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1.
Nagoya J Med Sci ; 86(2): 292-303, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38962405

RESUMO

Endothelial dysfunction is important in the pathology of pulmonary hypertension, and circulating endothelial progenitor cells (EPCs) have been studied to evaluate endothelial dysfunction. In patients with chronic thromboembolic pulmonary hypertension (CTEPH), riociguat reportedly increases the number of circulating EPCs. However, the relationship between EPC numbers at baseline and changes in clinical parameters after riociguat administration has not been fully elucidated. Here, we evaluated 27 treatment-naïve patients with CTEPH and analyzed the relationships between EPC number at diagnosis and clinical variables (age, hemodynamics, atrial blood gas parameters, brain natriuretic peptide, and exercise tolerance) before and after riociguat initiation. EPCs were defined as CD45dim CD34+ CD133+ cells and measured by flow cytometry. A low number of circulating EPCs at diagnosis was significantly correlated with increased reductions in mean pulmonary arterial pressure (mPAP) (correlation coefficient = 0.535, P = 0.004) and right atrial pressure (correlation coefficient = 0.618, P = 0.001) upon riociguat treatment. We then divided the study population into two groups according to the mPAP change: a weak-response group (a decrease in mPAP of 4 mmHg or less) and a strong-response group (a decrease in mPAP of more than 4 mmHg). The number of EPCs at diagnosis was significantly lower in the strong-response group than in the weak-response group (P = 0.022), but there were no significant differences in other clinical variables or in medication profiles. In conclusion, circulating EPC numbers could be a potential predictor of the therapeutic effect of riociguat in CTEPH patients.


Assuntos
Células Progenitoras Endoteliais , Hipertensão Pulmonar , Pirazóis , Pirimidinas , Humanos , Pirimidinas/uso terapêutico , Pirimidinas/farmacologia , Pirazóis/uso terapêutico , Pirazóis/farmacologia , Masculino , Feminino , Pessoa de Meia-Idade , Hipertensão Pulmonar/tratamento farmacológico , Células Progenitoras Endoteliais/efeitos dos fármacos , Células Progenitoras Endoteliais/metabolismo , Idoso , Doença Crônica , Embolia Pulmonar/tratamento farmacológico , Embolia Pulmonar/sangue , Resultado do Tratamento
2.
Proc Natl Acad Sci U S A ; 121(28): e2320655121, 2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-38959043

RESUMO

SLC7A11 is a cystine transporter and ferroptosis inhibitor. How the stability of SLC7A11 is coordinately regulated in response to environmental cystine by which E3 ligase and deubiquitylase (DUB) remains elusive. Here, we report that neddylation inhibitor MLN4924 increases cystine uptake by causing SLC7A11 accumulation, via inactivating Cullin-RING ligase-3 (CRL-3). We identified KCTD10 as the substrate-recognizing subunit of CRL-3 for SLC7A11 ubiquitylation, and USP18 as SLC7A11 deubiquitylase. Upon cystine deprivation, the protein levels of KCTD10 or USP18 are decreased or increased, respectively, contributing to SLC7A11 accumulation. By destabilizing or stabilizing SLC7A11, KCTD10, or USP18 inversely regulates the cystine uptake and ferroptosis. Biologically, MLN4924 combination with SLC7A11 inhibitor Imidazole Ketone Erastin (IKE) enhanced suppression of tumor growth. In human breast tumor tissues, SLC7A11 levels were negatively or positively correlated with KCTD10 or USP18, respectively. Collectively, our study defines how SLC7A11 and ferroptosis is coordinately regulated by the CRL3KCTD10/E3-USP18/DUB axis, and provides a sound rationale of drug combination to enhance anticancer efficacy.


Assuntos
Sistema y+ de Transporte de Aminoácidos , Cistina , Ferroptose , Pirimidinas , Ubiquitina Tiolesterase , Humanos , Sistema y+ de Transporte de Aminoácidos/metabolismo , Sistema y+ de Transporte de Aminoácidos/genética , Pirimidinas/farmacologia , Ubiquitina Tiolesterase/metabolismo , Ubiquitina Tiolesterase/genética , Animais , Cistina/metabolismo , Ciclopentanos/metabolismo , Ciclopentanos/farmacologia , Linhagem Celular Tumoral , Ubiquitinação , Feminino , Camundongos , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Piperazinas/farmacologia , Células HEK293
3.
Sci Rep ; 14(1): 15436, 2024 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-38965280

RESUMO

Alzheimer disease (AD) is the cause of dementia and accounts for 60-80% cases. Tumor Necrosis Factor-alpha (TNF-α) is a multifunctional cytokine that provides resistance to infections, inflammation, and cancer. It developed as a prospective therapeutic target against multiple autoimmune and inflammatory disorders. Cholinergic insufficiency is linked to Alzheimer's disease, and several cholinesterase inhibitors have been created to treat it, including naturally produced inhibitors, synthetic analogs, and hybrids. In the current study, we tried to prepared compounds may also support the discovery and development of novel therapeutic and preventative drugs for Alzheimer's using manganese tetroxide nanoparticles (Mn3O4-NPs) as a catalyst to generate compounds with excellent reaction conditions. The Biginelli synthesis yields 4-(4-cyanophenyl)-6-oxo-2-thioxohexahydropyrimidine-5-carbonitrile when the 4-cyanobenzaldehyde, ethyl cyanoacetate, and thiourea were coupled with Mn3O4-NPs to produce compound 1. This multi-component method is non-toxic, safe, and environmentally friendly. The new approach reduced the amount of chemicals used and preserved time. Compound 1 underwent reactions with methyl iodide, acrylonitrile, chloroacetone, ethyl chloroacetate, and chloroacetic acid/benzaldehyde, each of the synthetized compounds was docked with TNF-α converting enzyme. These compounds may also support the discovery and development of novel therapeutic and preventative drugs for Alzheimer's disease. The majority of the produced compounds demonstrated pharmacokinetic features, making them potentially attractive therapeutic candidates for Alzheimer's disease treatment.


Assuntos
Doença de Alzheimer , Compostos de Manganês , Simulação de Acoplamento Molecular , Nanopartículas , Óxidos , Pirimidinas , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Pirimidinas/química , Pirimidinas/farmacologia , Pirimidinas/farmacocinética , Compostos de Manganês/química , Compostos de Manganês/farmacologia , Animais , Nanopartículas/química , Óxidos/química , Óxidos/farmacologia , Humanos , Ratos , Masculino
4.
Biochemistry (Mosc) ; 89(6): 1094-1108, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38981703

RESUMO

Despite significant progress made over the past two decades in the treatment of chronic myeloid leukemia (CML), there is still an unmet need for effective and safe agents to treat patients with resistance and intolerance to the drugs used in clinic. In this work, we designed 2-arylaminopyrimidine amides of isoxazole-3-carboxylic acid, assessed in silico their inhibitory potential against Bcr-Abl tyrosine kinase, and determined their antitumor activity in K562 (CML), HL-60 (acute promyelocytic leukemia), and HeLa (cervical cancer) cells. Based on the analysis of computational and experimental data, three compounds with the antitumor activity against K562 and HL-60 cells were identified. The lead compound efficiently suppressed the growth of these cells, as evidenced by the low IC50 values of 2.8 ± 0.8 µM (K562) and 3.5 ± 0.2 µM (HL-60). The obtained compounds represent promising basic structures for the design of novel, effective, and safe anticancer drugs able to inhibit the catalytic activity of Bcr-Abl kinase by blocking the ATP-binding site of the enzyme.


Assuntos
Antineoplásicos , Desenho de Fármacos , Proteínas de Fusão bcr-abl , Inibidores de Proteínas Quinases , Humanos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Proteínas de Fusão bcr-abl/metabolismo , Células K562 , Células HeLa , Pirimidinas/farmacologia , Pirimidinas/química , Simulação de Acoplamento Molecular , Células HL-60 , Ensaios de Seleção de Medicamentos Antitumorais , Proliferação de Células/efeitos dos fármacos , Simulação por Computador
5.
Drug Dev Res ; 85(5): e22232, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38992915

RESUMO

The human aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor, plays a pivotal role in a diverse array of pathways in biological and pathophysiological events. This position AhR as a promising target for both carcinogenesis and antitumor strategies. In this study we utilized computational modeling to screen and identify FDA-approved drugs binding to the allosteric site between α2 of bHLH and PAS-A domains of AhR, with the aim of inhibiting its canonical pathway activity. Our findings indicated that nilotinib effectively fits into the allosteric pocket and forms interactions with crucial residues F82, Y76, and Y137. Binding free energy value of nilotinib is the lowest among top hits and maintains stable within its pocket throughout entire (MD) simulations time. Nilotinib has also substantial interactions with F295 and Q383 when it binds to orthosteric site and activate AhR. Surprisingly, it does not influence AhR nuclear translocation in the presence of AhR agonists; instead, it hinders the formation of the functional AhR-ARNT-DNA heterodimer assembly, preventing the upregulation of regulated enzymes like CYP1A1. Importantly, nilotinib exhibits a dual impact on AhR, modulating AhR activity via the PAS-B domain and working as a noncompetitive allosteric antagonist capable of blocking the canonical AhR signaling pathway in the presence of potent AhR agonists. These findings open a new avenue for the repositioning of nilotinib beyond its current application in diverse diseases mediated via AhR.


Assuntos
Sítio Alostérico , Receptores de Hidrocarboneto Arílico , Receptores de Hidrocarboneto Arílico/metabolismo , Receptores de Hidrocarboneto Arílico/antagonistas & inibidores , Receptores de Hidrocarboneto Arílico/química , Humanos , Regulação Alostérica/efeitos dos fármacos , Pirimidinas/farmacologia , Pirimidinas/química , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/antagonistas & inibidores , Fatores de Transcrição Hélice-Alça-Hélice Básicos/química , Simulação de Dinâmica Molecular , Aprovação de Drogas , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP1A1/antagonistas & inibidores
6.
Molecules ; 29(13)2024 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-38999049

RESUMO

Aberrant activation of hedgehog (Hh) signaling has been implicated in various cancers. Current FDA-approved inhibitors target the seven-transmembrane receptor Smoothened, but resistance to these drugs has been observed. It has been proposed that a more promising strategy to target this pathway is at the GLI1 transcription factor level. GANT61 was the first small molecule identified to directly suppress GLI-mediated activity; however, its development as a potential anti-cancer agent has been hindered by its modest activity and aqueous chemical instability. Our study aimed to identify novel GLI1 inhibitors. JChem searches identified fifty-two compounds similar to GANT61 and its active metabolite, GANT61-D. We combined high-throughput cell-based assays and molecular docking to evaluate these analogs. Five of the fifty-two GANT61 analogs inhibited activity in Hh-responsive C3H10T1/2 and Gli-reporter NIH3T3 cellular assays without cytotoxicity. Two of the GANT61 analogs, BAS 07019774 and Z27610715, reduced Gli1 mRNA expression in C3H10T1/2 cells. Treatment with BAS 07019774 significantly reduced cell viability in Hh-dependent glioblastoma and lung cancer cell lines. Molecular docking indicated that BAS 07019774 is predicted to bind to the ZF4 region of GLI1, potentially interfering with its ability to bind DNA. Our findings show promise in developing more effective and potent GLI inhibitors.


Assuntos
Proteínas Hedgehog , Simulação de Acoplamento Molecular , Piridinas , Pirimidinas , Proteína GLI1 em Dedos de Zinco , Piridinas/farmacologia , Piridinas/química , Proteína GLI1 em Dedos de Zinco/metabolismo , Proteína GLI1 em Dedos de Zinco/genética , Pirimidinas/farmacologia , Pirimidinas/química , Proteínas Hedgehog/metabolismo , Humanos , Animais , Camundongos , Linhagem Celular Tumoral , Células NIH 3T3 , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Transdução de Sinais/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos
7.
Int J Mol Sci ; 25(13)2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-39000375

RESUMO

Angiogenesis is critical for rheumatoid arthritis (RA) progression. The effects of tofacitinib, a JAK-STAT inhibitor used for RA treatment, on angiogenesis in RA are unclear. We, therefore, evaluated the levels of angiogenic factors in two systems of a human co-culture of fibroblast (HT1080) and monocytic (U937) cell lines treated with tofacitinib and in serum samples from RA patients before and after six months of tofacitinib treatment. Tofacitinib reduced CD147 levels, matrix metalloproteinase-9 (MMP-9) activity, and angiogenic potential but increased endostatin levels and secreted proteasome 20S activity. In vitro, tofacitinib did not change CD147 mRNA but increased miR-146a-5p expression and reduced STAT3 phosphorylation. We recently showed that CD147 regulates the ability of MMP-9 and secreted proteasome 20S to cleave collagen XVIIIA into endostatin. We show here that tofacitinib-enhanced endostatin levels are mediated by CD147, as CD147-siRNA or an anti-CD147 antibody blocked proteasome 20S activity. The correlation between CD147 and different disease severity scores supported this role. Lastly, tofacitinib reduced endostatin' s degradation by inhibiting cathepsin S activity and recombinant cathepsin S reversed this in both systems. Thus, tofacitinib inhibits angiogenesis by reducing pro-angiogenic factors and enhancing the anti-angiogenic factor endostatin in a dual effect mediated partly through CD147 and partly through cathepsin S.


Assuntos
Artrite Reumatoide , Basigina , Catepsinas , Endostatinas , Piperidinas , Pirimidinas , Humanos , Basigina/metabolismo , Basigina/genética , Piperidinas/farmacologia , Endostatinas/metabolismo , Endostatinas/farmacologia , Pirimidinas/farmacologia , Catepsinas/metabolismo , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Metaloproteinase 9 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Fator de Transcrição STAT3/metabolismo , Neovascularização Patológica/metabolismo , Neovascularização Patológica/tratamento farmacológico , Inibidores da Angiogênese/farmacologia , Feminino , Pessoa de Meia-Idade , Masculino , Pirróis/farmacologia , Linhagem Celular
8.
Int J Mol Sci ; 25(13)2024 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-39000566

RESUMO

Staphylococcal toxic shock syndrome (STSS) is a rare, yet potentially fatal disease caused by Staphylococcus aureus (S. aureus) enterotoxins, known as superantigens, which trigger an intense immune response. Our previous study demonstrated the protective effect of tofacitinib against murine toxin-induced shock and a beneficial effect against S. aureus sepsis. In the current study, we examined the effects of tofacitinib on T-cell response in peripheral blood using a mouse model of enterotoxin-induced shock. Our data revealed that tofacitinib suppresses the activation of both CD4+ and CD8+ T cells in peripheral blood. Furthermore, both gene and protein levels of Th1 cytokines were downregulated by tofacitinib treatment in mice with enterotoxin-induced shock. Importantly, we demonstrated that CD4+ cells, but not CD8+ cells, are pathogenic in mice with enterotoxin-induced shock. In conclusion, our findings suggest that tofacitinib treatment suppresses CD4+ T-cell activation and Th1 response, thereby aiding in protection against staphylococcal toxic shock in mice. This insight may guide the future development of novel therapies for STSS.


Assuntos
Linfócitos T CD4-Positivos , Ativação Linfocitária , Piperidinas , Pirimidinas , Choque Séptico , Infecções Estafilocócicas , Células Th1 , Animais , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Células Th1/imunologia , Células Th1/efeitos dos fármacos , Células Th1/metabolismo , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Choque Séptico/tratamento farmacológico , Choque Séptico/imunologia , Choque Séptico/induzido quimicamente , Camundongos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/microbiologia , Enterotoxinas , Staphylococcus aureus/efeitos dos fármacos , Citocinas/metabolismo , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Camundongos Endogâmicos C57BL , Feminino , Modelos Animais de Doenças , Superantígenos/imunologia
9.
Signal Transduct Target Ther ; 9(1): 181, 2024 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-38992067

RESUMO

Mitotic catastrophe (MC), which occurs under dysregulated mitosis, represents a fascinating tactic to specifically eradicate tumor cells. Whether pyroptosis can be a death form of MC remains unknown. Proteasome-mediated protein degradation is crucial for M-phase. Bortezomib (BTZ), which inhibits the 20S catalytic particle of proteasome, is approved to treat multiple myeloma and mantle cell lymphoma, but not solid tumors due to primary resistance. To date, whether and how proteasome inhibitor affected the fates of cells in M-phase remains unexplored. Here, we show that BTZ treatment, or silencing of PSMC5, a subunit of 19S regulatory particle of proteasome, causes G2- and M-phase arrest, multi-polar spindle formation, and consequent caspase-3/GSDME-mediated pyroptosis in M-phase (designated as mitotic pyroptosis). Further investigations reveal that inhibitor of WEE1/PKMYT1 (PD0166285), but not inhibitor of ATR, CHK1 or CHK2, abrogates the BTZ-induced G2-phase arrest, thus exacerbates the BTZ-induced mitotic arrest and pyroptosis. Combined BTZ and PD0166285 treatment (named BP-Combo) selectively kills various types of solid tumor cells, and significantly lessens the IC50 of both BTZ and PD0166285 compared to BTZ or PD0166285 monotreatment. Studies using various mouse models show that BP-Combo has much stronger inhibition on tumor growth and metastasis than BTZ or PD0166285 monotreatment, and no obvious toxicity is observed in BP-Combo-treated mice. These findings disclose the effect of proteasome inhibitors in inducing pyroptosis in M-phase, characterize pyroptosis as a new death form of mitotic catastrophe, and identify dual inhibition of proteasome and WEE family kinases as a promising anti-cancer strategy to selectively kill solid tumor cells.


Assuntos
Bortezomib , Proteínas de Ciclo Celular , Mitose , Complexo de Endopeptidases do Proteassoma , Proteínas Tirosina Quinases , Piroptose , Piroptose/efeitos dos fármacos , Humanos , Camundongos , Animais , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Mitose/efeitos dos fármacos , Mitose/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Complexo de Endopeptidases do Proteassoma/genética , Bortezomib/farmacologia , Linhagem Celular Tumoral , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/metabolismo , Inibidores de Proteassoma/farmacologia , Pirimidinas/farmacologia , Pirazóis/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Ensaios Antitumorais Modelo de Xenoenxerto , Gasderminas , Pirimidinonas
10.
Cells ; 13(13)2024 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-38995006

RESUMO

Immunotherapies have shown significant promise as an impactful strategy in cancer treatment. However, in glioblastoma multiforme (GBM), the most prevalent primary brain tumor in adults, these therapies have demonstrated lower efficacy than initially anticipated. Consequently, there is an urgent need for strategies to enhance the effectiveness of immune treatments. AURKA has been identified as a potential drug target for GBM treatment. An analysis of the GBM cell transcriptome following AURKA inhibition revealed a potential influence on the immune system. Our research revealed that AURKA influenced PD-L1 levels in various GBM model systems in vitro and in vivo. Disrupting AURKA function genetically led to reduced PD-L1 levels and increased MHC-I expression in both established and patient-derived xenograft GBM cultures. This process involved both transcriptional and non-transcriptional pathways, partly implicating GSK3ß. Interfering with AURKA also enhanced NK-cell-mediated elimination of GBM by reducing PD-L1 expression, as evidenced in rescue experiments. Furthermore, using a mouse model that mimics GBM with patient-derived cells demonstrated that Alisertib decreased PD-L1 expression in living organisms. Combination therapy involving anti-PD-1 treatment and Alisertib significantly prolonged overall survival compared to vehicle treatment. These findings suggest that targeting AURKA could have therapeutic implications for modulating the immune environment within GBM cells.


Assuntos
Aurora Quinase A , Antígeno B7-H1 , Glioblastoma , Células Matadoras Naturais , Aurora Quinase A/metabolismo , Aurora Quinase A/antagonistas & inibidores , Humanos , Glioblastoma/patologia , Glioblastoma/tratamento farmacológico , Glioblastoma/imunologia , Glioblastoma/genética , Antígeno B7-H1/metabolismo , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/metabolismo , Animais , Camundongos , Linhagem Celular Tumoral , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Azepinas/farmacologia , Pirimidinas/farmacologia , Citotoxicidade Imunológica/efeitos dos fármacos , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Sci Adv ; 10(27): eadg3747, 2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-38959314

RESUMO

Vaccination can help prevent infection and can also be used to treat cancer, allergy, and potentially even drug overdose. Adjuvants enhance vaccine responses, but currently, the path to their advancement and development is incremental. We used a phenotypic small-molecule screen using THP-1 cells to identify nuclear factor-κB (NF-κB)-activating molecules followed by counterscreening lead target libraries with a quantitative tumor necrosis factor immunoassay using primary human peripheral blood mononuclear cells. Screening on primary cells identified an imidazopyrimidine, dubbed PVP-037. Moreover, while PVP-037 did not overtly activate THP-1 cells, it demonstrated broad innate immune activation, including NF-κB and cytokine induction from primary human leukocytes in vitro as well as enhancement of influenza and SARS-CoV-2 antigen-specific humoral responses in mice. Several de novo synthesis structural enhancements iteratively improved PVP-037's in vitro efficacy, potency, species-specific activity, and in vivo adjuvanticity. Overall, we identified imidazopyrimidine Toll-like receptor-7/8 adjuvants that act in synergy with oil-in-water emulsion to enhance immune responses.


Assuntos
Adjuvantes Imunológicos , Pirimidinas , Receptor 7 Toll-Like , Receptor 8 Toll-Like , Humanos , Receptor 8 Toll-Like/agonistas , Receptor 8 Toll-Like/metabolismo , Animais , Camundongos , Adjuvantes Imunológicos/farmacologia , Receptor 7 Toll-Like/agonistas , Pirimidinas/farmacologia , Pirimidinas/química , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/imunologia , Imidazóis/farmacologia , Imidazóis/química , Células THP-1 , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/imunologia , COVID-19/virologia , COVID-19/imunologia , NF-kappa B/metabolismo , Feminino , Descoberta de Drogas/métodos , Imunidade Inata/efeitos dos fármacos
12.
J Agric Food Chem ; 72(28): 15427-15448, 2024 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-38967261

RESUMO

With fungal diseases posing a major threat to agricultural production, the application of fungicides to control related diseases is often considered necessary to ensure the world's food supply. The search for new bioactive agents has long been a priority in crop protection due to the continuous development of resistance against currently used types of active compounds. Heterocyclic compounds are an inseparable part of the core structures of numerous lead compounds, these rings constitute pharmacophores of a significant number of fungicides developed over the past decade by agrochemists. Among heterocycles, nitrogen-based compounds play an essential role. To date, diazole (imidazole and pyrazole) and diazine (pyrimidine, pyridazine, and pyrazine) derivatives make up an important series of synthetic fungicides. In recent years, many reports have been published on the design, synthesis, and study of the fungicidal activity of these scaffolds, but there was a lack of a comprehensive classified review on nitrogen-containing scaffolds. Regarding this issue, here we have reviewed the published articles on the fungicidal activity of the diazole and diazine families. In current review, we have classified the molecules synthesized so far based on the size of the ring.


Assuntos
Fungicidas Industriais , Fungicidas Industriais/química , Fungicidas Industriais/farmacologia , Fungicidas Industriais/síntese química , Fungos/efeitos dos fármacos , Fungos/crescimento & desenvolvimento , Pirazóis/química , Pirazóis/farmacologia , Desenho de Fármacos , Doenças das Plantas/microbiologia , Doenças das Plantas/prevenção & controle , Pirimidinas/química , Pirimidinas/farmacologia , Estrutura Molecular , Imidazóis/química , Imidazóis/farmacologia
13.
Environ Sci Pollut Res Int ; 31(32): 44789-44799, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38954331

RESUMO

Cyprodinil, a globally utilized broad-spectrum pyrimidine amine fungicide, has been observed to elicit cardiac abnormality. Resveratrol (RSV), a naturally occurring polyphenolic compound, showcases remarkable defensive properties in nurturing cardiac development. To investigate whether RSV could protect against cyprodinil-induced cardiac defects, we exposed zebrafish embryos to cyprodinil (500 µg/L) in the presence or absence of RSV (1 µM). Our results showed that RSV significantly mitigated the decrease of survival rate and embryo movement and the hatching delay induced by cyprodinil. In addition, RSV also improved cyprodinil-induced zebrafish cardiac developmental toxicity, including pericardial edema and cardiac function impairment. In mechanism, RSV attenuated the cyprodinil-induced changes in mRNA expression involved in cardiac development, such as myh6, myl7, tbx5, and gata4, and calcium ion channels, such as ncx1h, slc8a4a, and atp2a2b. We further showed that RSV might inhibit the activity of aryl hydrocarbon receptor (AhR) signaling pathways induced by cyprodinil. In summary, our findings establish that the protective effects of RSV against the cardiac developmental toxicity are induced by cyprodinil due to its remarkable ability to inhibit AhR activity. Our findings not only shed light on a new avenue for regulating and ensuring the safe utilization of cyprodinil but also presents a novel concept to promote its responsible use.


Assuntos
Coração , Pirimidinas , Receptores de Hidrocarboneto Arílico , Resveratrol , Peixe-Zebra , Animais , Peixe-Zebra/embriologia , Resveratrol/farmacologia , Pirimidinas/toxicidade , Pirimidinas/farmacologia , Coração/efeitos dos fármacos , Embrião não Mamífero/efeitos dos fármacos
14.
Hematol Oncol ; 42(4): e3294, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38847437

RESUMO

Bruton's tyrosine kinase (BTK) inhibitors have revolutionized the treatment of B-cell malignancies. They target BTK, a key effector in the B-cell receptor (BCR) signaling pathway, crucial for B-cell survival and proliferation. The first-in-class irreversible BTK inhibitor, ibrutinib, was approved for various B-cell malignancies but has limitations due to off-target effects. Second-generation inhibitors, such as acalabrutinib and zanubrutinib, offer improved selectivity and reduced side effects. However, resistance to BTK inhibitors, driven by BTK mutations, remains a challenge. Combinatorial therapies with PI3K inhibitors, immune checkpoint inhibitors, BH3 mimetics, and anti-CD20 antibodies show promise in overcoming resistance. Noncovalent BTK inhibitors and proteolysis-targeting chimeras (PROTACs) are emerging strategies with potential to combat resistance. Overall, advancements in BTK-targeted therapies provide hope for improved outcomes in patients with B-cell malignancies and a promising avenue to address drug resistance. Further research is needed to optimize combination therapies and identify optimal treatment regimens.


Assuntos
Tirosina Quinase da Agamaglobulinemia , Resistencia a Medicamentos Antineoplásicos , Piperidinas , Inibidores de Proteínas Quinases , Pirazóis , Pirimidinas , Humanos , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Pirazóis/uso terapêutico , Pirazóis/farmacologia , Pirimidinas/uso terapêutico , Pirimidinas/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Piperidinas/uso terapêutico , Piperidinas/farmacologia , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/metabolismo , Linfoma de Células B/patologia
15.
Int J Mol Sci ; 25(12)2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38928035

RESUMO

The development of resistance to tyrosine kinase inhibitors (TKIs) is a major cause of treatment failure in metastatic renal cell carcinoma (mRCC). A deeper understanding of the metabolic mechanisms associated with TKI resistance is critical for refining therapeutic strategies. In this study, we established resistance to sunitinib and pazopanib by exposing a parental Caki-1 cell line to increasing concentrations of sunitinib and pazopanib. The intracellular and extracellular metabolome of sunitinib- and pazopanib-resistant mRCC cells were investigated using a nuclear magnetic resonance (NMR)-based metabolomics approach. Data analysis included multivariate and univariate methods, as well as pathway and network analyses. Distinct metabolic signatures in sunitinib- and pazopanib-resistant RCC cells were found for the first time in this study. A common metabolic reprogramming pattern was observed in amino acid, glycerophospholipid, and nicotinate and nicotinamide metabolism. Sunitinib-resistant cells exhibited marked alterations in metabolites involved in antioxidant defence mechanisms, while pazopanib-resistant cells showed alterations in metabolites associated with energy pathways. Sunitinib-resistant RCC cells demonstrated an increased ability to proliferate, whereas pazopanib-resistant cells appeared to restructure their energy metabolism and undergo alterations in pathways associated with cell death. These findings provide potential targets for novel therapeutic strategies to overcome TKI resistance in mRCC through metabolic regulation.


Assuntos
Carcinoma de Células Renais , Resistencia a Medicamentos Antineoplásicos , Indazóis , Neoplasias Renais , Metabolômica , Inibidores de Proteínas Quinases , Pirimidinas , Sulfonamidas , Sunitinibe , Humanos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Renais/metabolismo , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Inibidores de Proteínas Quinases/farmacologia , Linhagem Celular Tumoral , Sunitinibe/farmacologia , Sulfonamidas/farmacologia , Metabolômica/métodos , Indazóis/farmacologia , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Pirimidinas/farmacologia , Metaboloma/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos
16.
J Am Heart Assoc ; 13(12): e032357, 2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38842296

RESUMO

BACKGROUND: We recently demonstrated that acute administration of ibrutinib, a Bruton's tyrosine kinase inhibitor used in chemotherapy for blood malignancies, increases ventricular arrhythmia (VA) vulnerability. A pathway of ibrutinib-induced vulnerability to VA that can be modulated for cardioprotection remains unclear. METHODS AND RESULTS: The effects of ibrutinib on cardiac electrical activity and Ca2+ dynamics were investigated in Langendorff-perfused hearts using optical mapping. We also conducted Western blotting analysis to evaluate the impact of ibrutinib on various regulatory and Ca2+-handling proteins in rat cardiac tissues. Treatment with ibrutinib (10 mg/kg per day) for 4 weeks was associated with an increased VA inducibility (72.2%±6.3% versus 38.9±7.0% in controls, P<0.002) and shorter action potential durations during pacing at various frequencies (P<0.05). Ibrutinib also decreased heart rate thresholds for beat-to-beat duration alternans of the cardiac action potential (P<0.05). Significant changes in myocardial Ca2+ transients included lower amplitude alternans ratios (P<0.05), longer times-to-peak (P<0.05), and greater spontaneous intracellular Ca2+ elevations (P<0.01). We also found lower abundance and phosphorylation of myocardial AMPK (5'-adenosine monophosphate-activated protein kinase), indicating reduced AMPK activity in hearts after ibrutinib treatment. An acute treatment with the AMPK activator 5-aminoimidazole-4-carboxamide-1-ß-D-ribofuranoside ameliorated abnormalities in action potential and Ca2+ dynamics, and significantly reduced VA inducibility (37.1%±13.4% versus 72.2%±6.3% in the absence of 5-aminoimidazole-4-carboxamide-1-ß-D-ribofuranoside, P<0.05) in hearts from ibrutinib-treated rats. CONCLUSIONS: VA vulnerability inflicted by ibrutinib may be mediated in part by an impairment of myocardial AMPK activity. Pharmacological activation of AMPK may be a protective strategy against ibrutinib-induced cardiotoxicity.


Assuntos
Proteínas Quinases Ativadas por AMP , Potenciais de Ação , Adenina , Arritmias Cardíacas , Piperidinas , Pirazóis , Pirimidinas , Animais , Adenina/análogos & derivados , Adenina/farmacologia , Piperidinas/farmacologia , Potenciais de Ação/efeitos dos fármacos , Pirimidinas/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , Pirazóis/farmacologia , Masculino , Arritmias Cardíacas/induzido quimicamente , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/fisiopatologia , Arritmias Cardíacas/prevenção & controle , Inibidores de Proteínas Quinases/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Preparação de Coração Isolado , Cálcio/metabolismo , Ratos , Modelos Animais de Doenças , Ratos Sprague-Dawley , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/enzimologia , Miócitos Cardíacos/patologia , Sinalização do Cálcio/efeitos dos fármacos , Fatores de Tempo
17.
Int J Mol Sci ; 25(11)2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38892396

RESUMO

Cardiac arrhythmias remain a significant concern with Ibrutinib (IBR), a first-generation Bruton's tyrosine kinase inhibitor (BTKi). Acalabrutinib (ABR), a next-generation BTKi, is associated with reduced atrial arrhythmia events. However, the role of ABR in ventricular arrhythmia (VA) has not been adequately evaluated. Our study aimed to investigate VA vulnerability and ventricular electrophysiology following chronic ABR therapy in male Sprague-Dawley rats utilizing epicardial optical mapping for ventricular voltage and Ca2+ dynamics and VA induction by electrical stimulation in ex-vivo perfused hearts. Ventricular tissues were snap-frozen for protein analysis for sarcoplasmic Ca2+ and metabolic regulatory proteins. The results show that both ABR and IBR treatments increased VA vulnerability, with ABR showing higher VA regularity index (RI). IBR, but not ABR, is associated with the abbreviation of action potential duration (APD) and APD alternans. Both IBR and ABR increased diastolic Ca2+ leak and Ca2+ alternans, reduced conduction velocity (CV), and increased CV dispersion. Decreased SERCA2a expression and AMPK phosphorylation were observed with both treatments. Our results suggest that ABR treatment also increases the risk of VA by inducing proarrhythmic changes in Ca2+ signaling and membrane electrophysiology, as seen with IBR. However, the different impacts of these two BTKi on ventricular electrophysiology may contribute to differences in VA vulnerability and distinct VA characteristics.


Assuntos
Tirosina Quinase da Agamaglobulinemia , Arritmias Cardíacas , Benzamidas , Piperidinas , Ratos Sprague-Dawley , Animais , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Masculino , Ratos , Tirosina Quinase da Agamaglobulinemia/metabolismo , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/induzido quimicamente , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Potenciais de Ação/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/farmacologia , Cálcio/metabolismo , Adenina/análogos & derivados , Adenina/farmacologia , Adenina/efeitos adversos , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/metabolismo , Ventrículos do Coração/fisiopatologia , Pirimidinas/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Pirazóis/farmacologia
18.
Cancer Med ; 13(11): e7291, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38826119

RESUMO

BACKGROUND: We previously reported that metastases are generally characterized by a core program of gene expression that activates tissue remodeling/vascularization, alters ion homeostasis, induces the oxidative metabolism, and silences extracellular matrix interactions. This core program distinguishes metastases from their originating primary tumors as well as from their destination host tissues. Therefore, the gene products involved are potential targets for anti-metastasis drug treatment. METHODS: Because the silencing of extracellular matrix interactions predisposes to anoiks in the absence of active survival mechanisms, we tested inhibitors against the other three components. RESULTS: Individually, the low-specificity VEGFR blocker pazopanib (in vivo combined with marimastat), the antioxidant dimethyl sulfoxide (or the substitute atovaquone, which is approved for internal administration), and the ionic modulators bumetanide and tetrathiomolybdate inhibited soft agar colony formation by breast and pancreatic cancer cell lines. The individual candidate agents have a record of use in humans (with limited efficacy when administered individually) and are available for repurposing. In combination, the effects of these drugs were additive or synergistic. In two mouse models of cancer (utilizing 4T1 cells or B16-F10 cells), the combination treatment with these medications, applied immediately (to prevent metastasis formation) or after a delay (to suppress established metastases), dramatically reduced the occurrence of disseminated foci. CONCLUSIONS: The combination of tissue remodeling inhibitors, suppressors of the oxidative metabolism, and ion homeostasis modulators has very strong promise for the treatment of metastases by multiple cancers.


Assuntos
Indazóis , Pirimidinas , Sulfonamidas , Animais , Humanos , Camundongos , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Sulfonamidas/administração & dosagem , Linhagem Celular Tumoral , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Pirimidinas/administração & dosagem , Feminino , Indazóis/farmacologia , Indazóis/uso terapêutico , Indazóis/administração & dosagem , Metástase Neoplásica , Molibdênio/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Bioorg Med Chem ; 108: 117774, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38833750

RESUMO

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb), which remains a significant global health challenge. The emergence of multidrug-resistant (MDR) Mtb strains imposes the development of new therapeutic strategies. This study focuses on the identification and evaluation of potential inhibitors against Mtb H37Ra through a comprehensive screening of an in-house chemolibrary. Subsequently, a promising pyrimidine derivative (LQM495) was identified as promising and then further investigated by experimental and in silico approaches. In this context, computational techniques were used to elucidate the potential molecular target underlying the inhibitory action of LQM495. Then, a consensus reverse docking (CRD) protocol was used to investigate the interactions between this compound and several Mtb targets. Out of 98 Mtb targets investigated, the enhanced intracellular survival (Eis) protein emerged as a target for LQM495. To gain insights into the stability of the LQM495-Eis complex, molecular dynamics (MD) simulations were conducted over a 400 ns trajectory. Further insights into its binding modes within the Eis binding site were obtained through a Quantum mechanics (QM) approach, using density functional theory (DFT), with B3LYP/D3 basis set. These calculations shed light on the electronic properties and reactivity of LQM495. Subsequently, inhibition assays and kinetic studies of the Eis activity were used to investigate the activity of LQM495. Then, an IC50 value of 11.0 ± 1.4 µM was found for LQM495 upon Eis protein. Additionally, its Vmax, Km, and Ki parameters indicated that it is a competitive inhibitor. Lastly, this study presents LQM495 as a promising inhibitor of Mtb Eis protein, which could be further explored for developing novel anti-TB drugs in the future.


Assuntos
Antituberculosos , Proteínas de Bactérias , Simulação de Acoplamento Molecular , Mycobacterium tuberculosis , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/enzimologia , Antituberculosos/farmacologia , Antituberculosos/química , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/metabolismo , Relação Estrutura-Atividade , Testes de Sensibilidade Microbiana , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Estrutura Molecular , Acetiltransferases/antagonistas & inibidores , Acetiltransferases/metabolismo , Relação Dose-Resposta a Droga , Simulação de Dinâmica Molecular , Pirimidinas/química , Pirimidinas/farmacologia , Pirimidinas/síntese química
20.
Bioorg Med Chem ; 108: 117775, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38851000

RESUMO

4-[(5-[2-Methyl-5-(methylsulfonyl)pentan-2-yl]sulfonylpyrimidin-4-yl)amino]benzonitrile 2 was identified as a novel potent aldosterone synthase inhibitor. Compound 2 was found to inhibit human CYP11B2 in the nanomolar range, and showed an aldosterone-lowering effect in a furosemide-treated cynomolgus monkey model. Although human CYP11B2 has the high homology sequence with human CYP11B1, compound 2 showed more than 80 times higher selectivity over human CYP11B1 in vitro.


Assuntos
Citocromo P-450 CYP11B2 , Inibidores Enzimáticos , Macaca fascicularis , Pirimidinas , Citocromo P-450 CYP11B2/antagonistas & inibidores , Citocromo P-450 CYP11B2/metabolismo , Humanos , Animais , Pirimidinas/química , Pirimidinas/farmacologia , Pirimidinas/síntese química , Relação Estrutura-Atividade , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Aldosterona/metabolismo , Aldosterona/química , Estrutura Molecular
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