools for innovative anti-cancer treatments, warranting further exploration for enhanced clinical applications and patient outcomes.


Assuntos
Antineoplásicos , Neoplasias , Sulfonamidas , Humanos , Sulfonamidas/química , Sulfonamidas/farmacologia , Sulfonamidas/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Neoplasias/metabolismo , Estrutura Molecular , Proliferação de Células/efeitos dos fármacos , Animais , Relação Estrutura-Atividade
12.
J Med Chem ; 67(10): 7825-7835, 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38729623

RESUMO

Cardiac myosin activation has been shown to be a viable approach for the treatment of heart failure with reduced ejection fraction. Here, we report the discovery of nelutroctiv (CK-136), a selective cardiac troponin activator intended for patients with cardiovascular conditions where cardiac contractility is reduced. Discovery of nelutroctiv began with a high-throughput screen that identified compound 1R, a muscle selective cardiac sarcomere activator devoid of phosphodiesterase-3 activity. Optimization of druglike properties for 1R led to the replacement of the sulfonamide and aniline substituents which resulted in improved pharmacokinetic (PK) profiles and a reduced potential for human drug-drug interactions. In vivo echocardiography assessment of the optimized leads showed concentration dependent increases in fractional shortening and an improved pharmacodynamic window compared to myosin activator CK-138. Overall, nelutroctiv was found to possess the desired selectivity, a favorable pharmacodynamic window relative to myosin activators, and a preclinical PK profile to support clinical development.


Assuntos
Contração Miocárdica , Humanos , Animais , Contração Miocárdica/efeitos dos fármacos , Doenças Cardiovasculares/tratamento farmacológico , Ratos , Relação Estrutura-Atividade , Masculino , Descoberta de Drogas , Troponina/metabolismo , Camundongos , Ratos Sprague-Dawley , Sulfonamidas/farmacologia , Sulfonamidas/farmacocinética , Sulfonamidas/química , Sulfonamidas/uso terapêutico , Sulfonamidas/síntese química
13.
Cell Mol Life Sci ; 81(1): 238, 2024 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-38795180

RESUMO

BRAFV600E represents a constitutively active onco-kinase and stands as the most prevalent genetic alteration in thyroid cancer. However, the clinical efficacy of small-molecule inhibitors targeting BRAFV600E is often limited by acquired resistance. Here, we find that nerve/glial antigen 2 (NG2), also known as chondroitin sulfate proteoglycan 4 (CSPG4), is up-regulated in thyroid cancers, and its expression is increased with tumor progression in a BRAFV600E-driven thyroid cancer mouse model. Functional studies show that NG2 knockout almost does not affect tumor growth, but significantly improves the response of BRAF-mutant thyroid cancer cells to BRAF inhibitor PLX4720. Mechanistically, the blockade of ERK-dependent feedback by BRAF inhibitor can activate receptor tyrosine kinase (RTK) signaling, causing the resistance to this inhibitor. NG2 knockout attenuates the PLX4720-mediated feedback activation of several RTKs, improving the sensitivity of BRAF-mutant thyroid cancer cells to this inhibitor. Based on this finding, we propose and demonstrate an alternative strategy for targeting NG2 to effectively treat BRAF-mutant thyroid cancers by combining multiple kinase inhibitor (MKI) Sorafenib or Lenvatinib with PLX4720. Thus, this study uncovers a new mechanism in which NG2 contributes to the resistance of BRAF-mutant thyroid cancer cells to BRAF inhibitor, and provides a promising therapeutic option for BRAF-mutant thyroid cancers.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Indóis , Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas B-raf , Sulfonamidas , Neoplasias da Glândula Tireoide , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/metabolismo , Humanos , Animais , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/metabolismo , Indóis/farmacologia , Camundongos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Sulfonamidas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Linhagem Celular Tumoral , Compostos de Fenilureia/farmacologia , Compostos de Fenilureia/uso terapêutico , Sorafenibe/farmacologia , Quinolinas/farmacologia , Mutação , Antígenos/metabolismo , Proteoglicanas/metabolismo , Proteínas de Membrana , Proteoglicanas de Sulfatos de Condroitina
14.
Acta Derm Venereol ; 104: adv39950, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38751178

RESUMO

Pruritus in the elderly, particularly those cases without skin dryness or other identifiable causes, makes treatment challenging due to the lack of evidence regarding the therapeutic effects of antipruritics. This study proposes an age-related alloknesis mouse model for an evaluation system for such cases, and aimed to investigate the effectiveness and mechanisms of action of several drugs commonly used as antipruritics in Japan, utilizing this model. Mice 69-80 weeks old were used as aged mice, and the level of mechanical alloknesis was counted as the number of scratching behaviours in response to innocuous stimuli. Bepotastine, neurotropin, pregabalin, baricitinib, and abrocitinib were used as antipruritics, and yohimbine and methysergide as inhibitors of the descending inhibitory pathway. The findings suggest that mechanical alloknesis in aged mice is a suitable animal model for assessing pruritus in the elderly without xerosis, and pregabalin, neurotropin, baricitinib, and abrocitinib may be effective antipruritics in the elderly through activating both the noradrenergic and serotonergic descending inhibitory pathways. These findings may be useful for the selection of antipruritics for pruritus in the elderly without skin lesions or dryness.


Assuntos
Antipruriginosos , Modelos Animais de Doenças , Prurido , Animais , Prurido/tratamento farmacológico , Antipruriginosos/farmacologia , Antipruriginosos/uso terapêutico , Doença Crônica , Comportamento Animal/efeitos dos fármacos , Camundongos , Fatores Etários , Masculino , Sulfonamidas/farmacologia , Pregabalina/farmacologia , Pregabalina/uso terapêutico , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Purinas/farmacologia , Purinas/uso terapêutico , Envelhecimento/efeitos dos fármacos , Azetidinas/farmacologia , Azetidinas/uso terapêutico
15.
FASEB J ; 38(10): e23671, 2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-38752538

RESUMO

NLRP3 inflammasome activation has emerged as a critical initiator of inflammatory response in ischemic retinopathy. Here, we identified the effect of a potent, selective NLRP3 inhibitor, MCC950, on autophagy and apoptosis under hypoxia. Neonatal mice were exposed to hyperoxia for 5 days to establish oxygen-induced retinopathy (OIR) model. Intravitreal injection of MCC950 was given, and then autophagy and apoptosis markers were assessed. Retinal autophagy, apoptosis, and related pathways were evaluated by western blot, immunofluorescent labeling, transmission electron microscopy, and TUNEL assay. Autophagic activity in Müller glia after NLRP3 inflammasome inhibition, together with its influence on photoreceptor death, was studied using western blot, immunofluorescence staining, mRFP-GFP-LC3 adenovirus transfection, cell viability, proliferation, and apoptosis assays. Results showed that activation of NLRP3 inflammasome in Müller glia was detected in OIR model. MCC950 could improve impaired retinal autophagic flux and attenuate retinal apoptosis while it regulated the retinal AMPK/mTOR/ULK-1 pathway. Suppressed autophagy and depressed proliferation capacity resulting from hypoxia was promoted after MCC950 treatment in Müller glia. Inhibition of AMPK and ULK-1 pathway significantly interfered with the MCC950-induced autophagy activity, indicating MCC950 positively modulated autophagy through AMPK/mTOR/ULK-1 pathway in Müller cells. Furthermore, blockage of autophagy in Müller glia significantly induced apoptosis in the cocultured 661W photoreceptor cells, whereas MCC950 markedly preserved the density of photoreceptor cells. These findings substantiated the therapeutic potential of MCC950 against impaired autophagy and subsequent apoptosis under hypoxia. Such protective effect might involve the modulation of AMPK/mTOR/ULK-1 pathway. Targeting NLRP3 inflammasome in Müller glia could be beneficial for photoreceptor survival under hypoxic conditions.


Assuntos
Apoptose , Autofagia , Células Ependimogliais , Furanos , Indenos , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Sulfonamidas , Animais , Autofagia/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Camundongos , Apoptose/efeitos dos fármacos , Sulfonamidas/farmacologia , Inflamassomos/metabolismo , Furanos/farmacologia , Células Ependimogliais/metabolismo , Células Ependimogliais/efeitos dos fármacos , Indenos/farmacologia , Camundongos Endogâmicos C57BL , Hipóxia/metabolismo , Óxidos S-Cíclicos/farmacologia , Sulfonas/farmacologia , Células Fotorreceptoras de Vertebrados/metabolismo , Células Fotorreceptoras de Vertebrados/efeitos dos fármacos , Células Fotorreceptoras de Vertebrados/patologia , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Células Fotorreceptoras/metabolismo , Células Fotorreceptoras/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
17.
Sci Rep ; 14(1): 10973, 2024 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-38744889

RESUMO

In this study, we synthesized new series of 5-oxo-2-phenyl-4-(arylsulfamoyl)sulphenyl) hydrazono)-4,5-dihydro-1H-pyrrole-3-carboxylate hybrids 4a-f with the goal of overcoming sulfonamide resistance and identifying novel therapeutic candidates by chemical changes. The chemical structures of the synthesized hybrids were established over the spectroscopic tools. The frontier molecular orbitals configuration and energetic possessions of the synthesized compounds were discovered utilizing DFT/B3LYP/6-311++ G** procedure. The 3D plots of both HOMO and LUMO showed comparable configuration of both HOMO and LUMO led to close values of their energies. Amongst the prepared analogues, the sulfonamide hybrids 4a-f, hybrid 4a presented potent inhibitory towards S. typhimurium with (IZD = 15 mm, MIC = 19.24 µg/mL) and significant inhibition with (IZD = 19 mm, MIC = 11.31 µg/mL) against E.coli in contrast to sulfonamide (Sulfamethoxazole) reference Whereas, hybrid 4d demonstrated potent inhibition with (IZD = 16 mm, MIC = 19.24 µg/mL) against S. typhimurium with enhanced inhibition against E. Coli, Additionally, the generated sulfonamide analogues'' molecular docking was estimated over (PDB: 3TZF and 6CLV) proteins. Analogue 4e had the highest documented binding score as soon as linked to the other analogues. The docking consequences were fitting and addressed with the antibacterial valuation.


Assuntos
Antibacterianos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Pirróis , Sulfonamidas , Sulfonamidas/química , Sulfonamidas/farmacologia , Sulfonamidas/síntese química , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Pirróis/química , Pirróis/farmacologia , Pirróis/síntese química , Salmonella typhimurium/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Modelos Moleculares , Relação Estrutura-Atividade , Estrutura Molecular
18.
Immunohorizons ; 8(5): 363-370, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38775688

RESUMO

Although the pathogenesis of choroidal neovascularization (CNV) is largely unknown in age-related macular degeneration (AMD), inflammasomes may contribute to CNV development and progression. To understand the role NLRP3 inflammasomes in CNV, we used Ccr2RFPCx3cr1GFP dual-reporter mice and immunostaining techniques to confirm localization of NLRP3 inflammasomes in the laser-induced CNV (LCNV) lesions. Confocal microscopy was used to image and quantify LCNV volumes. MCC950 was used as NLRP3 inhibitor. ELISA and quantitative RT-PCR were used to confirm the activation of NLRP3 by monitoring the expression of IL-1ß protein and mRNA in choroidal tissues from LCNV mice. In addition, NLRP3 (-/-) LCNV mice were used to investigate whether NLRP3 inflammasomes contribute to the development of LCNV lesions. We observed that red fluorescent protein (RFP)-positive monocyte-derived macrophages and GFP-positive microglia-derived macrophages, in addition to other cell types, were localized in LCNV lesions at day 7 post-laser injury. In addition, NLRP3 inflammasomes are associated with LCNV lesions. Inhibition of NLRP3 inflammasomes, using MCC950, caused an increased Ccr2RFP-positive macrophages, Cx3cr1GFP-positive microglia, and other cells, resulting in an increase in total lesion size. NLRP3 (-/-) LCNV mice showed significantly increased lesion size compared with age-matched controls. Inhibition of NLRP3 resulted in decreased IL-1ß mRNA and protein expression in the choroidal tissues, suggesting that increased lesion size may not be directly related to IL-1ß.


Assuntos
Neovascularização de Coroide , Indenos , Inflamassomos , Interleucina-1beta , Microglia , Monócitos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Animais , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Neovascularização de Coroide/metabolismo , Neovascularização de Coroide/patologia , Camundongos , Inflamassomos/metabolismo , Interleucina-1beta/metabolismo , Microglia/metabolismo , Monócitos/metabolismo , Camundongos Knockout , Sulfonas/farmacologia , Camundongos Endogâmicos C57BL , Furanos/farmacologia , Receptores CCR2/metabolismo , Receptores CCR2/genética , Macrófagos/metabolismo , Macrófagos/imunologia , Sulfonamidas/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Proteínas de Transporte/metabolismo , Proteínas de Transporte/genética , Corioide/metabolismo , Corioide/patologia , Modelos Animais de Doenças , Lasers/efeitos adversos , Degeneração Macular/patologia , Degeneração Macular/metabolismo , Degeneração Macular/genética
19.
Sci Rep ; 14(1): 10228, 2024 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-38702418

RESUMO

Chitosan (CH) exhibits low antimicrobial activity. This study addresses this issue by modifying the chitosan with a sulfonamide derivative, 3-(4-(N,N-dimethylsulfonyl)phenyl)acrylic acid. The structure of the sulfonamide-chitosan derivative (DMS-CH) was confirmed using Fourier transform infrared spectroscopy and Nuclear magnetic resonance. The results of scanning electron microscopy, thermal gravimetric analysis, and X-ray diffraction indicated that the morphology changed to a porous nature, the thermal stability decreased, and the crystallinity increased in the DMS-CH derivative compared to chitosan, respectively. The degree of substitution was calculated from the elemental analysis data and was found to be moderate (42%). The modified chitosan exhibited enhanced antimicrobial properties at low concentrations, with a minimum inhibitory concentration (MIC) of 50 µg/mL observed for B. subtilis and P. aeruginosa, and a value of 25 µg/mL for S. aureus, E. coli, and C. albicans. In the case of native chitosan, the MIC values doubled or more, with 50 µg/mL recorded for E. coli and C. albicans and 100 µg/mL recorded for B. subtilis, S. aureus, and P. aeruginosa. Furthermore, toxicological examinations conducted on MCF-7 (breast adenocarcinoma) cell lines demonstrated that DMS-CH exhibited greater toxicity (IC50 = 225.47 µg/mL) than pure CH, while still maintaining significant safety limits against normal lung fibroblasts (WI-38). Collectively, these results suggest the potential use of the newly modified chitosan in biomedical applications.


Assuntos
Anti-Infecciosos , Quitosana , Testes de Sensibilidade Microbiana , Sulfonamidas , Quitosana/química , Quitosana/farmacologia , Humanos , Sulfonamidas/farmacologia , Sulfonamidas/química , Anti-Infecciosos/farmacologia , Anti-Infecciosos/química , Candida albicans/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Espectroscopia de Infravermelho com Transformada de Fourier , Sobrevivência Celular/efeitos dos fármacos , Difração de Raios X , Células MCF-7
20.
J Cancer Res Clin Oncol ; 150(5): 231, 2024 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-38703241

RESUMO

PURPOSE: Acute myeloid leukemia (AML) is a refractory hematologic malignancy that poses a serious threat to human health. Exploring alternative therapeutic strategies capable of inducing alternative modes of cell death, such as ferroptosis, holds great promise as a viable and effective intervention. METHODS: We analyzed online database data and collected clinical samples to verify the expression and function of BMAL1 in AML. We conducted experiments on AML cell proliferation, cell cycle, ferroptosis, and chemotherapy resistance by overexpressing/knocking down BMAL1 and using assays such as MDA detection and BODIPY 581/591 C11 staining. We validated the transcriptional regulation of HMGB1 by BMAL1 through ChIP assay, luciferase assay, RNA level detection, and western blotting. Finally, we confirmed the results of our cell experiments at the animal level. RESULTS: BMAL1 up-regulation is an observed phenomenon in AML patients. Furthermore, there existed a strong correlation between elevated levels of BMAL1 expression and inferior prognosis in individuals with AML. We found that knocking down BMAL1 inhibited AML cell growth by blocking the cell cycle. Conversely, overexpressing BMAL1 promoted AML cell proliferation. Moreover, our research results revealed that BMAL1 inhibited ferroptosis in AML cells through BMAL1-HMGB1-GPX4 pathway. Finally, knocking down BMAL1 can enhance the efficacy of certain first-line cancer therapeutic drugs, including venetoclax, dasatinib, and sorafenib. CONCLUSION: Our research results suggest that BMAL1 plays a crucial regulatory role in AML cell proliferation, drug resistance, and ferroptosis. BMAL1 could be a potential important therapeutic target for AML.


Assuntos
Fatores de Transcrição ARNTL , Resistencia a Medicamentos Antineoplásicos , Ferroptose , Proteína HMGB1 , Leucemia Mieloide Aguda , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Transdução de Sinais , Animais , Feminino , Humanos , Masculino , Camundongos , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ferroptose/efeitos dos fármacos , Proteína HMGB1/metabolismo , Proteína HMGB1/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/genética , Camundongos Nus , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Prognóstico , Sulfonamidas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
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