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1.
Molecules ; 29(19)2024 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-39407708

RESUMO

Despite the great effort that has gone into developing new molecules as multitarget compounds to treat Alzheimer's disease (AD), none of these have been approved to treat this disease. Therefore, it will be interesting to determine whether benzazoles such as benzimidazole, benzoxazole, and benzothiazole, employed as pharmacophores, could act as multitarget drugs. AD is a multifactorial disease in which several pharmacological targets have been identified-some are involved with amyloid beta (Aß) production, such as beta secretase (BACE1) and beta amyloid aggregation, while others are involved with the cholinergic system as acetylcholinesterase (AChE) and butirylcholinesterase (BChE) and nicotinic and muscarinic receptors, as well as the hyperphosphorylation of microtubule-associated protein (tau). In this review, we describe the in silico and in vitro evaluation of benzazoles on three important targets in AD: AChE, BACE1, and Aß. Benzothiazoles and benzimidazoles could be the best benzazoles to act as multitarget drugs for AD because they have been widely evaluated as AChE inhibitors, forming π-π interactions with W286, W86, Y72, and F338, as well as in the AChE gorge and catalytic site. In addition, the sulfur atom from benzothiazol interacts with S286 and the aromatic ring from W84, with these compounds having an IC50 value in the µM range. Also, benzimidazoles and benzothiazoles can inhibit Aß aggregation. However, even though benzazoles have not been widely evaluated on BACE1, benzimidazoles evaluated in vitro showed an IC50 value in the nM range. Therefore, important chemical modifications could be considered to improve multitarget benzazoles' activity, such as substitutions in the aromatic ring with electron withdrawal at position five, or a linker 3 or 4 carbons in length, which would allow for better interaction with targets.


Assuntos
Acetilcolinesterase , Doença de Alzheimer , Secretases da Proteína Precursora do Amiloide , Peptídeos beta-Amiloides , Inibidores da Colinesterase , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/metabolismo , Humanos , Acetilcolinesterase/metabolismo , Acetilcolinesterase/química , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/síntese química , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ácido Aspártico Endopeptidases/metabolismo , Agregados Proteicos/efeitos dos fármacos , Benzimidazóis/química , Benzimidazóis/farmacologia , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Animais
2.
Mol Med Rep ; 30(6)2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-39392050

RESUMO

Acute myeloid leukemia (AML) is the most common hematological cancer in the adult population worldwide. Approximately 35% of patients with AML present internal tandem duplication (ITD) mutations in the FMS­like tyrosine kinase 3 (FLT3) receptor associated with poor prognosis, and thus, this receptor is a relevant target for potential therapeutics. Tyrosine kinase inhibitors (TKIs) are used to treat AML; however, their molecular interactions and effects on leukemic cells are poorly understood. The present study aimed to gain insights into the molecular interactions and affinity forces of four TKI drugs (sorafenib, midostaurin, gilteritinib and quizartinib) with the wild­type (WT)­FLT3 and ITD­mutated (ITD­FLT3) structural models of FLT3, in its inactive aspartic acid­phenylalanine­glycine motif (DFG­out) and active aspartic acid­phenylalanine­glycine motif (DFG­in) conformations. Furthermore, the present study evaluated the effects of the second­generation TKIs gilteritinib and quizartinib on cancer cell viability, apoptosis and proliferation in the MV4­11 (ITD­FLT3) and HL60 (WT­FLT3) AML cell lines. Peripheral blood mononuclear cells (PBMCs) from a healthy volunteer were included as an FLT3­negative group. Molecular docking analysis indicated higher affinities of second­generation TKIs for WT­FLT3/DFG­out and WT­FLT3/DFG­in compared with those of the first­generation TKIs. However, the ITD mutation changed the affinity of all TKIs. The in vitro data supported the in silico predictions: MV4­11 cells presented high selective sensibility to gilteritinib and quizartinib compared with the HL60 cells, whereas the drugs had no effect on PBMCs. Thus, the current study presented novel information about molecular interactions between the FLT3 receptors (WT or ITD­mutated) and some of their inhibitors. It also paves the way for the search for novel inhibitory molecules with potential use against AML.


Assuntos
Leucemia Mieloide Aguda , Inibidores de Proteínas Quinases , Estaurosporina , Tirosina Quinase 3 Semelhante a fms , Humanos , Compostos de Anilina/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Benzotiazóis/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Simulação por Computador , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Tirosina Quinase 3 Semelhante a fms/genética , Tirosina Quinase 3 Semelhante a fms/metabolismo , Tirosina Quinase 3 Semelhante a fms/química , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/genética , Simulação de Acoplamento Molecular , Mutação , Compostos de Fenilureia/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/farmacologia , Sorafenibe/farmacologia , Estaurosporina/análogos & derivados , Estaurosporina/farmacologia , Triazinas/farmacologia , Triazinas/química
3.
J Bras Nefrol ; 46(4): e20230187, 2024.
Artigo em Inglês, Português | MEDLINE | ID: mdl-39412512

RESUMO

Diabetic kidney disease (DKD) remains the leading cause of chronic kidney disease (CKD) worldwide. The pathogenesis of DKD is influenced by functional, histopathological, and immune mechanisms, including NLRP3 inflammasome activity and oxidative stress. The sodium-glucose cotransporter 2 inhibitors (SGLT2i) have shown metabolic benefits and the ability to slow the progression of DKD in several clinical studies over the years. Recent studies suggest that the antidiabetic activity also extends to inhibition of the inflammatory response, including modulation of the NLRP3 inflammasome, reduction of pro-inflammatory markers and reduction of oxidative stress. Here we review the efficacy of SGLT2i in the treatment of CKD and discuss the role of the inflammatory response in the development of DKD, including its relationship to the NLRP3 inflammasome and oxidative stress.


Assuntos
Nefropatias Diabéticas , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/metabolismo , Inflamassomos/antagonistas & inibidores , Estresse Oxidativo/efeitos dos fármacos
4.
Front Immunol ; 15: 1455469, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39355246

RESUMO

Purines and pyrimidines are signaling molecules in the tumor microenvironment that affect cancer immunity. The purinergic signaling pathways have been shown to play an important role in the development and progression of cancer. CD39 and CD73 are ectonucleotidases responsible for breaking down ATP or ADP into adenosine, which regulates immunosuppression in various types of cancer. These enzymes have been studied as a potential therapeutic target in immunotherapy, and recent research suggests a correlation between ectonucleotidases and clinical outcomes in cancer.Prostate cancer is the most diagnosed cancer in men, after non-melanoma skin tumors, and is the second leading cause of death in men in the world. Despite having long survival periods, patients often receive excessive or insufficient treatment. Within this complex landscape, the adenosine/CD73 pathway plays a crucial role. Therefore, this review aims to highlight new findings on the potential role of purinergic signaling in cancer treatment and emphasizes the importance of anti-CD73 as a pharmacological strategy for prostate cancer therapy.


Assuntos
5'-Nucleotidase , Neoplasias da Próstata , Transdução de Sinais , Humanos , 5'-Nucleotidase/metabolismo , 5'-Nucleotidase/imunologia , Masculino , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/terapia , Neoplasias da Próstata/imunologia , Neoplasias da Próstata/tratamento farmacológico , Animais , Proteínas Ligadas por GPI/metabolismo , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/imunologia , Microambiente Tumoral/imunologia , Adenosina/metabolismo , Imunoterapia/métodos , Terapia de Alvo Molecular
6.
Sci Rep ; 14(1): 23882, 2024 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-39396074

RESUMO

Beyond its clinical diversity and severity, acute myeloid leukemia (AML) is known for its complex molecular background and for rewiring biological processes to aid disease onset and maintenance. FLT3 mutations are among the most recurring molecular entities that cooperatively drive AML, and their inhibition is a critical molecularly oriented therapeutic strategy. Despite being a promising avenue, it still faces challenges such as intrinsic and acquired drug resistance, which led us to investigate whether and how autophagy and inflammasome interact and whether this interaction could be leveraged to enhance FLT3 inhibition as a therapeutic strategy. We observed a strong and positive correlation between the expression of key genes associated with autophagy and the inflammasome. Gene set enrichment analysis of the FLT3-ITD samples and their ex vivo response to five different FLT3 inhibitors revealed a common molecular signature compatible with autophagy and inflammasome activation across all poor responders. Inflammasome activation was also shown to strongly increase the likelihood of a poor ex vivo response to the FLT3 inhibitors quizartinib and sorafenib. These findings reveal a distinct molecular pattern within FLT3-ITD AML samples that underscores the necessity for further exploration into how approaching these supportive parallel yet altered pathways could improve therapeutic strategies.


Assuntos
Autofagia , Inflamassomos , Leucemia Mieloide Aguda , Inibidores de Proteínas Quinases , Tirosina Quinase 3 Semelhante a fms , Tirosina Quinase 3 Semelhante a fms/genética , Tirosina Quinase 3 Semelhante a fms/metabolismo , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Autofagia/efeitos dos fármacos , Inflamassomos/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Mutação , Feminino , Masculino , Benzotiazóis/farmacologia , Pessoa de Meia-Idade , Sorafenibe/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Idoso , Compostos de Fenilureia
7.
J Mol Model ; 30(11): 373, 2024 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-39387972

RESUMO

CONTEXT: Melanoma is one of the cancers with the highest mortality rate for its ability to metastasize. Several targets have undergone investigation for the development of drugs against this pathology. One of the main targets is the kinase BRAF (RAF, rapidly accelerated fibrosarcoma). The most common mutation in melanoma is BRAFV600E and has been reported in 50-90% of patients with melanoma. Due to the relevance of the BRAFV600E mutation, inhibitors to this kinase have been developed, vemurafenib-OMe and dabrafenib. Ursolic acid (UA) is a pentacyclic triterpene with a privileged structure, the pentacycle scaffold, which allows to have a broad variety of biological activity; the most studied is its anticancer capacity. In this work, we reported the interaction profile of vemurafenib-OMe, dabrafenib, and UA, to define whether UA has binding capacity to BRAFWT, BRAFV600E, and BRAFV600K. Homology modeling of BRAFWT, V600E, and V600K; molecular docking; and molecular dynamics simulations were carried out and interactions and residues relevant to the binding of the inhibitors were obtained. We found that UA, like the inhibitors, presents hydrogen bond interactions, and hydrophobic interactions of van der Waals, and π-stacking with I463, Q530, C532, and F583. The ΔG of ursolic acid in complex with BRAFV600K (- 63.31 kcal/mol) is comparable to the ΔG of the selective inhibitor dabrafenib (- 63.32 kcal/mol) in complex to BRAFV600K and presents a ΔG like vemurafenib-OMe with BRAFWT and V600E. With this information, ursolic acid could be considered as a lead compound for design cycles and to optimize the binding profile and the selectivity towards mutations for the development of new selective inhibitors for BRAFV600E and V600K to new potential melanoma treatments. METHODS: The homology modeling calculations were executed on the public servers I-TASSER and ROBETTA, followed by molecular docking calculations using AutoGrid 4.2.6, AutoDockGPU 1.5.3, and AutoDockTools 1.5.6. Molecular dynamics and metadynamics simulations were performed in the Desmond module of the academic version of the Schrödinger-Maestro 2020-4 program, utilizing the OPLS-2005 force field. Ligand-protein interactions were evaluated using Schrödinger-Maestro program, LigPlot + , and PLIP (protein-ligand interaction profiler). Finally, all of the protein figures presented in this article were made in the PyMOL program.


Assuntos
Melanoma , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Proteínas Proto-Oncogênicas B-raf , Triterpenos , Ácido Ursólico , Triterpenos/química , Triterpenos/farmacologia , Proteínas Proto-Oncogênicas B-raf/química , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/metabolismo , Proteínas Proto-Oncogênicas B-raf/genética , Humanos , Melanoma/tratamento farmacológico , Melanoma/genética , Imidazóis/química , Imidazóis/farmacologia , Ligação Proteica , Vemurafenib/farmacologia , Vemurafenib/química , Oximas/química , Oximas/farmacologia , Mutação , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Sítios de Ligação
9.
Retina ; 44(10): 1704-1713, 2024 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-39287533

RESUMO

PURPOSE: The Phase 3 Mylight study was designed to confirm clinical equivalence of proposed biosimilar aflibercept (SOK583A1; Sandoz [proposed biosimilar aflibercept, SDZ-AFL]) to its reference biologic (Eylea; Regeneron Pharmaceuticals, Inc; Bayer AG [reference aflibercept, Ref-AFL]). METHOD: Mylight was a prospective, double-masked, 2-arm, parallel Phase 3 study. Participants with neovascular age-related macular degeneration were randomized 1:1 to receive eight injections of SDZ-AFL (n = 244) or Ref-AFL (n = 240) over 48 weeks. The primary endpoint was mean change in best-corrected visual acuity score from baseline to Week 8. Secondary endpoints included anatomical outcomes, best-corrected visual acuity at Weeks 24 and 52, safety, and pharmacokinetics. RESULTS: Similarity in mean change in best-corrected visual acuity score was established between SDZ-AFL (n = 235) and Ref-AFL (n = 226) at Week 8 (difference: -0.3 [90% CI, -1.5 to 1.0]) and Week 52. No clinically meaningful differences occurred between groups in anatomical outcomes. Safety profiles were similar, with comparable incidences of treatment-related adverse events (SDZ-AFL: 2.5%; Ref-AFL: 2.9%). The incidence of anti-drug antibodies was similar between groups. Systemic free aflibercept concentrations 24 hours postdose were low and comparable between SDZ-AFL and Ref-AFL. CONCLUSION: Proposed biosimilar aflibercept matched reference aflibercept in efficacy, safety, and pharmacokinetics in participants with neovascular age-related macular degeneration. Therefore, this Phase 3 study confirmed biosimilarity of SDZ-AFL to Ref-AFL.


Assuntos
Inibidores da Angiogênese , Medicamentos Biossimilares , Injeções Intravítreas , Receptores de Fatores de Crescimento do Endotélio Vascular , Proteínas Recombinantes de Fusão , Acuidade Visual , Degeneração Macular Exsudativa , Humanos , Receptores de Fatores de Crescimento do Endotélio Vascular/administração & dosagem , Receptores de Fatores de Crescimento do Endotélio Vascular/uso terapêutico , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/efeitos adversos , Proteínas Recombinantes de Fusão/uso terapêutico , Método Duplo-Cego , Masculino , Feminino , Estudos Prospectivos , Idoso , Medicamentos Biossimilares/efeitos adversos , Medicamentos Biossimilares/uso terapêutico , Medicamentos Biossimilares/farmacocinética , Degeneração Macular Exsudativa/tratamento farmacológico , Degeneração Macular Exsudativa/diagnóstico , Degeneração Macular Exsudativa/fisiopatologia , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/efeitos adversos , Inibidores da Angiogênese/uso terapêutico , Inibidores da Angiogênese/farmacocinética , Idoso de 80 Anos ou mais , Resultado do Tratamento , Tomografia de Coerência Óptica , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Seguimentos , Fatores de Tempo
10.
Future Microbiol ; 19(17): 1475-1488, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39268668

RESUMO

Aim: To search for potential inhibitors to homoserine dehydrogenase (HSD) in Paracoccidioides brasiliensis the causative agent of paracoccidioidomycosis, an infection with a high mortality rate in Brazil.Materials & methods: The enzyme was modeled and used in the virtual screening of the compounds. The library was first screened by the Autodock, in which 66 molecules were better ranked than substrate, and then, also evaluated by the Molegro and Gold programs.Results: The HS23 and HS87 molecules were selected in common by the three programs, and ADME/Tox evaluation indicates they are not toxic. The molecular dynamics of PbHSD bonded to ligands showed stable complexes until 50 ns. To validate the results, compounds were purchased for assays of minimum inhibitory concentration (MIC), minimum fungicidal concentration (MFC), synergic profile with Amphotericin B (AmB) and cytotoxicity. The two molecules presented MIC of 32 µg/ml and MFC of 64 µg/ml against the P. brasiliensis (strain Pb18). They also showed synergistic activity with AmB and a lack of toxicity against Hela and Vero cell lines.Conclusion: These results suggest that the HS23 and HS87 are promising candidates as PbHSD inhibitors and may be used as hits for the development of new drugs against paracoccidioidomycosis.


[Box: see text].


Assuntos
Antifúngicos , Inibidores Enzimáticos , Homosserina Desidrogenase , Testes de Sensibilidade Microbiana , Paracoccidioides , Paracoccidioides/efeitos dos fármacos , Paracoccidioides/enzimologia , Antifúngicos/farmacologia , Antifúngicos/química , Humanos , Homosserina Desidrogenase/antagonistas & inibidores , Homosserina Desidrogenase/metabolismo , Homosserina Desidrogenase/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Animais , Células Vero , Chlorocebus aethiops , Simulação de Acoplamento Molecular , Paracoccidioidomicose/tratamento farmacológico , Paracoccidioidomicose/microbiologia , Células HeLa , Brasil , Anfotericina B/farmacologia , Simulação de Dinâmica Molecular , Simulação por Computador , Sinergismo Farmacológico , Proteínas Fúngicas/antagonistas & inibidores , Proteínas Fúngicas/metabolismo , Proteínas Fúngicas/química
11.
JCO Glob Oncol ; 10: e2400056, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39303197

RESUMO

PURPOSE: The optimal treatment sequence for hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) after progression on first-line cyclin-dependent kinase 4/6 inhibitor (CDKi) and endocrine therapy is unclear. Clinical and biological factors influencing treatment choices and outcomes in the second-line setting need to be elucidated. MATERIALS AND METHODS: This is a retrospective analysis of a real-world cohort including patients with HR+/HER2- ABC who received CDKi and endocrine therapy in the first-line setting and progressed, requiring second-line treatment. Clinical and biological factors were analyzed to evaluate their association with daily treatment decisions and the prognostic role of progression-free survival (PFS) in the second-line setting. RESULTS: Two hundred thirty-five patients were included. Second-line treatments were hormone therapy (HT) based in 60% and chemotherapy based in 40% of patients. The second-line median PFS was 6.6 months, with no difference between treatment types. In multivariable analysis, postmenopausal status, lower Ki-67 expression, and non-de novo stage IV disease were associated with improved second-line (2L) PFS. Menopausal status significantly interacted with treatment type, with reduced PFS in premenopausal patients receiving HT-based treatments (4.7 v 8.7 months, P = .00045). CONCLUSION: In our study, treatment decisions reflected the current algorithm incorporated in our clinical guidelines, and prior treatment response was the most relevant factor to determine 2L treatment decision. Menopausal status interacted with the subsequent therapy efficacy in this setting. Hence, we consider that menopausal status should be routinely evaluated in the subgroup analysis of clinical trials.


Assuntos
Neoplasias da Mama , Quinase 4 Dependente de Ciclina , Quinase 6 Dependente de Ciclina , Inibidores de Proteínas Quinases , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Pessoa de Meia-Idade , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Estudos Retrospectivos , Argentina/epidemiologia , Idoso , Adulto , Inibidores de Proteínas Quinases/uso terapêutico , Idoso de 80 Anos ou mais , Receptor ErbB-2/metabolismo , Intervalo Livre de Progressão
12.
Eur J Neurosci ; 60(8): 5849-5860, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39235324

RESUMO

The paraventricular nucleus of the hypothalamus (PVN) regulates physiological and behavioural responses evoked by stressful stimuli, but the local neurochemical and signalling mechanisms involved are not completely understood. The soluble guanylate cyclase (sGC) within the PVN is implicated in autonomic and cardiovascular control in rodents under resting conditions. However, the involvement of PVN sGC-mediated signalling in stress responses is unknown. Therefore, we investigated the role of sGC within the PVN in cardiovascular, autonomic, neuroendocrine, and local neuronal responses to acute restraint stress in rats. Bilateral microinjection of the selective sGC inhibitor ODQ (1 nmol/100 nl) into the PVN reduced both the increased arterial pressure and the drop in cutaneous tail temperature evoked by restraint stress, while the tachycardia was enhanced. Intra-PVN injection of ODQ did not alter the number of Fos-immunoreactive neurons in either the dorsal cap parvocellular (PaDC), ventromedial (PaV), medial parvocellular (PaMP), or lateral magnocelllular (PaLM) portions of the PVN following acute restraint stress. Local microinjection of ODQ into the PVN did not affect the restraint-induced increases in plasma corticosterone concentration. Taken together, these findings suggest that sGC-mediated signalling in the PVN plays a key role in acute stress-induced pressor responses and sympathetically mediated cutaneous vasoconstriction, whereas the tachycardiac response is inhibited. Absence of an effect of ODQ on corticosterone and PVN neuronal activation in and the PaV and PaMP suggests that PVN sGC is not involved in restraint-evoked hypothalamus-pituitary-adrenal (HPA) axis activation and further indicates that autonomic and neuroendocrine responses are dissociable at the level of the PVN.


Assuntos
Núcleo Hipotalâmico Paraventricular , Restrição Física , Estresse Psicológico , Animais , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/metabolismo , Masculino , Ratos , Estresse Psicológico/fisiopatologia , Estresse Psicológico/metabolismo , Guanilil Ciclase Solúvel/metabolismo , Sistema Nervoso Autônomo/efeitos dos fármacos , Sistema Nervoso Autônomo/fisiopatologia , Ratos Wistar , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Guanilato Ciclase/metabolismo , Guanilato Ciclase/antagonistas & inibidores
13.
Peptides ; 181: 171294, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39265809

RESUMO

Endometriosis is a gynecological condition characterized by the growth of endometrium-like tissues outside of the uterine cavity. Currently available drugs are efficacious in treating endometriosis-related pain, however it's not a targeted treatment. The aim of this work is to evaluate the effects of R-954, a bradykinin B1 receptor antagonist, in a murine model of endometriosis. The model was induced in animals through autologous transplantation of part of the uterine horn. After 51 days, it was observed that implants developed into endometriotic lesions. The administration of R-954 or progesterone, for 15 consecutive days, prevented the progression of cyst development, reduced the size and weight of the cysts. Both treatments also reduced cellular infiltrate and production of inflammatory mediators (interleukin-1ß, interleukin-6, tumor necrosis factor). However, only R-954 decreased angiogenic factors (VEGF and VEGF receptor). In addition, treatment with the antagonist did not interfere in the females' estrous cycle, as well as prevented gestational losses (reduction in the number of intermediate resorptions in pregnant females with endometriosis). Data suggested that R-954 has anti-inflammatory and anti-angiogenic effects; does not influence the estrous cycle; and prevents the number of gestational losses suggesting it as a good candidate for endometriosis treatment.


Assuntos
Antagonistas de Receptor B1 da Bradicinina , Modelos Animais de Doenças , Endometriose , Endometriose/tratamento farmacológico , Endometriose/patologia , Feminino , Animais , Antagonistas de Receptor B1 da Bradicinina/farmacologia , Antagonistas de Receptor B1 da Bradicinina/uso terapêutico , Camundongos , Humanos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Gravidez
14.
Peptides ; 181: 171296, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39265810

RESUMO

Exercise training leads to physiological cardiac hypertrophy and the protective axis of the renin-angiotensin system composed of angiotensin-converting enzyme 2, angiotensin-(1-7), and Mas receptor seems involved in this process. However, the role of the basal activity of the Mas receptor in exercise-induced physiological cardiac hypertrophy is still unclear. We evaluated the effects of the Mas receptor blockade on the left ventricular structure and function of rats submitted to running training. Rats were assigned to 4 groups: sedentary (S), sedentary + A-779 (Mas receptor antagonist, 120 µg/kg/day, i.p.; SA), trained (60-minute treadmill running sessions, five days a week, 8 weeks; T), and trained + A-779 (TA). Systolic blood pressure was higher in sedentary and trained rats treated with A-779 at the end of the experimental period. The A-779 treatment prevented the left ventricular hypertrophy evoked by physical exercise and increased collagen deposition in sedentary and trained rats. Cardiomyocytes from the SA group presented increased length and thickness of the sarcomeres, elongated mitochondria, glycogen deposits, and enlarged cisterns of the sarcoplasmic reticulum. TA group presented a reduced sarcomere thickness and cytoplasm with a degenerative aspect. These findings show that the basal activity of the Mas receptor is essential for the proper turnover of the extracellular matrix in the myocardium and the maintenance of the sarcomeric structure of cardiomyocytes.


Assuntos
Cardiomegalia , Condicionamento Físico Animal , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas , Ratos Wistar , Receptores Acoplados a Proteínas G , Animais , Ratos , Masculino , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Proteínas Proto-Oncogênicas/metabolismo , Cardiomegalia/metabolismo , Cardiomegalia/induzido quimicamente , Cardiomegalia/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Pressão Sanguínea/efeitos dos fármacos , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/patologia , Fragmentos de Peptídeos/farmacologia , Fragmentos de Peptídeos/metabolismo , Angiotensina II/análogos & derivados
15.
Cell Biol Int ; 48(11): 1637-1648, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39285521

RESUMO

Ectophosphatases catalyse the hydrolysis of phosphorylated molecules, such as phospho-amino acids, in the extracellular environment. Nevertheless, the hydrolysis of nucleotides in the extracellular environment is typically catalysed by ectonucleotidases. Studies have shown that acid ectophosphatase, or transmembrane-prostatic acid phosphatase (TM-PAP), a membrane-bound splice variant of prostatic acid phosphatase, has ecto-5'-nucleotidase activity. Furthermore, it was demonstrated that ectophosphatase cannot hydrolyse ATP, ADP, or AMP in triple-negative breast cancer cells. In contrast to previous findings in MDA-MB-231 cells, the ectophosphatase studied in the present work displayed a remarkable capacity to hydrolyse AMP in luminal A breast cancer cells (MCF-7). We showed that AMP dose-dependently inhibited p-nitrophenylphosphate (p-NPP) hydrolysis. The p-NPP and AMP hydrolysis showed similar biochemical behaviours, such as increased hydrolysis under acidic conditions and comparable inhibition by NiCl2, ammonium molybdate, and sodium orthovanadate. In addition, this ectophosphatase with ectonucleotidase activity was essential for the release of adenosine and inorganic phosphate from phosphorylated molecules available in the extracellular microenvironment. This is the first study to show that prostatic acid phosphatase on the membrane surface of breast cancer cells (MCF-7) is correlated with cell adhesion and migration.


Assuntos
Fosfatase Ácida , Neoplasias da Mama , Humanos , Células MCF-7 , Feminino , Hidrólise , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/enzimologia , Fosfatase Ácida/metabolismo , 5'-Nucleotidase/metabolismo , Monofosfato de Adenosina/metabolismo , Proteínas Tirosina Fosfatases/metabolismo , Proteínas Tirosina Fosfatases/antagonistas & inibidores , Nitrofenóis/farmacologia , Nitrofenóis/metabolismo , Linhagem Celular Tumoral , Compostos Organofosforados
16.
JNCI Cancer Spectr ; 8(5)2024 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-39254653

RESUMO

BACKGROUND: Cyclin-dependent kinases (CDK) 4/6 inhibitors have significantly improved outcomes for patients with ER+/HER2- breast cancer. Nevertheless, they differ from each other in terms of chemical, biological, and pharmacological features, as well as toxicity profiles. We aim to determine whether QTc prolongation is caused by CDK4/6i in general or if it is associated with ribociclib only. METHODS: We systematically searched PubMed, Embase, and Cochrane Library for randomized controlled trials (RCTs) comparing the prevalence of QTc prolongation as an adverse event in HR+ breast cancer patients treated with CDK4/6i vs those without CDK4/6i. We pooled relative risk (RR) and mean difference (MD) with 95% confidence interval (CI) for the binary endpoint of QT prolongation. RESULTS: We included 14 RCTs comprising 16 196 patients, of whom 8576 underwent therapy with CDK4/6i. An increased risk of QTc prolongation was associated with the use of CDK4/6i (RR = 2.35, 95% CI = 1.67 to 3.29, P < .001; I2 = 44%). Subgroup analyses revealed a significant increase in the QTc interval for the ribociclib and palbociclib cohorts. The ribociclib subgroup showed a relative risk of 3.12 (95% CI = 2.09 to 4.65, P < .001; I2 = 12%), whereas the palbociclib subgroup had a relative risk of 1.51 (95% CI = 1.05 to 2.15, P = .025; I2 = 0%). CONCLUSION: Palbociclib was associated with QTc prolongation; however, the relative risk for any grade QTc was quantitively twice with ribociclib. Furthermore, grade 3 QTc prolongations were observed exclusively with ribociclib. These results are important for guiding clinical decision-making and provide reassurance regarding the overall safety profile of this drug class.


Assuntos
Neoplasias da Mama , Quinase 4 Dependente de Ciclina , Quinase 6 Dependente de Ciclina , Síndrome do QT Longo , Inibidores de Proteínas Quinases , Feminino , Humanos , Aminopiridinas/efeitos adversos , Aminopiridinas/uso terapêutico , Aminopiridinas/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Síndrome do QT Longo/induzido quimicamente , Piperazinas/efeitos adversos , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/administração & dosagem , Purinas/efeitos adversos , Purinas/uso terapêutico , Purinas/administração & dosagem , Piridinas/efeitos adversos , Piridinas/uso terapêutico , Piridinas/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Roscovitina/efeitos adversos
17.
Molecules ; 29(17)2024 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-39275102

RESUMO

Four afatinib derivatives were designed and modeled. These derivatives were compared to the known tyrosine-kinase inhibitors in treating Chronic Myeloid Leukemia, i.e., imatinib and ponatinib. The molecules were evaluated through computational methods, including docking studies, the non-covalent interaction index, Electron Localization and Fukui Functions, in silico ADMET analysis, QTAIM, and Heat Map analysis. The AFA(IV) candidate significantly increases the score value compared to afatinib. Furthermore, AFA(IV) was shown to be relatively similar to the ponatinib profile when evaluating a range of molecular descriptors. The addition of a methylpiperazine ring seems to be well distributed in the structure of afatinib when targeting the BCR-ABL enzyme, providing an important hydrogen bond interaction with the Asp381 residue of the DFG-switch of BCR-ABL active site residue and the AFA(IV) new chemical entities. Finally, in silico toxicity predictions show a favorable index, with some molecules presenting the loss of the irritant properties associated with afatinib in theoretical predictions.


Assuntos
Afatinib , Proteínas de Fusão bcr-abl , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Proteínas de Fusão bcr-abl/genética , Proteínas de Fusão bcr-abl/química , Afatinib/química , Afatinib/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Humanos , Modelos Moleculares , Simulação por Computador , Mutação , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Ligação de Hidrogênio , Antineoplásicos/química , Antineoplásicos/farmacologia , Imidazóis/química , Imidazóis/farmacologia , Piridazinas
18.
Molecules ; 29(17)2024 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-39275072

RESUMO

Cruzipain (CZP), the major cysteine protease present in T. cruzi, the ethiological agent of Chagas disease, has attracted particular attention as a therapeutic target for the development of targeted covalent inhibitors (TCI). The vast chemical space associated with the enormous molecular diversity feasible to explore by means of modern synthetic approaches allows the design of CZP inhibitors capable of exhibiting not only an efficient enzyme inhibition but also an adequate translation to anti-T. cruzi activity. In this work, a computer-aided design strategy was developed to combinatorially construct and screen large libraries of 1,4-disubstituted 1,2,3-triazole analogues, further identifying a selected set of candidates for advancement towards synthetic and biological activity evaluation stages. In this way, a virtual molecular library comprising more than 75 thousand diverse and synthetically feasible analogues was studied by means of molecular docking and molecular dynamic simulations in the search of potential TCI of CZP, guiding the synthetic efforts towards a subset of 48 candidates. These were synthesized by applying a Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) centered synthetic scheme, resulting in moderate to good yields and leading to the identification of 12 hits selectively inhibiting CZP activity with IC50 in the low micromolar range. Furthermore, four triazole derivatives showed good anti-T. cruzi inhibition when studied at 50 µM; and Ald-6 excelled for its high antitrypanocidal activity and low cytotoxicity, exhibiting complete in vitro biological activity translation from CZP to T. cruzi. Overall, not only Ald-6 merits further advancement to preclinical in vivo studies, but these findings also shed light on a valuable chemical space where molecular diversity might be explored in the search for efficient triazole-based antichagasic agents.


Assuntos
Cisteína Endopeptidases , Simulação de Acoplamento Molecular , Proteínas de Protozoários , Triazóis , Trypanosoma cruzi , Triazóis/química , Triazóis/farmacologia , Triazóis/síntese química , Cisteína Endopeptidases/química , Proteínas de Protozoários/antagonistas & inibidores , Proteínas de Protozoários/química , Trypanosoma cruzi/efeitos dos fármacos , Trypanosoma cruzi/enzimologia , Inibidores de Cisteína Proteinase/química , Inibidores de Cisteína Proteinase/farmacologia , Inibidores de Cisteína Proteinase/síntese química , Simulação de Dinâmica Molecular , Relação Estrutura-Atividade , Desenho Assistido por Computador , Desenho de Fármacos , Humanos , Estrutura Molecular , Tripanossomicidas/farmacologia , Tripanossomicidas/química , Tripanossomicidas/síntese química , Doença de Chagas/tratamento farmacológico
19.
Cochrane Database Syst Rev ; 9: CD014741, 2024 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-39297531

RESUMO

BACKGROUND: Atherosclerotic cardiovascular disease (ACVD) is worsened by chronic inflammatory diseases. Interleukin receptor antagonists (IL-RAs) and tumour necrosis factor-alpha (TNF) inhibitors have been studied to see if they can prevent cardiovascular events. OBJECTIVES: The purpose of this study was to assess the clinical benefits and harms of IL-RAs and TNF inhibitors in the primary and secondary prevention of ACVD. SEARCH METHODS: The Cochrane Heart Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE (including In-Process & Other Non-Indexed Citations), Ovid Embase, EBSCO CINAHL plus, and clinical trial registries for ongoing and unpublished studies were searched in February 2024. The reference lists of relevant studies, reviews, meta-analyses and health technology reports were searched to identify additional studies. No limitations on language, date of publication or study type were set. SELECTION CRITERIA: RCTs that recruited people with and without pre-existing ACVD, comparing IL-RAs or TNF inhibitors versus placebo or usual care, were selected. The primary outcomes considered were all-cause mortality, myocardial infarction, unstable angina, and adverse events. DATA COLLECTION AND ANALYSIS: Two or more review authors, working independently at each step, selected studies, extracted data, assessed the risk of bias and used GRADE to judge the certainty of evidence. MAIN RESULTS: We included 58 RCTs (22,053 participants; 21,308 analysed), comparing medication efficacy with placebo or usual care. Thirty-four trials focused on primary prevention and 24 on secondary prevention. The interventions included IL-1 RAs (anakinra, canakinumab), IL-6 RA (tocilizumab), TNF-inhibitors (etanercept, infliximab) compared with placebo or usual care. The certainty of evidence was low to very low due to biases and imprecision; all trials had a high risk of bias. Primary prevention: IL-1 RAs The evidence is very uncertain about the effects of the intervention on all-cause mortality(RR 0.33, 95% CI 0.01 to 7.58, 1 trial), myocardial infarction (RR 0.71, 95% CI 0.04 to 12.48, I² = 39%, 2 trials), unstable angina (RR 0.24, 95% CI 0.03 to 2.11, I² = 0%, 2 trials), stroke (RR 2.42, 95% CI 0.12 to 50.15; 1 trial), adverse events (RR 0.85, 95% CI 0.59 to 1.22, I² = 54%, 3 trials), or infection (rate ratio 0.84, 95% 0.55 to 1.29, I² = 0%, 4 trials). Evidence is very uncertain about whether anakinra and cankinumab may reduce heart failure (RR 0.21, 95% CI 0.05 to 0.94, I² = 0%, 3 trials). Peripheral vascular disease (PVD) was not reported as an outcome. IL-6 RAs The evidence is very uncertain about the effects of the intervention on all-cause mortality (RR 0.68, 95% CI 0.12 to 3.74, I² = 30%, 3 trials), myocardial infarction (RR 0.27, 95% CI 0.04 to1.68, I² = 0%, 3 trials), heart failure (RR 1.02, 95% CI 0.11 to 9.63, I² = 0%, 2 trials), PVD (RR 2.94, 95% CI 0.12 to 71.47, 1 trial), stroke (RR 0.34, 95% CI 0.01 to 8.14, 1 trial), or any infection (rate ratio 1.10, 95% CI: 0.88 to 1.37, I2 = 18%, 5 trials). Adverse events may increase (RR 1.13, 95% CI 1.04 to 1.23, I² = 33%, 5 trials). No trial assessed unstable angina. TNF inhibitors The evidence is very uncertain about the effects of the intervention on all-cause mortality (RR 1.78, 95% CI 0.63 to 4.99, I² = 10%, 3 trials), myocardial infarction (RR 2.61, 95% CI 0.11 to 62.26, 1 trial), stroke (RR 0.46, 95% CI 0.08 to 2.80, I² = 0%; 3 trials), heart failure (RR 0.85, 95% CI 0.06 to 12.76, 1 trial). Adverse events may increase (RR 1.13, 95% CI 1.01 to 1.25, I² = 51%, 13 trials). No trial assessed unstable angina or PVD. Secondary prevention: IL-1 RAs The evidence is very uncertain about the effects of the intervention on all-cause mortality (RR 0.94, 95% CI 0.84 to 1.06, I² = 0%, 8 trials), unstable angina (RR 0.88, 95% CI 0.65 to 1.19, I² = 0%, 3 trials), PVD (RR 0.85, 95% CI 0.19 to 3.73, I² = 38%, 3 trials), stroke (RR 0.94, 95% CI 0.74 to 1.2, I² = 0%; 7 trials), heart failure (RR 0.91, 95% 0.5 to 1.65, I² = 0%; 7 trials), or adverse events (RR 0.92, 95% CI 0.78 to 1.09, I² = 3%, 4 trials). There may be little to no difference between the groups in myocardial infarction (RR 0.88, 95% CI 0.0.75 to 1.04, I² = 0%, 6 trials). IL6-RAs The evidence is very uncertain about the effects of the intervention on all-cause mortality (RR 1.09, 95% CI 0.61 to 1.96, I² = 0%, 2 trials), myocardial infarction (RR 0.46, 95% CI 0.07 to 3.04, I² = 45%, 3 trials), unstable angina (RR 0.33, 95% CI 0.01 to 8.02, 1 trial), stroke (RR 1.03, 95% CI 0.07 to 16.25, 1 trial), adverse events (RR 0.89, 95% CI 0.76 to 1.05, I² = 0%, 2 trials), or any infection (rate ratio 0.66, 95% CI 0.32 to 1.36, I² = 0%, 4 trials). No trial assessed PVD or heart failure. TNF inhibitors The evidence is very uncertain about the effect of the intervention on all-cause mortality (RR 1.16, 95% CI 0.69 to 1.95, I² = 47%, 5 trials), heart failure (RR 0.92, 95% 0.75 to 1.14, I² = 0%, 4 trials), or adverse events (RR 1.15, 95% CI 0.84 to 1.56, I² = 32%, 2 trials). No trial assessed myocardial infarction, unstable angina, PVD or stroke. Adverse events may be underestimated and benefits inflated due to inadequate reporting. AUTHORS' CONCLUSIONS: This Cochrane review assessed the benefits and harms of using interleukin-receptor antagonists and tumour necrosis factor inhibitors for primary and secondary prevention of atherosclerotic diseases compared with placebo or usual care. However, the evidence for the predetermined outcomes was deemed low or very low certainty, so there is still a need to determine whether these interventions provide clinical benefits or cause harm from this perspective. In summary, the different biases and imprecision in the included studies limit their external validity and represent a limitation to determining the effectiveness of the intervention for both primary and secondary prevention of ACVD.


Assuntos
Anticorpos Monoclonais Humanizados , Aterosclerose , Infarto do Miocárdio , Prevenção Primária , Receptores de Interleucina-1 , Prevenção Secundária , Fator de Necrose Tumoral alfa , Humanos , Angina Instável/prevenção & controle , Angina Instável/mortalidade , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Aterosclerose/prevenção & controle , Aterosclerose/mortalidade , Viés , Causas de Morte , Infarto do Miocárdio/prevenção & controle , Infarto do Miocárdio/mortalidade , Prevenção Primária/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , Prevenção Secundária/métodos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Receptores de Interleucina-1/antagonistas & inibidores
20.
Pest Manag Sci ; 80(12): 6600-6606, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-39221960

RESUMO

BACKGROUND: Italian ryegrass (Lolium multiflorum Lam.) is one of the most troublesome grass weeds in Argentina. The extensive and repetitive use of acetyl-CoA carboxylase (ACCase)-inhibiting herbicides has induced resistance in this weed species. The objectives of this study were to quantify the resistance levels to ACCase-inhibiting herbicides in two resistant populations and to identify the target-site mutations associated with their resistance. RESULTS: Two resistant Italian ryegrass populations, Roldán and H2, were studied. Roldán was a suspected haloxyfop-resistant population, located in a wheat field from Santa Fe province with a history of ACCase-inhibiting herbicide use. The H2 population was obtained from the susceptible Hernandarias population (H0) after two cycles of selection with the herbicide quizalofop-ethyl. Whole-plant dose-response assays revealed that the resistant populations exhibited a high resistance to haloxyfop, with resistance factors (RF) exceeding 97-fold. Additionally, both populations showed a moderate resistance to pinoxaden (RF > 7), while maintaining susceptibility to clethodim. Partial chloroplastic ACCase sequences revealed isoleucine-to-asparagine substitution at position 2041 (Ile-2041-Asn) in both resistant populations. CONCLUSION: This work provides a better understanding of cross-resistance to ACCase-inhibiting herbicides in L. multiflorum populations and represents the first report of the target-site mutation Ile-2041-Asn conferring resistance in populations from Argentina. © 2024 Society of Chemical Industry.


Assuntos
Acetil-CoA Carboxilase , Resistência a Herbicidas , Herbicidas , Lolium , Lolium/efeitos dos fármacos , Lolium/genética , Lolium/enzimologia , Resistência a Herbicidas/genética , Argentina , Herbicidas/farmacologia , Acetil-CoA Carboxilase/genética , Acetil-CoA Carboxilase/antagonistas & inibidores , Acetil-CoA Carboxilase/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Proteínas de Plantas/antagonistas & inibidores , Mutação , Plantas Daninhas/efeitos dos fármacos , Plantas Daninhas/genética , Plantas Daninhas/enzimologia
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