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1.
Int J Mol Sci ; 25(13)2024 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-39000295

RESUMO

Olprinone (OLP) is a selective inhibitor of phosphodiesterase III and is used clinically in patients with heart failure and those undergoing cardiac surgery; however, little is known about the effects of OLP on hepatoprotection. The purpose of this study aimed to determine whether OLP has protective effects in in vivo and in vitro rat models of endotoxin-induced liver injury after hepatectomy and to clarify the mechanisms of action of OLP. In the in vivo model, rats underwent 70% partial hepatectomy and lipopolysaccharide treatment (PH/LPS). OLP administration increased survival by 85.7% and decreased tumor necrosis factor-α, C-X-C motif chemokine ligand 1, and inducible nitric oxide synthase (iNOS) mRNA expression in the livers of rats treated with PH/LPS. OLP also suppressed nuclear translocation and/or DNA binding ability of nuclear factor kappa B (NF-κB). Pathological liver damage induced by PH/LPS was alleviated and neutrophil infiltration was reduced by OLP. Primary cultured rat hepatocytes treated with the pro-inflammatory cytokine interleukin-1ß (IL-1ß) were used as a model of in vitro liver injury. Co-treatment with OLP inhibited dose-dependently IL-1ß-stimulated iNOS induction and NF-κB activation. Our results demonstrate that OLP may partially inhibit the induction of several inflammatory mediators through the suppression of NF-κB and thus prevent liver injury induced by endotoxin after liver resection.


Assuntos
Modelos Animais de Doenças , Hepatectomia , Hepatócitos , Imidazóis , NF-kappa B , Óxido Nítrico Sintase Tipo II , Piridonas , Animais , Hepatectomia/efeitos adversos , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Ratos , Masculino , Piridonas/farmacologia , Piridonas/uso terapêutico , NF-kappa B/metabolismo , Imidazóis/farmacologia , Óxido Nítrico Sintase Tipo II/metabolismo , Inibidores da Fosfodiesterase 3/farmacologia , Inibidores da Fosfodiesterase 3/uso terapêutico , Interleucina-1beta/metabolismo , Lipopolissacarídeos/efeitos adversos , Lipopolissacarídeos/toxicidade , Sepse/tratamento farmacológico , Ratos Sprague-Dawley , Células Cultivadas , Fator de Necrose Tumoral alfa/metabolismo , Quimiocina CXCL1/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Fígado/metabolismo
2.
Int J Mol Sci ; 25(13)2024 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-39000409

RESUMO

Cardiac fibrosis is a severe outcome of Chagas disease (CD), caused by the protozoan Trypanosoma cruzi. Clinical evidence revealed a correlation between fibrosis levels with impaired cardiac performance in CD patients. Therefore, we sought to analyze the effect of inhibitors of TGF-ß (pirfenidone), p38-MAPK (losmapimod) and c-Jun (SP600125) on the modulation of collagen deposition in cardiac fibroblasts (CF) and in vivo models of T. cruzi chronic infection. Sirius Red/Fast Green dye was used to quantify both collagen expression and total protein amount, assessing cytotoxicity. The compounds were also used to treat C57/Bl6 mice chronically infected with T. cruzi, Brazil strain. We identified an anti-fibrotic effect in vitro for pirfenidone (TGF-ß inhibitor, IC50 114.3 µM), losmapimod (p38 inhibitor, IC50 17.6 µM) and SP600125 (c-Jun inhibitor, IC50 3.9 µM). This effect was independent of CF proliferation since these compounds do not affect T. cruzi-induced host cell multiplication as measured by BrdU incorporation. Assays of chronic infection of mice with T. cruzi have shown a reduction in heart collagen by pirfenidone. These results propose a novel approach to fibrosis therapy in CD, with the prospect of repurposing pirfenidone to prevent the onset of ECM accumulation in the hearts of the patients.


Assuntos
Cardiomiopatia Chagásica , Fibrose , Camundongos Endogâmicos C57BL , Piridonas , Animais , Piridonas/farmacologia , Piridonas/uso terapêutico , Cardiomiopatia Chagásica/tratamento farmacológico , Cardiomiopatia Chagásica/parasitologia , Cardiomiopatia Chagásica/metabolismo , Cardiomiopatia Chagásica/patologia , Camundongos , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/parasitologia , Miocárdio/patologia , Miocárdio/metabolismo , Colágeno/metabolismo , Trypanosoma cruzi/efeitos dos fármacos , Humanos , Doença Crônica , Fator de Crescimento Transformador beta/metabolismo , Modelos Animais de Doenças , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Masculino , Antracenos
3.
Int J Mol Sci ; 25(13)2024 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-39000539

RESUMO

Isocitrate dehydrogenase 1 (IDH1) is a necessary enzyme for cellular respiration in the tricarboxylic acid cycle. Mutant isocitrate dehydrogenase 1 (mIDH1) has been detected overexpressed in a variety of cancers. mIDH1 inhibitor ivosidenib (AG-120) was only approved by the Food and Drug Administration (FDA) for marketing, nevertheless, a range of resistance has been frequently reported. In this study, several mIDH1 inhibitors with the common backbone pyridin-2-one were explored using the three-dimensional structure-activity relationship (3D-QSAR), scaffold hopping, absorption, distribution, metabolism, excretion (ADME) prediction, and molecular dynamics (MD) simulations. Comparative molecular field analysis (CoMFA, R2 = 0.980, Q2 = 0.765) and comparative molecular similarity index analysis (CoMSIA, R2 = 0.997, Q2 = 0.770) were used to build 3D-QSAR models, which yielded notably decent predictive ability. A series of novel structures was designed through scaffold hopping. The predicted pIC50 values of C3, C6, and C9 were higher in the model of 3D-QSAR. Additionally, MD simulations culminated in the identification of potent mIDH1 inhibitors, exhibiting strong binding interactions, while the analyzed parameters were free energy landscape (FEL), radius of gyration (Rg), solvent accessible surface area (SASA), and polar surface area (PSA). Binding free energy demonstrated that C2 exhibited the highest binding free energy with IDH1, which was -93.25 ± 5.20 kcal/mol. This research offers theoretical guidance for the rational design of novel mIDH1 inhibitors.


Assuntos
Isocitrato Desidrogenase , Simulação de Dinâmica Molecular , Relação Quantitativa Estrutura-Atividade , Isocitrato Desidrogenase/antagonistas & inibidores , Isocitrato Desidrogenase/química , Isocitrato Desidrogenase/metabolismo , Isocitrato Desidrogenase/genética , Humanos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Piridonas/química , Piridonas/farmacologia
4.
Oncol Res ; 32(7): 1197-1207, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38948022

RESUMO

Breast cancer, a predominant global health issue, requires ongoing exploration of new therapeutic strategies. Palbociclib (PAL), a well-known cyclin-dependent kinase (CDK) inhibitor, plays a critical role in breast cancer treatment. While its efficacy is recognized, the interplay between PAL and cellular autophagy, particularly in the context of the RAF/MEK/ERK signaling pathway, remains insufficiently explored. This study investigates PAL's inhibitory effects on breast cancer using both in vitro (MCF7 and MDA-MB-468 cells) and in vivo (tumor-bearing nude mice) models. Aimed at elucidating the impact of PAL on autophagic processes and exploring the potential of combining it with trametinib (TRA), an MEK inhibitor, our research seeks to address the challenge of PAL-induced drug resistance. Our findings reveal that PAL significantly decreases the viability of MCF7 and MDA-MB-468 cells and reduces tumor size in mice while showing minimal cytotoxicity in MCF10A cells. However, PAL also induces protective autophagy, potentially leading to drug resistance via the RAF/MEK/ERK pathway activation. Introducing TRA effectively neutralized this autophagy, enhancing PAL's anti-tumor efficacy. A combination of PAL and TRA synergistically reduced cell viability and proliferation, and in vivo studies showed notable tumor size reduction. In conclusion, the PAL and TRA combination emerges as a promising strategy for overcoming PAL-induced resistance, offering a new horizon in breast cancer treatment.


Assuntos
Autofagia , Neoplasias da Mama , Piperazinas , Piridinas , Piridonas , Pirimidinonas , Ensaios Antitumorais Modelo de Xenoenxerto , Humanos , Animais , Autofagia/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Piridinas/farmacologia , Piridinas/uso terapêutico , Piridonas/farmacologia , Piridonas/uso terapêutico , Feminino , Pirimidinonas/farmacologia , Pirimidinonas/uso terapêutico , Camundongos , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camundongos Nus , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Sobrevivência Celular/efeitos dos fármacos , Células MCF-7
5.
Anal Cell Pathol (Amst) ; 2024: 2751280, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38946862

RESUMO

Background: Biliary atresia (BA) is a devastating congenital disease characterized by inflammation and progressive liver fibrosis. Activation of hepatic stellate cells (HSCs) plays a central role in the pathogenesis of hepatic fibrosis. Our study aimed to investigate the pharmacological effect and potential mechanism of pirfenidone (PFD) and andrographolide (AGP) separately and together on liver fibrosis of BA. Materials and Methods: The bile ducts of male C57BL/6J mice were ligated or had the sham operation. The in vivo effects of PFD and/or AGP on liver fibrosis of BA were evaluated. Human hepatic stellate cells (LX-2) were also treated with PFD and/or AGP in vitro. Results: PFD and/or AGP ameliorates liver fibrosis and inflammation in the mice model of BA, as evidenced by significant downregulated in the accumulation of collagen fibers, hepatic fibrosis markers (α-SMA, collagen I, and collagen IV), and inflammatory markers (IL-1ß, IL-6, and TNF-α). Moreover, compared with monotherapy, these changes are more obvious in the combined treatment of PFD and AGP. Consistent with animal experiments, hepatic fibrosis markers (α-SMA, collagen I, and CTGF) and inflammatory markers (IL-1ß, IL-6, and TNF-α) were significantly decreased in activated LX-2 cells after PFD and/or AGP treatment. In addition, PFD and/or AGP inhibited the activation of HSCs by blocking the TGF-ß/Smad signaling pathway, and the combined treatment of PFD and AGP synergistically inhibited the phosphorylation of Smad2 and Smad3. Conclusion: The combined application of PFD and AGP exerted superior inhibitive effects on HSC activation and liver fibrosis by mediating the TGF-ß/Smad signaling pathway as compared to monotherapy. Therefore, the combination of PFD and AGP may be a promising treatment strategy for liver fibrosis in BA.


Assuntos
Diterpenos , Células Estreladas do Fígado , Cirrose Hepática , Camundongos Endogâmicos C57BL , Piridonas , Transdução de Sinais , Proteínas Smad , Fator de Crescimento Transformador beta , Células Estreladas do Fígado/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Animais , Cirrose Hepática/patologia , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Transdução de Sinais/efeitos dos fármacos , Diterpenos/farmacologia , Diterpenos/uso terapêutico , Masculino , Fator de Crescimento Transformador beta/metabolismo , Proteínas Smad/metabolismo , Humanos , Piridonas/farmacologia , Linhagem Celular , Camundongos , Atresia Biliar/patologia , Atresia Biliar/tratamento farmacológico , Atresia Biliar/metabolismo , Modelos Animais de Doenças , Quimioterapia Combinada
6.
Bioorg Med Chem Lett ; 109: 129849, 2024 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-38876177

RESUMO

Clinical studies have shown that inhibitors of bromodomain and extra-terminal domain (BET) proteins, particularly BRD4, have antitumor activity and efficacy. The BET protein has two domains, BD1 and BD2, and we previously focused on BD1 and reported orally bioavailable BD1-selective inhibitors. In this study, we obtained a BD1 inhibitor, a more potent and highly selective pyrazolopyridone derivative 13a, and confirmed its in vivo efficacy.


Assuntos
Piridonas , Humanos , Administração Oral , Relação Estrutura-Atividade , Animais , Piridonas/química , Piridonas/farmacologia , Piridonas/síntese química , Piridonas/farmacocinética , Pirazóis/química , Pirazóis/farmacologia , Pirazóis/síntese química , Descoberta de Drogas , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/metabolismo , Estrutura Molecular , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/metabolismo , Camundongos , Domínios Proteicos , Relação Dose-Resposta a Droga , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Ratos , Proteínas que Contêm Bromodomínio
7.
Nat Commun ; 15(1): 4893, 2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38849340

RESUMO

Amyotrophic lateral sclerosis (ALS) is a debilitating motor neuron disease and lacks effective disease-modifying treatments. This study utilizes a comprehensive multiomic approach to investigate the early and sex-specific molecular mechanisms underlying ALS. By analyzing the prefrontal cortex of 51 patients with sporadic ALS and 50 control subjects, alongside four transgenic mouse models (C9orf72-, SOD1-, TDP-43-, and FUS-ALS), we have uncovered significant molecular alterations associated with the disease. Here, we show that males exhibit more pronounced changes in molecular pathways compared to females. Our integrated analysis of transcriptomes, (phospho)proteomes, and miRNAomes also identified distinct ALS subclusters in humans, characterized by variations in immune response, extracellular matrix composition, mitochondrial function, and RNA processing. The molecular signatures of human subclusters were reflected in specific mouse models. Our study highlighted the mitogen-activated protein kinase (MAPK) pathway as an early disease mechanism. We further demonstrate that trametinib, a MAPK inhibitor, has potential therapeutic benefits in vitro and in vivo, particularly in females, suggesting a direction for developing targeted ALS treatments.


Assuntos
Esclerose Lateral Amiotrófica , Modelos Animais de Doenças , Sistema de Sinalização das MAP Quinases , Camundongos Transgênicos , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/tratamento farmacológico , Esclerose Lateral Amiotrófica/metabolismo , Humanos , Feminino , Animais , Masculino , Camundongos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Piridonas/farmacologia , Piridonas/uso terapêutico , Proteína FUS de Ligação a RNA/metabolismo , Proteína FUS de Ligação a RNA/genética , Córtex Pré-Frontal/metabolismo , Transcriptoma , Superóxido Dismutase-1/genética , Superóxido Dismutase-1/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Pessoa de Meia-Idade , MicroRNAs/genética , MicroRNAs/metabolismo , Proteína C9orf72/genética , Proteína C9orf72/metabolismo , Caracteres Sexuais , Idoso , Fatores Sexuais , Pirimidinonas
8.
Cells ; 13(12)2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38920644

RESUMO

Hepatocellular carcinoma (HCC) development is associated with altered modifications in DNA methylation, changing transcriptional regulation. Emerging evidence indicates that DNA methyltransferase 1 (DNMT1) plays a key role in the carcinogenesis process. This study aimed to investigate how pirfenidone (PFD) modifies this pathway and the effect generated by the association between c-Myc expression and DNMT1 activation. Rats F344 were used for HCC development using 50 mg/kg of diethylnitrosamine (DEN) and 25 mg/kg of 2-Acetylaminofluorene (2-AAF). The HCC/PFD group received simultaneous doses of 300 mg/kg of PFD. All treatments lasted 12 weeks. On the other hand, HepG2 cells were used to evaluate the effects of PFD in restoring DNA methylation in the presence of the inhibitor 5-Aza. Histopathological, biochemical, immunohistochemical, and western blot analysis were carried out and our findings showed that PFD treatment reduced the amount and size of tumors along with decreased Glipican-3, ß-catenin, and c-Myc expression in nuclear fractions. Also, this treatment improved lipid metabolism by modulating PPARγ and SREBP1 signaling. Interestingly, PFD augmented DNMT1 and DNMT3a protein expression, which restores global methylation, both in our in vivo and in vitro models. In conclusion, our results suggest that PFD could slow down HCC development by controlling DNA methylation.


Assuntos
Carcinoma Hepatocelular , DNA (Citosina-5-)-Metiltransferase 1 , Metilação de DNA , Antígeno Nuclear de Célula em Proliferação , Piridonas , Animais , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , DNA (Citosina-5-)-Metiltransferase 1/genética , Metilação de DNA/efeitos dos fármacos , Metilação de DNA/genética , Piridonas/farmacologia , Ratos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Humanos , Células Hep G2 , Antígeno Nuclear de Célula em Proliferação/metabolismo , Masculino , Ratos Endogâmicos F344 , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Dietilnitrosamina , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Neoplasias Hepáticas Experimentais/patologia , Neoplasias Hepáticas Experimentais/metabolismo , Neoplasias Hepáticas Experimentais/genética
9.
Molecules ; 29(12)2024 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-38930946

RESUMO

Cisplatin, a platinum-based chemotherapeutic, is effective against various solid tumors, but its use is often limited by its nephrotoxic effects. This study evaluated the protective effects of trametinib, an FDA-approved selective inhibitor of mitogen-activated protein kinase kinase 1/2 (MEK1/2), against cisplatin-induced acute kidney injury (AKI) in mice. The experimental design included four groups, control, trametinib, cisplatin, and a combination of cisplatin and trametinib, each consisting of eight mice. Cisplatin was administered intraperitoneally at a dose of 20 mg/kg to induce kidney injury, while trametinib was administered via oral gavage at 3 mg/kg daily for three days. Assessments were conducted 72 h after cisplatin administration. Our results demonstrate that trametinib significantly reduces the phosphorylation of MEK1/2 and extracellular signal-regulated kinase 1/2 (ERK1/2), mitigated renal dysfunction, and ameliorated histopathological abnormalities. Additionally, trametinib significantly decreased macrophage infiltration and the expression of pro-inflammatory cytokines in the kidneys. It also lowered lipid peroxidation by-products, restored the reduced glutathione/oxidized glutathione ratio, and downregulated NADPH oxidase 4. Furthermore, trametinib significantly inhibited both apoptosis and necroptosis in the kidneys. In conclusion, our data underscore the potential of trametinib as a therapeutic agent for cisplatin-induced AKI, highlighting its role in reducing inflammation, oxidative stress, and tubular cell death.


Assuntos
Injúria Renal Aguda , Cisplatino , Modelos Animais de Doenças , Inflamação , Estresse Oxidativo , Piridonas , Pirimidinonas , Animais , Cisplatino/efeitos adversos , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/patologia , Piridonas/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Camundongos , Pirimidinonas/farmacologia , Inflamação/tratamento farmacológico , Inflamação/induzido quimicamente , Inflamação/metabolismo , Masculino , Morte Celular/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Túbulos Renais/patologia , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Citocinas/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos
10.
Eur J Pharmacol ; 977: 176721, 2024 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-38851561

RESUMO

Underactive bladder (UAB), characterized by a complex set of symptoms with few treatment options, can significantly reduce the quality of life of affected people. UAB is characterized by hyperplasia and fibrosis of the bladder wall as well as decreased bladder compliance. Pirfenidone is a powerful anti-fibrotic agent that inhibits the progression of fibrosis in people with idiopathic pulmonary fibrosis. In the current study, we evaluated the efficacy of pirfenidone in the treatment of bladder fibrosis in a UAB rat model. UAB was induced by crushing damage to nerve bundles in the major pelvic ganglion. Forty-two days after surgery, 1 mL distilled water containing pirfenidone (100, 300, or 500 mg/kg) was orally administered once every 2 days for a total of 10 times for 20 days to the rats in the pirfenidone-treated groups. Crushing damage to the nerve bundles caused voiding dysfunction, resulting in increased bladder weight and the level of fibrous related factors in the bladder, leading to UAB symptoms. Pirfenidone treatment improved urinary function, increased bladder weight and suppressed the expression of fibrosis factors. The results of this experiment suggest that pirfenidone can be used to ameliorate difficult-to-treat urological conditions such as bladder fibrosis. Therefore, pirfenidone treatment can be considered an option to improve voiding function in patient with incurable UAB.


Assuntos
Fibrose , Piridonas , Ratos Sprague-Dawley , Bexiga Inativa , Bexiga Urinária , Micção , Animais , Piridonas/farmacologia , Piridonas/uso terapêutico , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/patologia , Bexiga Urinária/fisiopatologia , Ratos , Micção/efeitos dos fármacos , Bexiga Inativa/tratamento farmacológico , Bexiga Inativa/fisiopatologia , Bexiga Inativa/etiologia , Modelos Animais de Doenças , Feminino , Masculino
11.
Acta Chim Slov ; 71(2): 264-287, 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38919094

RESUMO

Combined in silico strategy for molecular mechanisms exploration of a series 3H-thiazolo[4,5-b]pyridin-2-ones exhibiting strong anti-exudative action through QSAR analysis, molecular docking and pharmacophore modelling is reported. GA-ML technique was used for QSAR models generation with 2D autocorrelation descriptors. One- and two-parameter regressions revealed that certain structural patterns or heteroatoms contribute mutually to the anti-exudative activity potentiation. Possible action mechanisms were discovered through flexible docking simulations with cyclooxygenase pathway enzymes (COX-1, COX-2, mPGES-1). Docking results indicated the possibility of stable complexes formation with the effective docking scores and proper orientation of ligands within the enzymes active sites. Pharmacophore modelling was carried out using protein-ligand interaction fingerprints methodology. Two- and three-centre 3D pharmacophore queries were constructed. Their analysis indicated the functionality of bicyclic thiazolopyridine scaffold proved by the steric placement of heteroatoms in the corresponding pharmacophore centres.


Assuntos
Simulação de Acoplamento Molecular , Relação Quantitativa Estrutura-Atividade , Tiazóis , Tiazóis/química , Tiazóis/farmacologia , Simulação por Computador , Piridonas/farmacologia , Piridonas/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Piridinas/farmacologia , Piridinas/química , Ciclo-Oxigenase 2/metabolismo , Inflamação/tratamento farmacológico
12.
Int J Nanomedicine ; 19: 5681-5703, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38882541

RESUMO

Introduction: Diabetes mellitus is frequently associated with foot ulcers, which pose significant health risks and complications. Impaired wound healing in diabetic patients is attributed to multiple factors, including hyperglycemia, neuropathy, chronic inflammation, oxidative damage, and decreased vascularization. Rationale: To address these challenges, this project aims to develop bioactive, fast-dissolving nanofiber dressings composed of polyvinylpyrrolidone loaded with a combination of an antibiotic (moxifloxacin or fusidic acid) and anti-inflammatory drug (pirfenidone) using electrospinning technique to prevent the bacterial growth, reduce inflammation, and expedite wound healing in diabetic wounds. Results: The fabricated drug-loaded fibers exhibited diameters of 443 ± 67 nm for moxifloxacin/pirfenidone nanofibers and 488 ± 92 nm for fusidic acid/pirfenidone nanofibers. The encapsulation efficiency, drug loading and drug release studies for the moxifloxacin/pirfenidone nanofibers were found to be 70 ± 3% and 20 ± 1 µg/mg, respectively, for moxifloxacin, and 96 ± 6% and 28 ± 2 µg/mg, respectively, for pirfenidone, with a complete release of both drugs within 24 hours, whereas the fusidic acid/pirfenidone nanofibers were found to be 95 ± 6% and 28 ± 2 µg/mg, respectively, for fusidic acid and 102 ± 5% and 30 ± 2 µg/mg, respectively, for pirfenidone, with a release rate of 66% for fusidic acid and 80%, for pirfenidone after 24 hours. The efficacy of the prepared nanofiber formulations in accelerating wound healing was evaluated using an induced diabetic rat model. All tested formulations showed an earlier complete closure of the wound compared to the controls, which was also supported by the histopathological assessment. Notably, the combination of fusidic acid and pirfenidone nanofibers demonstrated wound healing acceleration on day 8, earlier than all tested groups. Conclusion: These findings highlight the potential of the drug-loaded nanofibrous system as a promising medicated wound dressing for diabetic foot applications.


Assuntos
Antibacterianos , Bandagens , Pé Diabético , Liberação Controlada de Fármacos , Ácido Fusídico , Moxifloxacina , Nanofibras , Piridonas , Cicatrização , Pé Diabético/tratamento farmacológico , Pé Diabético/terapia , Nanofibras/química , Animais , Moxifloxacina/administração & dosagem , Moxifloxacina/farmacologia , Moxifloxacina/química , Moxifloxacina/farmacocinética , Cicatrização/efeitos dos fármacos , Antibacterianos/química , Antibacterianos/farmacologia , Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Piridonas/química , Piridonas/farmacologia , Piridonas/farmacocinética , Piridonas/administração & dosagem , Ácido Fusídico/administração & dosagem , Ácido Fusídico/farmacologia , Ácido Fusídico/química , Ácido Fusídico/farmacocinética , Ratos , Masculino , Diabetes Mellitus Experimental , Povidona/química , Ratos Sprague-Dawley
13.
Biomed Pharmacother ; 176: 116896, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38876049

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a severe disability due to progressive lung dysfunction. IPF has long been viewed as a non-immune form of pulmonary fibrosis, but nowadays it is accepted that a chronic inflammatory response can exacerbate fibrotic patterns. IL-1-like cytokines and ATP are highly detected in the lung and broncho-alveolar lavage fluid of IPF patients. Because ATP binds the purinergic receptor P2RX7 involved in the release of IL-1-like cytokines, we aimed to understand the role of P2RX7 in IPF. PBMCs from IPF patients were treated with nintedanib or pirfenidone in the presence of ATP. Under these conditions, PBMCs still released IL-1-like cytokines and the pro-fibrotic TGFß. Bulk and scRNAseq demonstrated that lung tissues of IPF patients had higher levels of P2RX7, especially on macrophages, which were correlated to T cell activity and inflammatory response with a TGFBI and IL-10 signature. A subcluster of macrophages in IPF lung tissues had 2055 genes that were not in common with the other subclusters, and that were involved in metabolic and PDGF, FGF and VEGF associated pathways. These data confirmed what observed on circulating cells that, although treated with anti-fibrotic agents, nintedanib or pirfenidone, they were still able to release IL-1 cytokines and the fibrogenic TGFß. In conclusion, these data imply that because nintedanib and pirfenidone do not block ATP-induced IL-1-like cytokines and TGFß induced during P2RX7 activation, it is plausible to consider P2RX7 on circulating cells and/or tissue biopsies as potential pharmacological tool for IPF patients.


Assuntos
Trifosfato de Adenosina , Fibrose Pulmonar Idiopática , Indóis , Piridonas , Receptores Purinérgicos P2X7 , Humanos , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/metabolismo , Fibrose Pulmonar Idiopática/patologia , Piridonas/farmacologia , Piridonas/uso terapêutico , Indóis/farmacologia , Indóis/uso terapêutico , Trifosfato de Adenosina/metabolismo , Receptores Purinérgicos P2X7/metabolismo , Masculino , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/metabolismo , Feminino , Citocinas/metabolismo , Idoso , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Pessoa de Meia-Idade , Fator de Crescimento Transformador beta/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Transdução de Sinais/efeitos dos fármacos
14.
J Zoo Wildl Med ; 55(2): 313-321, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38875188

RESUMO

High pathogenicity avian influenza is an acute zoonotic disease with high mortality in birds caused by a high pathogenicity avian influenza virus (HPAIV). Recently, HPAIV has rapidly spread worldwide and has killed many wild birds, including endangered species. Baloxavir marboxil (BXM), an anti-influenza agent used for humans, was reported to reduce mortality and virus secretion from HPAIV-infected chickens (Gallus domesticus, order Galliformes) at a dosage of ≥2.5 mg/kg when administered simultaneously with viral challenge. Application of this treatment to endangered birds requires further information on potential avian-specific toxicity caused by repeated exposure to BXM over the long term. To obtain information of potential avian-specific toxicity, a 4-wk oral repeated-dose study of BXM was conducted in chickens (n = 6 or 7 per group), which are commonly used as laboratory avian species. The study was conducted in reference to the human pharmaceutical guidelines for nonclinical repeated-dose drug toxicity studies to evaluate systemic toxicity and exposure. No adverse changes were observed in any organs examined, and dose proportional increases in systemic exposure to active pharmaceutical ingredients were noted from 12.5 to 62.5 mg/kg per day. BXM showed no toxicity to chickens at doses of up to 62.5 mg/kg per day, at which systemic exposure was approximately 71 times higher than systemic exposure at 2.5 mg/kg, the reported efficacious dosage amount, in HPAIV-infected chickens. These results also suggest that BXM could be considered safe for treating HPAIV-infected endangered birds due to its high safety margin compared with the efficacy dose. The data in this study could contribute to the preservation of endangered birds by using BXM as a means of protecting biodiversity.


Assuntos
Antivirais , Galinhas , Dibenzotiepinas , Morfolinas , Piridonas , Triazinas , Animais , Triazinas/administração & dosagem , Dibenzotiepinas/administração & dosagem , Administração Oral , Antivirais/administração & dosagem , Antivirais/farmacologia , Morfolinas/administração & dosagem , Morfolinas/farmacologia , Piridonas/administração & dosagem , Piridonas/farmacologia , Piridinas/administração & dosagem , Tiepinas/administração & dosagem , Tiepinas/farmacologia , Masculino , Influenza Aviária/tratamento farmacológico , Feminino , Oxazinas , Hidroxibutiratos/administração & dosagem
15.
Biochem Biophys Res Commun ; 716: 150020, 2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-38692011

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive disease with high mortality rates. It has been shown that pirfenidone (PFD) and nintedanib (Ofev) can slow down the decline in lung function of IPF patients, but their efficacy remains suboptimal. Some studies have suggested that the combination of PFD and Ofev may yield promising results. However, there is a lack of research on the combined application of these two medications in the treatment of IPF. A mouse model of bleomycin-induced (BLM) pulmonary fibrosis was established to investigate the impact of combination therapy on pulmonary fibrosis of mice. The findings demonstrated a significant reduction in lung tissue damage in mice treated with the combination therapy. Subsequent transcriptome analysis identified the differential gene secreted phosphoprotein 1 (SPP1), which was found to be associated with macrophages and fibroblasts based on multiple immunofluorescence staining results. Analysis of a phosphorylated protein microarray indicated that SPP1 plays a regulatory role in macrophages and fibroblasts via the AKT pathway. Consequently, the regulation of macrophages and fibroblasts in pulmonary fibrosis by the combination of PFD and Ofev is mediated by SPP1 through the AKT pathway, potentially offering a novel therapeutic option for IPF patients. Further investigation into the targeting of SPP1 for the treatment of pulmonary fibrosis is warranted.


Assuntos
Fibroblastos , Indóis , Macrófagos , Camundongos Endogâmicos C57BL , Osteopontina , Proteínas Proto-Oncogênicas c-akt , Piridonas , Animais , Piridonas/farmacologia , Piridonas/uso terapêutico , Indóis/farmacologia , Indóis/uso terapêutico , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Osteopontina/metabolismo , Osteopontina/genética , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/metabolismo , Fibrose Pulmonar Idiopática/patologia , Fibrose Pulmonar Idiopática/induzido quimicamente , Transdução de Sinais/efeitos dos fármacos , Antifibróticos/farmacologia , Antifibróticos/uso terapêutico , Masculino , Quimioterapia Combinada , Bleomicina
16.
Nat Commun ; 15(1): 3912, 2024 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-38724509

RESUMO

Direct oral anticoagulants (DOACs) targeting activated factor Xa (FXa) are used to prevent or treat thromboembolic disorders. DOACs reversibly bind to FXa and inhibit its enzymatic activity. However, DOAC treatment carries the risk of anticoagulant-associated bleeding. Currently, only one specific agent, andexanet alfa, is approved to reverse the anticoagulant effects of FXa-targeting DOACs (FXaDOACs) and control life-threatening bleeding. However, because of its mechanism of action, andexanet alfa requires a cumbersome dosing schedule, and its use is associated with the risk of thrombosis. Here, we present the computational design, engineering, and evaluation of FXa-variants that exhibit anticoagulation reversal activity in the presence of FXaDOACs. Our designs demonstrate low DOAC binding affinity, retain FXa-enzymatic activity and reduce the DOAC-associated bleeding by restoring hemostasis in mice treated with apixaban. Importantly, the FXaDOACs reversal agents we designed, unlike andexanet alfa, do not inhibit TFPI, and consequently, may have a safer thrombogenic profile.


Assuntos
Inibidores do Fator Xa , Hemorragia , Hemostasia , Pirazóis , Piridonas , Animais , Humanos , Masculino , Camundongos , Anticoagulantes/farmacologia , Anticoagulantes/efeitos adversos , Fator Xa/metabolismo , Inibidores do Fator Xa/farmacologia , Hemorragia/tratamento farmacológico , Hemorragia/induzido quimicamente , Hemostasia/efeitos dos fármacos , Pirazóis/farmacologia , Piridonas/farmacologia , Proteínas Recombinantes
17.
Microbes Infect ; 26(5-6): 105353, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38763478

RESUMO

The obligate intracellular parasite Leishmania binds several receptors to trigger uptake by phagocytic cells, ultimately resulting in visceral or cutaneous leishmaniasis. A series of signaling pathways in host cells, which are critical for establishment and persistence of infection, are activated during Leishmania internalization. Thus, preventing Leishmania uptake by phagocytes could be a novel therapeutic strategy for leishmaniasis. However, the host cellular machinery mediating promastigote and amastigote uptake is not well understood. Here, using small molecule inhibitors of Mitogen-activated protein/Extracellular signal regulated kinases (MAPK/ERK), we demonstrate that ERK1/2 mediates Leishmania amazonensis uptake and (to a lesser extent) phagocytosis of beads by macrophages. We find that inhibiting host MEK1/2 or ERK1/2 leads to inefficient amastigote uptake. Moreover, using inhibitors and primary macrophages lacking spleen tyrosine kinase (SYK) or Abl family kinases, we show that SYK and Abl family kinases mediate Raf, MEK, and ERK1/2 activity and are necessary for uptake. Finally, we demonstrate that trametinib, a MEK1/2 inhibitor used to treat cancer, reduces disease severity and parasite burden in Leishmania-infected mice, even if it is started after lesions develop. Our results show that maximal Leishmania infection requires MAPK/ERK and highlight potential for MAPK/ERK-mediated signaling pathways to be novel therapeutic targets for leishmaniasis.


Assuntos
Macrófagos , Animais , Macrófagos/parasitologia , Macrófagos/metabolismo , Macrófagos/imunologia , Camundongos , Fagocitose , Piridonas/farmacologia , Leishmaniose/parasitologia , Leishmaniose/imunologia , Quinase Syk/metabolismo , Quinase Syk/antagonistas & inibidores , Sistema de Sinalização das MAP Quinases , Camundongos Endogâmicos C57BL , Leishmania mexicana/enzimologia , Leishmania , Leishmaniose Cutânea/parasitologia , Leishmaniose Cutânea/metabolismo , Leishmaniose Cutânea/imunologia , Leishmaniose Cutânea/patologia , Pirimidinonas
18.
Anticancer Res ; 44(6): 2533-2544, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38821596

RESUMO

BACKGROUND/AIM: Chemotherapy is mainly used in the clinical treatment of prostate cancer. Different anticancer mechanisms can induce cell death in various cancers. Reactive oxygen species (ROS) play crucial roles in cell proliferation, differentiation, apoptosis, and signal transduction. It is widely accepted that ROS accumulation is closely related to chemical drug-induced cancer cell death. MATERIALS AND METHODS: We utilized the MTT assay to detect changes in cell proliferation. Additionally, colony formation and wound healing assay were conducted to investigate the effect of hispidin on cell colony formation and migration ability. Fluorescence microscopy was used to detect intracellular and mitochondrial ROS levels, while western blot was used for detection of cell apoptosis. RESULTS: Hispidin treatment significantly decreased viability of PC3 and DU145 cancer cells but exhibited no cytotoxicity in WPMY-1 cells. Furthermore, hispidin treatment inhibited cell migration and colony formation and triggered cellular and mitochondrial ROS accumulation, leading to mitochondrial dysfunction and mitochondrion-dependent apoptosis. Moreover, hispidin treatment induced ferroptosis in PC3 cells. Scavenging of ROS with N-acetyl cysteine significantly inhibited hispidin-induced apoptosis by altering the expression of apoptosis-related proteins, such as cleaved caspase-3, 9, Bax, and Bcl2. Furthermore, hispidin treatment dramatically up-regulated MAPK (involving p38, ERK, and JNK proteins) and NF-kB signaling pathways while down-regulating AKT phosphorylation. Hispidin treatment also inhibited ferroptosis signaling pathways (involving P53, Nrf-2, and HO-1 proteins) in PC3 cells. In addition, inhibiting these signaling pathways via treatment with specific inhibitors significantly reversed hispidin-induced apoptosis, cellular ROS levels, mitochondrial dysfunction, and ferroptosis. CONCLUSION: Hispidin may represent a potential candidate for treating prostate cancer.


Assuntos
Apoptose , Ferroptose , Neoplasias da Próstata , Espécies Reativas de Oxigênio , Humanos , Masculino , Ferroptose/efeitos dos fármacos , Neoplasias da Próstata/patologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Apoptose/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Piridonas/farmacologia , Fosfatidilinositol 3-Quinase/metabolismo , Pironas
19.
J Biol Chem ; 300(6): 107409, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38796063

RESUMO

About 18% of all human cancers carry a mutation in the KRAS gene making it among the most sought-after anticancer targets. However, mutant KRas protein has proved remarkably undruggable. The recent approval of the first generation of RAS inhibitors therefore marks a seminal milestone in the history of cancer research. It also raises the predictable challenges of limited drug efficacies and acquired resistance. Hence, new approaches that improve our understanding of the tumorigenic mechanisms of oncogenic RAS within more physiological settings continue to be essential. Here, we have used the near-diploid hTERT RPE-1 cells to generate isogenic cell lines in which one of the endogenous KRAS alleles carries an oncogenic KRAS mutation at glycine 12. Cells with a KRASG12V/+, KRASG12C/+, or KRASG12D/+ genotype, together with WT KRASG12G(WT)/+ cells, reveal that oncogenic KRAS.G12X mutations increase cell proliferation rate and cell motility and reduced focal adhesions in KRASG12V/+ cells. Epidermal growth factor -induced phosphorylation of ERK and AKT was comparable between KRASG12V/+, KRASG12C/+, KRASG12D/+, and KRASG12G(WT)/+ cells. Interestingly, KRASG12X/+ cells showed varying responses to distinct inhibitors with the KRASG12V/+ and KRASG12D/+ cells more sensitive to hydroxyurea and MEK inhibitors, U0126 and trametinib, but more resistant to PI3K inhibitor, PIK-90, than the KRASG12G(WT)/+ cells. A combination of low doses of hydroxyurea and U0126 showed an additive inhibition on growth rate that was greater in KRASG12V/+ than WT cells. Collectively, these cell lines will be a valuable resource for studying oncogenic RAS signaling and developing effective anti-KRAS reagents with minimum cytotoxicity on WT cells.


Assuntos
Movimento Celular , Proliferação de Células , Proteínas Proto-Oncogênicas p21(ras) , Humanos , Movimento Celular/efeitos dos fármacos , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Proliferação de Células/efeitos dos fármacos , Telomerase/genética , Telomerase/metabolismo , Proteínas ras/metabolismo , Proteínas ras/genética , Pirimidinonas/farmacologia , Piridonas/farmacologia , Mutação de Sentido Incorreto , Linhagem Celular , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas/genética , Nitrilas/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Butadienos/farmacologia , Substituição de Aminoácidos , Mutação
20.
Biochem Pharmacol ; 225: 116267, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38723721

RESUMO

Acute liver failure (ALF) is a critical condition that can lead to substantial liver dysfunction. It is characterized by complex clinical manifestations and rapid progression, presenting significant challenges in diagnosis and treatment. We investigated the protective effect of mefunidone (MFD), a novel antifibrosis pyridone agent, on ALF in mice, and explored its potential mechanism of action. MFD pretreatment can alleviate lipopolysaccharide (LPS) and d-galactosamine (D-GalN)-induced ALF, reduce hepatocyte apoptosis, and reduce inflammation and oxidative stress. Additionally, MFD alleviated LPS/D-GalN-stimulated reactive oxygen species (ROS) production and cell death in AML12 cells. RNA sequencing enrichment analysis showed that MFD significantly affected the Mitogen-Activated Protein Kinase (MAPK) pathway. In vivo and in vitro experiments showed that MFD inhibited MKK4 and JNK phosphorylation. JNK activation caused by MKK4 and JNK activators could eliminate the therapeutic effect of MFD on AML12. In addition, MFD pretreatment alleviated ConA-induced ALF, reduced inflammation and oxidative stress in mice, and reduced mouse mortality. These results suggest that MFD can potentially protect against ALF, partially by inhibiting the MKK4-JNK pathway, and is a promising new therapeutic drug for ALF.


Assuntos
Falência Hepática Aguda , MAP Quinase Quinase 4 , Piperazinas , Piridonas , Animais , Masculino , Camundongos , Linhagem Celular , Galactosamina/toxicidade , Lipopolissacarídeos/toxicidade , Falência Hepática Aguda/tratamento farmacológico , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/metabolismo , Falência Hepática Aguda/patologia , MAP Quinase Quinase 4/metabolismo , MAP Quinase Quinase 4/antagonistas & inibidores , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/fisiologia , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Piridonas/farmacologia , Piridonas/uso terapêutico , Piperazinas/farmacologia , Piperazinas/uso terapêutico
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