RESUMO
Rho family GTPases regulate cellular processes and promote tumour growth and metastasis; thus, RhoA is a potential target for tumour metastasis inhibition. However, limited progress has been made in the development of RhoA targeting anticancer drugs. Here, we synthesised benzo[b]thiophene-3-carboxylic acid 1,1-dioxide derivatives based on a covalent inhibitor of RhoA (DC-Rhoin), reported in our previous studies. The observed structure-activity relationship (contributed by carboxamide in C-3 and 1-methyl-1H-pyrazol in C-5) enhanced the anti-proliferative activity of the derivatives. Compound b19 significantly inhibited the proliferation, migration, and invasion of MDA-MB-231 cells and promoted their apoptosis. The suppression of myosin light chain phosphorylation and the formation of stress fibres confirmed the inhibitory activity of b19 via the RhoA/ROCK pathway. b19 exhibited a different binding pattern from DC-Rhoin, as observed in molecular docking analysis. This study provides a reference for the development of anticancer agents targeting the RhoA/ROCK pathway.
Assuntos
Antineoplásicos , Apoptose , Proliferação de Células , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Tiofenos , Quinases Associadas a rho , Proteína rhoA de Ligação ao GTP , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Quinases Associadas a rho/antagonistas & inibidores , Quinases Associadas a rho/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo , Proteína rhoA de Ligação ao GTP/antagonistas & inibidores , Relação Estrutura-Atividade , Proliferação de Células/efeitos dos fármacos , Estrutura Molecular , Apoptose/efeitos dos fármacos , Tiofenos/farmacologia , Tiofenos/química , Tiofenos/síntese química , Movimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Simulação de Acoplamento MolecularRESUMO
Hepatic microvascular disruption caused by injury to liver sinusoidal endothelial cells (LSECs) is an aggravating factor for drug-induced liver injury (DILI). It is suggested that prostaglandin E2 (PGE2) may be able to attenuate LSEC injury. However, it is also known that 15-keto PGE2, a metabolite of PGE2 produced by 15-prostaglandin dehydrogenase (15-PGDH) that is not a ligand of PGE2 receptors, suppresses inflammatory acute liver injury as a ligand of peroxisome proliferator-activated receptor γ. In this study, we aimed to understand whether 15-PGDH activity is essential for preventing DILI by suppressing hepatic microvascular disruption in a mouse model of acetaminophen (APAP)-induced liver injury. To inhibit 15-PGDH activity prior to APAP-induced LSEC injury, we administered the 15-PGDH inhibitor, SW033291, 1 h before and 3 h after APAP treatment. We observed that LSEC injury preceded hepatocellular injury in APAP administered mice. Hepatic endogenous PGE2 levels did not increase up till the initiation of LSEC injury but rather increased after hepatocellular injury. Moreover, hepatic 15-PGDH activity was downregulated in APAP-induced liver injury. The inhibition of 15-PGDH attenuated LSEC injury and subsequently hepatic injury by inhibiting apoptosis in APAP administered mice. Our in vitro studies also suggested that PGE2 inhibited APAP-induced apoptosis via the EP4/PI3K pathway in endothelial cells. Therefore, a decrease in 15-PGDH activity would be beneficial for preventing APAP-induced liver injury by attenuating LSEC injury.
Assuntos
Acetaminofen , Apoptose , Doença Hepática Induzida por Substâncias e Drogas , Dinoprostona , Células Endoteliais , Hidroxiprostaglandina Desidrogenases , Fígado , Animais , Acetaminofen/efeitos adversos , Acetaminofen/toxicidade , Apoptose/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Camundongos , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Doença Hepática Induzida por Substâncias e Drogas/patologia , Hidroxiprostaglandina Desidrogenases/metabolismo , Hidroxiprostaglandina Desidrogenases/antagonistas & inibidores , Dinoprostona/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Piridinas , TiofenosRESUMO
This article provides a narrative review of recent developments in mood-stabilizing drugs, considering their mechanism of action, efficacy, safety, and therapeutic potential in the treatment of mood disorders, particularly bipolar disorder and schizophrenia. The review focuses on the mechanism and clinical aspects of second-generation antipsychotic medications; aripiprazole, classified as a third-generation antipsychotic medication; lamotrigine, as a representative of antiepileptic drugs; and lurasidone, a novel second-generation antipsychotic medication. Moreover, the article refers to one of the newest and most highly effective normothymic drugs, cariprazine. The potential of new mood stabilizer candidates lumateperone and brexpiprazole is also presented. Covered topics include the clinical efficacy of new drugs in reducing manic and depressive symptoms during acute episodes, as well as their role in preventing relapse. In addition, we analyzed the incidence of adverse effects of each drug. Many of the new drugs have strong potential to be beneficial and safe in cases of many comorbidities, as they do not cause many adverse effects and do not require high doses of use. The results underscore the importance of ongoing and future research to better understand the action and efficacy of these mood stabilizers and their implications in the treatment of mood disorders, aiming to achieve euthymia and improve the quality of life of affected patients. In this article, we aim to review current drug treatments for the management of mood disorders, including bipolar disorder and schizophrenia.
Assuntos
Antipsicóticos , Transtorno Bipolar , Transtornos do Humor , Esquizofrenia , Humanos , Antipsicóticos/uso terapêutico , Antipsicóticos/farmacologia , Transtorno Bipolar/tratamento farmacológico , Esquizofrenia/tratamento farmacológico , Transtornos do Humor/tratamento farmacológico , Aripiprazol/uso terapêutico , Aripiprazol/farmacologia , Anticonvulsivantes/uso terapêutico , Anticonvulsivantes/farmacologia , Lamotrigina/uso terapêutico , Cloridrato de Lurasidona/uso terapêutico , Piperazinas , Tiofenos , QuinolonasRESUMO
BACKGROUND: Portal vein tumor thrombosis (PVTT) commonly occurs in patients with primary liver cancer (PLC). Transarterial chemoembolization (TACE) is a treatment for patients with PLC and PVTT. Some studies have shown that combining TACE therapy with hepatic arterial infusion chemotherapy (HAIC) might improve the survival rate of PLC patients with PVTT. However, few studies have compared the different regimens of PLC with PVTT. We aimed to compare the differences between the oxaliplatin + raltetrexed regimen and FOLFOX regimen. METHODS: We divided the 248 patients into two groups. There were 60 patients in the oxaliplatin + ratitetrexed group and 74 patients in the FOLFOX group. The primary endpoints were OS and PFS. The secondary endpoints were ORR and adverse events. We used SPSS software, the Kaplan-Meier method, the t test, and the rank sum test to compare the differences between the two groups. RESULTS: The median OS was 10.82 months in the oxaliplatin + raltitrexed group and 8.67 months in the FOLFOX group. The median PFS time was greater in the oxaliplatin + raltitrexed group (10.0 months) than that in the FOLFOX group (7.1 months). The ORR was greater in the oxaliplatin + raltitrexed group than that in the FOLFOX group (18.3% vs. 13.5%; P = 0.445). The DCR in the oxaliplatin + raltitrexed group was higher than that in the FOLFOX group (70.0% vs. 64.8%; P = 0.529). However, in the subgroup analysis, the difference between them was more significant in the type II PVTT subgroup. The OS was 12.08 months in the oxaliplatin + raltitrexed group and 7.26 months in the FOLFOX group (P = 0.008). The PFS was 11.68 months in the oxaliplatin + raltitrexed group and 6.26 months in the FOLFOX group (P = 0.014). In the right branch of type II PVTT, the OS was 13.54 months in the oxaliplatin + raltitrexed group and 6.89 months in the FOLFOX group (P = 0.015), and the PFS was 13.35 months in the oxaliplatin + raltitrexed group and 6.27 months in the FOLFOX group (P = 0.030). The incidence of adverse reactions was similar between the two groups. CONCLUSIONS: Compared with the FOLFOX regimen, the oxaliplatin + raltitrexed chemoembolization regimen had longer OS, PFS time and ORR and DCR and it was safe and tolerable.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Fluoruracila , Infusões Intra-Arteriais , Leucovorina , Neoplasias Hepáticas , Compostos Organoplatínicos , Oxaliplatina , Veia Porta , Trombose Venosa , Humanos , Masculino , Feminino , Neoplasias Hepáticas/tratamento farmacológico , Pessoa de Meia-Idade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Veia Porta/patologia , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Oxaliplatina/administração & dosagem , Oxaliplatina/uso terapêutico , Oxaliplatina/efeitos adversos , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/uso terapêutico , Idoso , Trombose Venosa/tratamento farmacológico , Trombose Venosa/etiologia , Leucovorina/administração & dosagem , Leucovorina/uso terapêutico , Leucovorina/efeitos adversos , Adulto , Artéria Hepática , Tiofenos/administração & dosagem , Tiofenos/uso terapêutico , Quinazolinas/administração & dosagem , Quinazolinas/uso terapêutico , Quinazolinas/efeitos adversos , Estudos Retrospectivos , Quimioembolização Terapêutica/métodosRESUMO
Background and aims: Reduced bone mineral density (BMD) and microarchitectural deterioration contribute to increased fracture risk. Although the effects of anti-fracture medications (AFMs) on BMD are well-documented, their impact on bone material properties (BMPs) remains poorly characterized. Accordingly, we conducted a systematic review and meta-analysis to evaluate the effects of AFMs on BMPs. Based on data availability, we further categorized AFMs into anti-resorptives, bisphosphonates alone, and strontium ranelate subgroups to perform additional analyses of BMPs in osteoporotic patients. Methods: We did a comprehensive search of three databases, namely, PubMed, Web of Science, and Google Scholar, using various permutation combinations, and used Comprehensive Meta-Analysis software to analyze the extracted data. Results: The 15 eligible studies (randomized and non-randomized) compared the following: (1) 301 AFM-treated patients with 225 on placebo; (2) 191 patients treated with anti-resorptives with 131 on placebo; (3) 86 bisphosphonate-treated patients with 66 on placebo; and (4) 84 strontium ranelate-treated patients with 70 on placebo. Pooled analysis showed that AFMs significantly decreased cortical bone crystallinity [standardized difference in means (SDM) -1.394] and collagen maturity [SDM -0.855], and collagen maturity in cancellous bone [SDM -0.631]. Additionally, anti-resorptives (bisphosphonates and denosumab) significantly increased crystallinity [SDM 0.387], mineral-matrix ratio [SDM 0.771], microhardness [SDM 0.858], and contact hardness [SDM 0.952] of cortical bone. Anti-resorptives increased mineral-matrix ratio [SDM 0.543] and microhardness [SDM 0.864] and decreased collagen maturity [SDM -0.539] in cancellous bone. Restricted analysis of only bisphosphonate-treated studies showed a significant decrease in collagen maturity [SDM -0.650] in cancellous bone and an increase in true hardness [SDM 1.277] in cortical bone. In strontium ranelate-treated patients, there was no difference in BMPs compared to placebo. Conclusion: Collectively, our study suggests that AFMs improve bone quality, which explains their anti-fracture ability that is not fully accounted for by increased BMD in osteoporosis patients.
Assuntos
Conservadores da Densidade Óssea , Densidade Óssea , Humanos , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Densidade Óssea/efeitos dos fármacos , Conservadores da Densidade Óssea/uso terapêutico , Conservadores da Densidade Óssea/farmacologia , Difosfonatos/uso terapêutico , Difosfonatos/farmacologia , Osteoporose/complicações , Osteoporose/tratamento farmacológico , Fraturas por Osteoporose/prevenção & controle , Tiofenos/uso terapêuticoAssuntos
Síndrome Mão-Pé , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos , Humanos , Síndrome Mão-Pé/etiologia , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Feminino , Tiofenos/efeitos adversos , Tiofenos/uso terapêutico , Pessoa de Meia-Idade , Pirazóis , QuinoxalinasRESUMO
An evaluation was made of the larvicidal efficacy of lotilaner (Credeli®) in the treatment of dogs naturally infested with Dermatobia hominis larvae. A total of 12 dogs presenting at least three live D. hominis larvae were medicated. The animals were medicated orally with a single dose of no less than 20 mg/kg lotilaner. After drug administration, the animals remained at their homes, and observations were made to verify the larvicidal effect 6 hours after treatment. Live larvae were considered any parasite that exhibited motility after removal. For each animal was using the formula: 100 x [(total of live larvae before treatment - total live larvae after treatment) /total of live larvae before treatment] as criteria for evaluating lotilaner efficacy. A total of 98 larvae were counted in 12 dogs, with an average of 8.1 larvae per animal. The effectiveness of lotilaner was 80.6%. Nineteen larvae were found alive, albeit presenting hypomobility and lethargic behavior. However, note that the evaluation was performed just six hours after administration of the drug. Lotilaner administered orally in a single dose of 20 mg/kg showed 80.6% efficacy six hours after treating dogs naturally infested with D. hominis.
Assuntos
Dípteros , Doenças do Cão , Miíase , Animais , Cães , Doenças do Cão/tratamento farmacológico , Doenças do Cão/parasitologia , Miíase/veterinária , Miíase/tratamento farmacológico , Miíase/diagnóstico , Miíase/parasitologia , Dípteros/efeitos dos fármacos , Larva/efeitos dos fármacos , Resultado do Tratamento , Masculino , Feminino , Inseticidas/administração & dosagem , Oxazóis , TiofenosRESUMO
OBJECTIVES: Clinical studies have shown that bevacizumab plus chemotherapy significantly improves efficacy in metastatic colorectal cancer (mCRC). This prospective study aims to investigate the efficacy and safety of changing second-line treatment to raltitrexed-based chemotherapy regimens plus bevacizumab in mCRC patients who have failed the first-line fluorouracil-based chemotherapy regimen with or without bevacizumab/cetuximab. METHODS: This is a prospective, open-label, multicenter, phase II clinical study. A total of 100 patients with mCRC after failure of the first-line fluorouracil-based chemotherapy regimen with or without bevacizumab/cetuximab were enrolled from November 2016 to October 2021, and received second-line raltitrexed-based chemotherapy regimen plus bevacizumab. Patients were treated for 6 cycles, and efficacy evaluation over stable disease were followed by maintenance treatment of bevacizumab and raltitrexed until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), safety, and toxicity. RESULTS: Ninety-four patients were treated with SALIRI (raltitrexed + irinotecan) plus bevacizumab, and six patients with SALOX (raltitrexed + oxaliplatin) plus bevacizumab. Median PFS was 8.4 (95% CI: 6.2-11.0) months, including 8.2 (95% CI 6.2, 11.0) months in the SALIRI group and 11.6 (95% CI 3.1, NA) months in the SALOX group. Median OS was 17.6 (95% CI 15.2, 22.0) months in the SALIRI group and 17.1 (95% CI 4.1, NA) months in the SALOX group. ORR and DCR were 25.5% and 87.2% in the SALIRI group, and 33.3% and 83.3% in the SALOX group, respectively. A low incidence of grade 3-4 adverse events was observed. CONCLUSIONS: Raltitrexed-based chemotherapy regimens plus bevacizumab improved survival duration in mCRC patients with failed first-line therapy. Therefore, treatment with raltitrexed-based chemotherapy regimens plus bevacizumab could be a superior therapeutic option for second-line chemotherapy in mCRC (ClinicalTrials.gov registration number: NCT03126071).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Bevacizumab , Neoplasias Colorretais , Quinazolinas , Tiofenos , Humanos , Bevacizumab/administração & dosagem , Bevacizumab/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Masculino , Feminino , Quinazolinas/administração & dosagem , Quinazolinas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Pessoa de Meia-Idade , Estudos Prospectivos , Idoso , Adulto , Tiofenos/administração & dosagem , Tiofenos/uso terapêuticoRESUMO
The endemic nature of the Ebola virus disease in Africa underscores the need for prophylactic and therapeutic drugs that are affordable and easy to administer. Through a phenotypic screening employing viral pseudotypes and our in-house chemical library, we identified a promising hit featuring a thiophene scaffold, exhibiting antiviral activity in the micromolar range. Following up on this thiophene hit, a new series of compounds that retain the five-membered heterocyclic scaffold while modifying several substituents was synthesized. Initial screening using a pseudotype viral system and validation assays employing authentic Ebola virus demonstrated the potential of this new chemical class as viral entry inhibitors. Subsequent investigations elucidated the mechanism of action through site-directed mutagenesis. Furthermore, we conducted studies to assess the pharmacokinetic profile of selected compounds to confirm its pharmacological and therapeutic potential.
Assuntos
Antivirais , Barreira Hematoencefálica , Ebolavirus , Tiofenos , Internalização do Vírus , Tiofenos/química , Tiofenos/farmacocinética , Tiofenos/farmacologia , Tiofenos/síntese química , Ebolavirus/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Humanos , Antivirais/farmacologia , Antivirais/química , Antivirais/farmacocinética , Antivirais/síntese química , Internalização do Vírus/efeitos dos fármacos , Relação Estrutura-Atividade , Animais , Descoberta de Drogas , Administração Oral , Disponibilidade Biológica , Doença pelo Vírus Ebola/tratamento farmacológico , Doença pelo Vírus Ebola/virologiaRESUMO
AIM: Most of the subarachnoid hemorrhage (SAH) patients experienced the symptom of severe headache caused by intracranial hypertension. Piezo1 is a mechanosensitive ion channel protein. This study aimed to investigate the effect of Piezo1 on neurons in response to intracranial hypertension. METHODS: The SAH rat model was performed by the modified endovascular perforation method. Piezo1 inhibitor GsMTx4 was administered intraperitoneally after SAH induction. To investigate the underlying mechanism, the selective Piezo1 agonist Yoda1, Piezo1 shRNA, and MY-875 were administered via intracerebroventricular injection before SAH induction. In vitro, we designed a pressurizing device to exclusively explore the effect of Piezo1 activation on primary neurons. Neurons were pretreated with Piezo1 inhibition followed by intracranial hypertension treatment, and then apoptosis-related proteins were detected. RESULTS: Piezo1 inhibition significantly attenuated neuronal apoptosis and improved the outcome of neurological deficits in rats after SAH. The Hippo pathway agonist MY-875 reversed the anti-apoptotic effects of Piezo1 knockdown. In vitro, intracranial hypertension mimicked by the pressurizing device induced Piezo1 expression, resulting in Hippo pathway activation and neuronal apoptosis. The Hippo pathway inhibitor Xmu-mp-1 attenuated Yoda1-induced neuronal apoptosis. In addition, the combination of hypertension and oxyhemoglobin treatment exacerbated neuronal apoptosis. CONCLUSIONS: Intracranial hypertension induced Piezo1 expression, neuronal apoptosis, and the Hippo pathway activation; the Hippo signaling pathway is involved in Piezo1 activation-induced neuronal apoptosis in respond to intracranial hypertension. Primary neurons treated with intracranial hypertension and oxyhemoglobin together can better characterize the circumstance of SAH in vivo, which is contributed to construct an ideal in vitro SAH model.
Assuntos
Apoptose , Hipertensão Intracraniana , Neurônios , Proteínas Serina-Treonina Quinases , Ratos Sprague-Dawley , Hemorragia Subaracnóidea , Animais , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Apoptose/fisiologia , Apoptose/efeitos dos fármacos , Ratos , Masculino , Hemorragia Subaracnóidea/metabolismo , Hemorragia Subaracnóidea/patologia , Hemorragia Subaracnóidea/complicações , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Canais Iônicos/metabolismo , Transdução de Sinais/fisiologia , Transdução de Sinais/efeitos dos fármacos , Tiofenos/farmacologia , Tiadiazóis/farmacologia , Células Cultivadas , Modelos Animais de Doenças , Oligopeptídeos/farmacologia , Pirazinas , Venenos de Aranha , Peptídeos e Proteínas de Sinalização IntercelularRESUMO
BACKGROUND: This study aims to compare the effectiveness and safety of the combination of raltitrexed, S-1 (RS), and fruquintinib with the combination of RS and bevacizumab in patients with refractory metastatic colorectal cancer (mCRC). METHODS: This retrospective cohort included mCRC patients who received the RS plus fruquintinib or regorafenib as the third-line therapy from May 2019 to April 2023. A propensity score matching (PSM) analysis was used to balance the baseline characteristics of all patients. Overall survival (OS), progression-free survival (PFS), tumor response, and safety of the two regimens were evaluated. RESULTS: Of the 153 patients enrolled, 123 patients received the RS plus bevacizumab and 30 patients received the RS plus fruquintinib. After PSM, 30 pairs were analyzed. Patients treated with RS plus fruquintinib had a longer PFS than those treated with RS plus bevacizumab before PSM (5.0 months vs. 4.3 months, p = 0.008) and after PSM (5.0 months vs. 4.4 months, p = 0.012). A longer OS was also observed in RS plus fruquintinib group before PSM and after PSM, but there was no statistic difference between two groups after PSM. Both objective response rate and disease control rate were higher in the RS plus fruquintinib cohort than those in the RS plus bevacizumab cohort before PSM, and the difference in values between the two groups reduced after PSM. The adverse effects (AEs) of both groups were well tolerated. CONCLUSION: In patients with refractory mCRC, RS plus fruquintinib demonstrated a superior OS, PFS than RS plus bevacizumab and had manageable AEs.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Bevacizumab , Neoplasias Colorretais , Combinação de Medicamentos , Pontuação de Propensão , Quinazolinas , Tegafur , Humanos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Bevacizumab/administração & dosagem , Bevacizumab/uso terapêutico , Bevacizumab/efeitos adversos , Masculino , Feminino , Estudos Retrospectivos , Pessoa de Meia-Idade , Quinazolinas/uso terapêutico , Quinazolinas/efeitos adversos , Quinazolinas/administração & dosagem , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Tegafur/administração & dosagem , Tegafur/uso terapêutico , Tegafur/efeitos adversos , Ácido Oxônico/administração & dosagem , Ácido Oxônico/uso terapêutico , Ácido Oxônico/efeitos adversos , Benzofuranos/uso terapêutico , Benzofuranos/administração & dosagem , Benzofuranos/efeitos adversos , Adulto , Intervalo Livre de Progressão , TiofenosRESUMO
Allergens and Th2 cytokines affect the homeostatic environment in the airways, leading to increased mucus production by goblet cells associated with altered adherens junctional complex (AJC) and tight junction (TJ) proteins responsible for maintaining epithelial barrier function. Circadian clock-dependent regulatory mechanisms such as inflammation and epithelial barrier function are gaining more attention due to their therapeutic potential against allergic inflammatory lung diseases. Currently, there are no studies to support whether REV-ERBα activation can attenuate Th2 cytokine-induced epithelial barrier dysfunction in human bronchial epithelial cells. We hypothesized that Th2 cytokine-induced epithelial barrier dysfunction may be protected by activating REV-ERBα. Treatment with Th2 cytokines or HDM significantly reduced the cell impedance, as confirmed by transepithelial electrical resistance (TEER). However, pre-treatment with SR10067 attenuated Th2 cytokine-induced barrier dysfunction, such as decreased permeability, improved TEER, localization of AJC and TJ proteins, and mRNA and protein levels of selected epithelial barrier and circadian clock targets. Overall, we showed for the first time that REV-ERBα activation regulates altered epithelial barrier function that may have direct implications for the treatment of asthma and other allergic diseases.
Assuntos
Brônquios , Citocinas , Células Epiteliais , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares , Células Th2 , Humanos , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/agonistas , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/metabolismo , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/genética , Citocinas/metabolismo , Brônquios/efeitos dos fármacos , Brônquios/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Th2/efeitos dos fármacos , Células Th2/imunologia , Células Th2/metabolismo , Junções Íntimas/metabolismo , Junções Íntimas/efeitos dos fármacos , Impedância Elétrica , Tiofenos/farmacologia , Junções Aderentes/efeitos dos fármacos , Junções Aderentes/metabolismoRESUMO
A 72-year-old woman with relapsed FLT3-ITD-positive acute myeloid leukemia was treated with gilteritinib and achieved complete remission with incomplete hematological recovery. However, two months later, she developed optic nerve infiltration and lost vision in her right eye while maintaining hematological remission on gilteritinib. Intrathecal injection of cytotoxic drugs reduced the number of blasts in the cerebrospinal fluid (CSF), but her vision did not recover. At the onset of optic nerve infiltration, at a dose of 80 mg/day gilteritinib, the plasma trough and CSF levels of gilteritinib were 151.9 ng/ml and 1.9 ng/ml, respectively, with a central nervous system (CNS) penetration rate of 1.3%. Hematologic progressive disease (PD) was detected after 40 days, and the patient died one month later. Target sequencing at the time of hematologic PD revealed the FLT3 F691L mutation, which is known to confer resistance to gilteritinib. In this patient, pharmacokinetic (low CNS penetration of gilteritinib) and pharmacodynamic (acquisition of a drug resistance mutation) mechanisms were thought to be responsible for the CNS relapse and hematologic PD, respectively. We believe this is a valuable case to report considering the scarcity of data on CNS penetration of FLT3 inhibitors and their effects on CNS disease in the literature.
Assuntos
Compostos de Anilina , Leucemia Mieloide Aguda , Pirazinas , Recidiva , Tirosina Quinase 3 Semelhante a fms , Humanos , Tirosina Quinase 3 Semelhante a fms/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Pirazinas/administração & dosagem , Pirazinas/uso terapêutico , Idoso , Feminino , Compostos de Anilina/uso terapêutico , Compostos de Anilina/administração & dosagem , Tiofenos/administração & dosagem , Tiofenos/uso terapêutico , Nervo Óptico/patologia , Mutação , Evolução FatalRESUMO
BACKGROUND: Colorectal cancer is the third most common cancer and the second leading cause of cancer death. There are limited therapeutic options for the treatment of locally advanced or metastatic colorectal cancers which fail first-line chemotherapy. Phase I/II studies showed that the combined application of the raltitrexed and irinotecan has significant synergistic effect and acceptable toxicity. However, most of these previous studies have relatively small sample size. METHODS: This is a prospective open-label, single-arm, multi-center, Phase II trial. Brief inclusion criteria: patients were aged 18 to 75 years with locally advanced or metastatic colorectal cancer after failure of 5-FU and oxaliplatin therapy. Enrolled patients received raltitrexed (3 mg/m2, d1) and irinotecan (180 mg/m2, d1) each 21-day cycle until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival, and the secondary endpoints were disease control rate, objective response rate, overall survival and safety. RESULTS: A total of 108 patients were enrolled between September 2016 and May 2020. The median age was 61 years, ECOG 1 score accounts for 67.6%, the rest were ECOG 0. A total of 502 cycles were completed, with an average of 4.6 cycles and a median of 4 cycles. 108 patients were evaluated, with an objective response rate of 17.6%, and disease control rate of 76.9%. The median follow-up time was 27 months (range:3.1-61.0 m) at data cut-off on March 2023. Median progression-free survival was 4.9 months (95% CI 4.1-5.7) and median overall survival was 13.1 months (95% CI 12.2-15.5). The most common adverse events that were elevated are alanine aminotransferase increased, aspartate aminotransferase increased, fatigue, diarrhoea, neutrocytopenia, thrombocytopenia, hypohemoglobin, and leukocytopenia. Most of the adverse events were Grade I/II, which were relieved after symptomatic treatment, and there were no treatment-related cardiotoxicities and deaths. CONCLUSIONS: The combination of raltitrexed and irinotecan as second-line treatment for mCRC could be a reliable option after failure of standard 5-Fu-first-line chemotherapy in locally advanced or metastatic colorectal cancers, especially for patients with 5-FU intolerance (cardiac events or DPD deficiency patients). TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03053167, registration date was 14/2/2017.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Colorretais , Irinotecano , Quinazolinas , Tiofenos , Humanos , Pessoa de Meia-Idade , Quinazolinas/uso terapêutico , Quinazolinas/efeitos adversos , Masculino , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias Colorretais/mortalidade , Irinotecano/uso terapêutico , Irinotecano/administração & dosagem , Idoso , Feminino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Tiofenos/uso terapêutico , Tiofenos/administração & dosagem , Tiofenos/efeitos adversos , Estudos Prospectivos , Adulto , Intervalo Livre de Progressão , Adulto JovemRESUMO
The rising incidences of atherosclerosis have necessitated efforts to identify novel targets for therapeutic interventions. In the present study, we observed increased expression of the mechanosensitive calcium channel Piezo1 transcript in mouse and human atherosclerotic plaques, correlating with infiltration of PIEZO1-expressing macrophages. In vitro administration of Yoda1, a specific agonist for PIEZO1, led to increased foam cell apoptosis and enhanced phagocytosis by macrophages. Mechanistically, PIEZO1 activation resulted in intracellular F-actin rearrangement, elevated mitochondrial ROS levels and induction of mitochondrial fragmentation upon PIEZO1 activation, as well as increased expression of anti-inflammatory genes. In vivo, ApoE-/- mice treated with Yoda1 exhibited regression of atherosclerosis, enhanced stability of advanced lesions, reduced plaque size and necrotic core, increased collagen content, and reduced expression levels of inflammatory markers. Our findings propose PIEZO1 as a novel and potential therapeutic target in atherosclerosis.
Assuntos
Apoptose , Aterosclerose , Células Espumosas , Canais Iônicos , Macrófagos , Fagocitose , Animais , Canais Iônicos/metabolismo , Canais Iônicos/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Aterosclerose/genética , Camundongos , Células Espumosas/metabolismo , Células Espumosas/patologia , Humanos , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Tiofenos/farmacologia , Masculino , Espécies Reativas de Oxigênio/metabolismo , Placa Aterosclerótica/patologia , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/genética , Mitocôndrias/metabolismo , Pirazinas , TiadiazóisAssuntos
Aminofenóis , Benzodioxóis , Fibrose Cística , Combinação de Medicamentos , Indóis , Humor Irritável , Pirazóis , Quinolonas , Adulto , Feminino , Humanos , Masculino , Aminofenóis/efeitos adversos , Aminofenóis/uso terapêutico , Benzodioxóis/efeitos adversos , Agonistas dos Canais de Cloreto/uso terapêutico , Fibrose Cística/tratamento farmacológico , Indóis/efeitos adversos , Indóis/administração & dosagem , Humor Irritável/efeitos dos fármacos , Pirazóis/efeitos adversos , Piridinas/efeitos adversos , Pirróis/efeitos adversos , Quinolinas/efeitos adversos , Quinolinas/uso terapêutico , Quinolonas/efeitos adversos , Quinolonas/administração & dosagem , Tiofenos/efeitos adversos , Tiofenos/administração & dosagemRESUMO
Soft bioelectronic neural interfaces have great potential as mechanically favourable alternatives to implantable metal electrodes. In this pursuit, conductive hydrogels (CHs) are particularly viable, combining tissue compliance with the required electrochemical characteristics. Physically-aggregated CHs offer an additional advantage by their facile synthesis into injectable systems, enabling minimally invasive implantation, though they can be impeded by a lack of control over their particle size and packing. Guided by these principles, an injectable PEDOT:PSS/acetic acid-based hydrogel is presented herein whose mechanical and electrochemical properties are independently tuneable by modifying the relative acetic acid composition. The fabrication process further benefits from employing batch emulsion to decrease particle sizes and facilitate tighter packing. The resulting material is stable and anatomically compact upon injection both in tissue phantom and ex vivo, while retaining favourable electrochemical properties in both contexts. Biphasic current stimulation yielding voltage transients well below the charge injection limit as well as the gel's non-cytotoxicity further underscore its potential for safe and effective neural interfacing applications.
Assuntos
Condutividade Elétrica , Hidrogéis , Hidrogéis/química , Animais , Injeções , Eletrodos , Poliestirenos/química , Tamanho da Partícula , Materiais Biocompatíveis/química , Eletrodos Implantados , TiofenosRESUMO
In this study, heterocyclic compounds containing a benzothiophene scaffold were designed and synthetized, and their inhibitory activity against cholinesterases (ChE) and the viability of SH-SY5Y cells have been evaluated. Benzothiophenes 4a-4i and benzothiophene-chalcone hybrids 5a-5i were tested against both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), revealing interesting structure-activity relationships. In general, benzothiophene-chalcone hybrids from series 5 proved to be better inhibitors of both enzymes, with compound 5f being the best AChE inhibitor (IC50 = 62.10 µM) and compound 5h being the best BChE inhibitor (IC50 = 24.35 µM), the last one having an IC50 similar to that of galantamine (IC50 = 28.08 µM), the reference compound. The in silico ADME profile of the compounds was also studied. Molecular docking calculations were carried out to analyze the best binding scores and to elucidate enzyme-inhibitors' interactions.
Assuntos
Acetilcolinesterase , Butirilcolinesterase , Chalconas , Inibidores da Colinesterase , Simulação de Acoplamento Molecular , Tiofenos , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/síntese química , Humanos , Tiofenos/química , Tiofenos/farmacologia , Tiofenos/síntese química , Chalconas/química , Chalconas/síntese química , Chalconas/farmacologia , Butirilcolinesterase/metabolismo , Butirilcolinesterase/química , Relação Estrutura-Atividade , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Estrutura Molecular , Linhagem Celular TumoralRESUMO
Introduction: Eltrombopag (EPAG), a thrombopoietin receptor agonist, was approved for the treatment of severe aplastic anemia (SAA) combined with immunosuppressive therapy (IST). However, EPAG contains a typical biphenyl structure, which causes liver function damage. Methods: Twenty patients with SAA who were intolerant or refractory to EPAG were enrolled in a multicenter prospective registry of the Chinese Eastern Collaboration Group of Anemia (ChiCTR2100045895) from October 2020 to June 2023. Results: Eight patients who were ineffective to EPAG, six with kidney impairment, and nine with abnormal liver function (two with concomitant liver and kidney impairment) were converted to avatrombopag (AVA) therapy with the median duration of AVA treatment was 6 (3-24) months. 17 cases (85%) achieved trilineage hematological response (HR): complete remission (CR) in 3 cases (15%), good partial remission (GPR) in 4 cases (20%), partial remission (PR) in 10 cases (50%), and no response (NR) in 3 cases (15%). The median time to response was 1.7 (0.5-6.9) months, with 16 cases (94%) achieving response within six months and 17 cases (100%) within 12 months. 9 cases (50%) achieved transfusion independence. AVA converted treatment was associated with higher neutrophil counts (0.8×109/L vs 2.2×109/L, p=0.0003), platelet counts (11×109/L vs 39×109/L, p=0.0008), hemoglobin count (59g/L vs 98g/L, p=0.0002), red cell count (1.06×1012/L vs 2.97×1012/L, p=0.001), and absolute reticulocyte count (31.99 ×109/L vs 67.05×109/L p=0.0004) were all significantly elevated compared with the pre-treatment level. After the conversion to AVA therapy, liver and kidney function indexes were maintained within the normal range, no AVA related grade 2 or higher adverse events occurred, and no thrombotic events occurred. Conclusion: The conversion to AVA was an optimal choice for patients with SAA who were EPAG intolerant or refractory. Clinical trial registration: http://www.chictr.org.cn/showproj.html?proj=125480, identifier ChiCTR2100045895.
Assuntos
Anemia Aplástica , Benzoatos , Pirazóis , Humanos , Masculino , Feminino , Anemia Aplástica/tratamento farmacológico , Anemia Aplástica/terapia , Adulto , Benzoatos/uso terapêutico , Benzoatos/efeitos adversos , Pessoa de Meia-Idade , Pirazóis/uso terapêutico , Pirazóis/efeitos adversos , Adulto Jovem , Adolescente , Pirazolonas/uso terapêutico , Hidrazonas/uso terapêutico , Receptores de Trombopoetina/agonistas , Resultado do Tratamento , Estudos Prospectivos , Imunossupressores/uso terapêutico , Imunossupressores/efeitos adversos , Idoso , Hidrazinas/uso terapêutico , Hidrazinas/efeitos adversos , Tiazóis , TiofenosRESUMO
As a step toward the development of novel small-molecule positive allosteric modulators (PAMs) of glucagon-like peptide 1 receptor (GLP-1R) for the treatment of type 2 diabetes, obesity, and heart diseases, we discovered a novel 2-amino-thiophene (2-AT) based lead compound bearing an ethyl 3-carboxylate appendage. In this work, we report the syntheses and biological studies of more than forty 2-AT analogs, that have revealed a 2-aminothiophene-3-arylketone analogue 7 (MW 299) showing approximately a 2-fold increase in insulin secretion at 5 µM when combined with the GLP-1 peptide at 10 nM. In vivo studies using CD1 mice at a dose of 10 mg/kg, clearly demonstrated that the blood plasma glucose level was lowered by 50% after 60 min. Co-treatment of 7 with sitagliptin, an inhibitor of GLP-1 degrading enzyme Dipeptidyl Peptidase IV, further confirmed 7 to be an effective PAM of GLP-1R. The small molecular weight and demonstrated allosteric modulating properties of these compound series, show the potential of these scaffolds for future drug development.