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1.
Chem Commun (Camb) ; 56(7): 1042-1045, 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31868189

RESUMO

A novel enzyme-responsive supramolecular polysaccharide assembly composed of disulfide linked adamantane-naphthalimide fluorescent camptothecin prodrug (AdaCPT) and ß-CD modified hyaluronic acid (HACD) was constructed, possessing low cellular cytotoxicity and exhibiting targeted cellular imaging and controlled drug release at specific sites while providing a concurrent means for the real-time tracking of drug delivery.


Assuntos
Antineoplásicos/farmacologia , Camptotecina/farmacologia , Portadores de Fármacos/química , Corantes Fluorescentes/farmacologia , Pró-Fármacos/farmacologia , Adamantano/análogos & derivados , Adamantano/síntese química , Adamantano/farmacologia , Adamantano/toxicidade , Animais , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Camptotecina/síntese química , Camptotecina/toxicidade , Liberação Controlada de Fármacos , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/toxicidade , Células HCT116 , Humanos , Ácido Hialurônico/química , Camundongos , Microscopia Confocal/métodos , Microscopia de Fluorescência/métodos , Células NIH 3T3 , Naftalimidas/síntese química , Naftalimidas/farmacologia , Naftalimidas/toxicidade , Pró-Fármacos/síntese química , Pró-Fármacos/toxicidade , beta-Ciclodextrinas/química
2.
Exp Parasitol ; 206: 107730, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31494215

RESUMO

Phospholipids are the main component of membranes and are responsible for cell integrity. Alkylphospholipid analogues (APs) were first designed as antitumoral agents and were later tested against different cell types. Trypanosoma cruzi, the Chagas disease etiological agent, is sensitive to APs (edelfosine, miltefosine and ilmofosine) in vitro. We investigated the effect of synthetic ring substituted AP against epimastigotes, amastigotes and trypomastigotes. TCAN26, could inhibit the in vitro growth of epimastigotes and amastigotes with the 50% inhibitory concentrations (IC50) in the nanomolar range. Trypomastigotes lysis was also induced with 24-h treatment and a LC50 of 2.3 µM. Ultrastructural analysis by electron microscopy demonstrated that TCAN26 mainly affected the parasite's membranes leading to mitochondrial and Golgi cisternae swelling, membrane blebs, and autophagic figures in the different parasite developmental stages. While the Golgi of the parasites was significantly affected, the Golgi complex of the host cells remained normal suggesting a specific mechanism of action. In summary, our results suggest that TCAN 26 is a potent and selective inhibitor of T. cruzi growth probably due to disturbances of phospholipid biosynthesis.


Assuntos
Adamantano/farmacologia , Fosforilcolina/análogos & derivados , Fosforilcolina/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Adamantano/química , Animais , Antiprotozoários/química , Antiprotozoários/farmacologia , Autofagia/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , Doença de Chagas/tratamento farmacológico , Doença de Chagas/parasitologia , Relação Dose-Resposta a Droga , Citometria de Fluxo , Complexo de Golgi/efeitos dos fármacos , Concentração Inibidora 50 , Dose Letal Mediana , Macrófagos Peritoneais/efeitos dos fármacos , Camundongos , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão , Microscopia de Fluorescência , Microscopia Imunoeletrônica , Mitocôndrias/efeitos dos fármacos , Fosforilcolina/química , Tripanossomicidas/química , Trypanosoma cruzi/crescimento & desenvolvimento , Trypanosoma cruzi/ultraestrutura
3.
Artif Cells Nanomed Biotechnol ; 47(1): 3239-3245, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31364869

RESUMO

Osteoarthritis (OA) is a major public health concern for which a reliable non-invasive treatment option has yet to be developed. In the present study, we investigated the effects of saxagliptin, a novel dipeptidyl peptidase IV (DPP-4) inhibitor, on several important aspects of the pathophysiology of OA using primary human chondrocytes. The results of real-time PCR and ELISA analyses show that saxagliptin treatment significantly decreased mRNA and protein expression of three key cartilage degrading enzymes: matrix metalloproteinase (MMP)-1, MMP-3, and MMP-13. The results of western blot confirmed that this decrease in MMP-1, -3, and -13 expression prevented degradation of type II collagen. We also found that saxagliptin significantly inhibited expression of a disintegrin and metalloproteinase with thrombospondin motif (ADAMTS)-4 and ADAMTS-5, which was reflected by markedly decreased degradation of aggrecan. Inhibition of DPP-4 by saxagliptin also reduced oxidative stress in human primary chondrocytes as evidenced by decreased production of reactive oxygen species (ROS) and increased glutathione (GSH) levels. Additionally, the results of western blot analysis show that the effects of saxagliptin are mediated through the p38/IκBα/NF-κB pathway, which is considered an important treatment target for OA. These findings suggest a potential role for saxagliptin as a novel treatment against OA.


Assuntos
Adamantano/análogos & derivados , Agrecanas/metabolismo , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Colágeno Tipo II/metabolismo , Dipeptídeos/farmacologia , Osteoartrite/tratamento farmacológico , Proteólise/efeitos dos fármacos , Proteína ADAMTS4/metabolismo , Proteína ADAMTS5/metabolismo , Adamantano/farmacologia , Adamantano/uso terapêutico , Condrócitos/patologia , Dipeptídeos/uso terapêutico , Progressão da Doença , Ativação Enzimática/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Produtos Finais de Glicação Avançada/farmacologia , Humanos , Metaloproteinases da Matriz/metabolismo , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/metabolismo , Osteoartrite/metabolismo , Osteoartrite/patologia , Espécies Reativas de Oxigênio/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
4.
Eur J Med Chem ; 180: 613-626, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31351393

RESUMO

The development of multitarget compounds against multifactorial diseases, such as Alzheimer's disease, is an area of very intensive research, due to the expected superior therapeutic efficacy that should arise from the simultaneous modulation of several key targets of the complex pathological network. Here we describe the synthesis and multitarget biological profiling of a new class of compounds designed by molecular hybridization of an NMDA receptor antagonist fluorobenzohomoadamantanamine with the potent acetylcholinesterase (AChE) inhibitor 6-chlorotacrine, using two different linker lengths and linkage positions, to preserve or not the memantine-like polycyclic unsubstituted primary amine. The best hybrids exhibit greater potencies than parent compounds against AChE (IC50 0.33 nM in the best case, 44-fold increased potency over 6-chlorotacrine), butyrylcholinesterase (IC50 21 nM in the best case, 24-fold increased potency over 6-chlorotacrine), and NMDA receptors (IC50 0.89 µM in the best case, 2-fold increased potency over the parent benzohomoadamantanamine and memantine), which suggests an additive effect of both pharmacophoric moieties in the interaction with the primary targets. Moreover, most of these compounds have been predicted to be brain permeable. This set of biological properties makes them promising leads for further anti-Alzheimer drug development.


Assuntos
Adamantano/farmacologia , Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Fármacos Neuroprotetores/farmacologia , Tacrina/análogos & derivados , Acetilcolinesterase/metabolismo , Adamantano/análogos & derivados , Adamantano/química , Doença de Alzheimer/metabolismo , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Relação Estrutura-Atividade , Tacrina/química , Tacrina/farmacologia
5.
Molecules ; 24(15)2019 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-31357420

RESUMO

For the first time, orthogonally substituted azole-carboxylate adamantane ligands were synthesized and used for preparation of coordination polymers. The angle-shaped ligands were prepared by the reaction of 1-adamantanecarboxylic acid and azoles (1H-1,2,4-triazole, 3-methyl-1H-1,2,4-triazole, 3,5-dimethyl-1H-1,2,4-triazole, 1H-tetrazole, 5-methyl-1H-tetrazole) in concentrated sulfuric acid. Variation of the solvent and substituents in azole rings allowed to prepare both 1D and 2D copper(II) and nickel(II) coordination polymers, [Cu2(trzadc)4(H2O)0.7]∙DMF∙0.3H2O, [Cu(trzadc)2(MeOH)]∙MeOH, [Ni(trzadc)2(MeOH)2] and [Cu2(mtrzadc)3(MeOH)]+NO3- (trzadc-3-(1,2,4-triazol-1-yl)-adamantane-1-carboxylic acid; mtrzadc-3-(3-methyl-1,2,4-triazol-1-yl)-adamantane-1-carboxylic acid) which were structurally characterized by single crystal X-ray diffraction. Complex [Cu(trzadc)2(MeOH)]∙MeOH was shown to act as a catalyst in the Chan-Evans-Lam arylation reaction.


Assuntos
Adamantano/análogos & derivados , Polímeros/química , Adamantano/síntese química , Adamantano/química , Adamantano/farmacologia , Catálise , Técnicas de Química Sintética , Cristalografia por Raios X , Ligantes , Estruturas Metalorgânicas , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Polímeros/síntese química , Análise Espectral
6.
Cells ; 8(6)2019 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-31181818

RESUMO

Background: This study was performed to examine the effects of the Janus kinase (JAK) inhibitor peficitinib on fibroblast-like synoviocytes (FLS) obtained from patients with rheumatoid arthritis (RA). Methods: To examine the expression of JAK1, JAK2, and JAK3 in RA synovial tissue (ST) and FLS, immunohistochemistry was performed. We investigated the effects of peficitinib on interleukin 6 and IL-6 receptor responses in RA FLS. Phosphorylation of STAT was determined by western blot. To examine the functional analysis of peficitinib, we performed a proliferation and chemotaxis assays with FLS using THP-1 and peripheral blood mononuclear cells (PBMC). The inflammatory mediator expression of FLS was estimated by enzyme-linked immunosorbent assay. Results: JAK1, JAK2, and JAK3 were expressed in RA STs and FLS. Phosphorylation of STAT1, STAT3, and STAT5 in RA FLS was suppressed by peficitinib in a concentration-dependent manner. Peficitinib-treated RA FLS-conditioned medium reduced THP-1 and PBMC migration (p < 0.05) and proliferation of RA FLS (p < 0.05). Peficitinib suppressed the secretion of MCP-1/CCL2 in the RA FLS supernatant (p < 0.05). Conclusion: Peficitinib suppressed the JAK-STAT pathway in RA FLS and also suppressed monocyte chemotaxis and proliferation of FLS through inhibition of inflammatory cytokines.


Assuntos
Adamantano/análogos & derivados , Artrite Reumatoide/patologia , Quimiotaxia/efeitos dos fármacos , Citocinas/metabolismo , Monócitos/fisiologia , Niacinamida/análogos & derivados , Adamantano/farmacologia , Proliferação de Células/efeitos dos fármacos , Fibroblastos/citologia , Fibroblastos/metabolismo , Humanos , Interleucina-6/farmacologia , Janus Quinase 1/metabolismo , Janus Quinase 2 , Janus Quinase 3 , Monócitos/imunologia , Niacinamida/farmacologia , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sinoviócitos/citologia , Sinoviócitos/metabolismo
7.
Neoplasma ; 66(5): 776-784, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31169018

RESUMO

Hypoxia-inducible factor 1α (HIF1α) has been demonstrated to be involved in the resistance of various human cancer cells to chemotherapies. However, the correlation between HIF1α and the sensitivity of human non-small cell lung cancer (NSCLC) cells to cisplatin has not been illuminated. The aim of the present study was to investigate the effects of HIF1α on drug resistance in NSCLC cells. A549 cells were incubated in 21% or 0.5% O2 followed by the assessment of the level of HIF1α with qRT-PCR and western blot and ROS level by DCFH-DA assays. Effects of hypoxia or HIF1α inhibitor LW6 on the proliferation and apoptosis of A549 cells were evaluated via CCK-8 and flow cytometry assays. IC50 of A549 cells to cisplatin was determined by MTT assay. The mitochondrial membrane potential (MMP) was measured via JC-1 staining. Moreover, the expression of apoptosis related protein (Bcl-2, Bax) and drug resistance related proteins (MDR1, MRP1) were measured by western blotting. Exposure of A549 cells to 1% O2 significantly up-regulated HIF1α expression, maintained cell viability to cisplatin but decreased the ROS level, which promoted chemoresistance to cisplatin. LW6-treated A549 cells showed an increase in ROS level that blocked the hypoxia induced resistance to cisplatin and in addition, decreased expression of MDR1 and MRP1 in cisplatin-treated cells. This study revealed that hypoxia-improved cisplatin chemoresistance of NSCLC cells by regulated MDR1 and MRP1 expression via HIF1α/ROS pathway is reversed by LW6, suggesting that LW6 may act as effective sensitizer in chemotherapy for NSCLC.


Assuntos
Acetanilidas , Adamantano/análogos & derivados , Cisplatino , Células A549 , Acetanilidas/farmacologia , Adamantano/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/fisiopatologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Concentração Inibidora 50 , Neoplasias Pulmonares/fisiopatologia
8.
Med Hypotheses ; 128: 54-57, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31203909

RESUMO

Hypogonadotropic hypogonadism (secondary hypogonadism), congenital or acquired, is a form of hypogonadism that is due to problems with either the hypothalamus or pituitary gland affecting gonadotropin levels. Pulsatile secretion of gonadotropin-releasing hormone (GnRH) by hypothalamus is a primer step to initiate the release of pituitary gonadotropins. Kisspeptin and gonadotropin-inhibitory hormone (GnIH) are accepted as two major players in the activation and inhibition of GnRH regarding the neuroendocrine functioning of the hypothalamic pituitary gonadal axis. Kisspeptin is known as the most potent activator of GnRH. Regarding the inhibition of GnRH, RF-amide-related peptide-3 (RFRP-3) is accepted as the mammalian orthologue of GnIH in avian species. RF9 (1-adamantane carbonyl-Arg-Phe-NH2) is an antagonist of RFRP-3/GnIH receptor (neuropeptide FF receptor 1 (NPFFR1; also termed as GPR147). In recent years, several studies have indicated that RF9 activates GnRH neurons and gonadotropins in a kisspeptin receptor (Kiss1r, formerly known as GPR54) dependent manner. These results suggest that RF9 may have a bimodal function as both an RFRP-3 antagonist and a kisspeptin agonist or it may be a kiss1r agonist rather than an RFRP-3/GnIH receptor antagonist. These interactions are possible because Kisspeptin and GnIH are members of the RF-amide family, and both possibilities are not far from explaining the potent gonadotropin stimulating effects of RF9. Therefore, we hypothesize that RF9 may be a new therapeutic option for the hypogonadotropic hypogonadism due to its potent GnRH stimulating effects. A constant or repeated administration of RF9 provides a sustained increase in plasma gonadotrophin levels. However, applications in the same way with GnRH analogues and kisspeptin may result in desensitization of the gonadotropic axis. The reasons reported above contribute to our hypothesis that RF9 may be a good option in the GnRH stimulating as a kisspeptin agonist. We suggest that further studies are needed to elucidate the potential effects of RF9 in the treatment of the hypogonadotropic hypogonadism.


Assuntos
Adamantano/análogos & derivados , Dipeptídeos/farmacologia , Hormônio Liberador de Gonadotropina/metabolismo , Gonadotropinas/metabolismo , Hipogonadismo/metabolismo , Hipotálamo/metabolismo , Adamantano/farmacologia , Animais , Células CHO , Cricetinae , Cricetulus , Humanos , Hipogonadismo/terapia , Camundongos , Modelos Biológicos , Modelos Teóricos , Neuropeptídeos/metabolismo , Ratos , Receptores de Kisspeptina-1/metabolismo , Receptores de Neuropeptídeos/metabolismo
9.
Expert Rev Clin Pharmacol ; 12(6): 547-554, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059310

RESUMO

Introduction: Rheumatoid arthritis (RA) is a chronic progressive autoimmune disease characterized by synovitis as well as symmetric and destructive arthropathy. Although several disease modified antirheumatic-drugs (DMARDs) have widely used in clinical practice, certain patients are nonresponsive to or cannot take such medications due to adverse reactions. It is evident that Janus kinase (JAK) inhibitors have the potential to provide a significant breakthrough in the treatment of RA. These potent, orally administered, JAK inhibitors simplify the treatment options for patients. Areas covered: We discuss the pharmacodynamics, pharmacokinetics, efficacy, and safety of peficitinib for the treatment of RA. Expert opinion: Peficitinib is a novel JAK3 inhibitor potently inhibiting JAK3 enzymatic activity and JAK1/3-mediated cell proliferation. Its selectivity for JAK family kinases is similar to that of tofacitinib, but slightly less potent for JAK2. It is currently being evaluated by the FDA to treat adult patients with moderately to severely active RA who show inadequate response to or are intolerant of methotrexate. It can be used either as monotherapy or combination therapy with methotrexate, or other DMARDs. However, we think that more cautious consideration and measurement for adverse events are needed, after considering the safety results of ongoing clinical studies of peficitinib.


Assuntos
Adamantano/análogos & derivados , Artrite Reumatoide/tratamento farmacológico , Inibidores de Janus Quinases/uso terapêutico , Niacinamida/análogos & derivados , Adamantano/efeitos adversos , Adamantano/farmacologia , Adamantano/uso terapêutico , Adulto , Antirreumáticos/efeitos adversos , Antirreumáticos/farmacologia , Antirreumáticos/uso terapêutico , Artrite Reumatoide/enzimologia , Proliferação de Células/efeitos dos fármacos , Humanos , Janus Quinase 3/antagonistas & inibidores , Inibidores de Janus Quinases/efeitos adversos , Inibidores de Janus Quinases/farmacologia , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Niacinamida/efeitos adversos , Niacinamida/farmacologia , Niacinamida/uso terapêutico , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Pirróis/farmacologia , Pirróis/uso terapêutico
10.
Drugs ; 79(8): 887-891, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31093950

RESUMO

Peficitinib [Smyraf® (Astellas Pharma)] is a Janus kinase (JAK)1, JAK2, JAK3 and tyrosine kinase (Tyk)2 (pan-JAK) inhibitor recently approved in Japan for the treatment of rheumatoid arthritis. Inhibition of JAK suppresses the activation of cytokine signalling pathways involved in inflammation and joint destruction in rheumatoid arthritis. Peficitinib has been shown to significantly improve ACR20 and other measures of disease severity and to reduce the mean modified total Sharp score change from baseline in clinical trials. This article summarizes the milestones in the development of peficitinib leading to this first approval as a treatment for rheumatoid arthritis in patients who have an inadequate response to conventional therapies.


Assuntos
Adamantano/análogos & derivados , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Niacinamida/análogos & derivados , Inibidores de Proteínas Quinases/uso terapêutico , Adamantano/farmacologia , Adamantano/uso terapêutico , Antirreumáticos/farmacologia , Aprovação de Drogas , Humanos , Janus Quinases/antagonistas & inibidores , Niacinamida/farmacologia , Niacinamida/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores
11.
Malar J ; 18(1): 126, 2019 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-30967148

RESUMO

BACKGROUND: Today, the development of new and well-tolerated anti-malarial drugs is strongly justified by the emergence of Plasmodium falciparum resistance. In 2014-2015, a phase 2b clinical study was conducted to evaluate the efficacy of a single oral dose of Artefenomel (OZ439)-piperaquine (PPQ) in Asian and African patients presenting with uncomplicated falciparum malaria. METHODS: Blood samples collected before treatment offered the opportunity to investigate the proportion of multidrug resistant parasite genotypes, including P. falciparum kelch13 mutations and copy number variation of both P. falciparum plasmepsin 2 (Pfpm2) and P. falciparum multidrug resistance 1 (Pfmdr1) genes. RESULTS: Validated kelch13 resistance mutations including C580Y, I543T, P553L and V568G were only detected in parasites from Vietnamese patients. In Africa, isolates with multiple copies of the Pfmdr1 gene were shown to be more frequent than previously reported (21.1%, range from 12.4% in Burkina Faso to 27.4% in Uganda). More strikingly, high proportions of isolates with multiple copies of the Pfpm2 gene, associated with piperaquine (PPQ) resistance, were frequently observed in the African sites, especially in Burkina Faso and Uganda (> 30%). CONCLUSIONS: These findings were considered to sharply contrast with the recent description of increased sensitivity to PPQ of Ugandan parasite isolates. This emphasizes the necessity to investigate in vitro susceptibility profiles to PPQ of African isolates with multiple copies of the Pfpm2 gene and estimate the risk of development of PPQ resistance in Africa. Trial registration Clinicaltrials.gov reference: NCT02083380. Study title: Phase II efficacy study of artefenomel and piperaquine in adults and children with P. falciparum malaria. https://clinicaltrials.gov/ct2/results?cond=&term=NCT02083380&cntry=&state=&city=&dist= . FSFV: 23-Jul-2014; LSLV: 09-Oct-2015.


Assuntos
Adamantano/análogos & derivados , Antimaláricos/farmacologia , Ácido Aspártico Endopeptidases/genética , Resistência a Medicamentos/genética , Peróxidos/farmacologia , Plasmodium falciparum/genética , Proteínas de Protozoários/genética , Quinolinas/farmacologia , Adamantano/farmacologia , Adolescente , Adulto , África , Idoso , Ácido Aspártico Endopeptidases/metabolismo , Biomarcadores/análise , Criança , Pré-Escolar , Variações do Número de Cópias de DNA , Combinação de Medicamentos , Feminino , Genótipo , Humanos , Lactente , Malária Falciparum , Masculino , Pessoa de Meia-Idade , Plasmodium falciparum/efeitos dos fármacos , Proteínas de Protozoários/metabolismo , Vietnã , Adulto Jovem
12.
Artif Cells Nanomed Biotechnol ; 47(1): 1288-1294, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30942641

RESUMO

Bacteria play a pivotal role in the pathological initiation and progression of pulpitis. Lipopolysaccharide (LPS) is recognized as a major component of the outer wall of Gram-negative bacteria. Saxagliptin, a potent inhibitor of dipeptidyl peptidase-4 (DPP-4), has been licensed for the treatment of type 2 diabetes. In this study, we aimed to evaluate the protective effects of saxagliptin against LPS-induced intracellular insults in human dental pulp cells (HDPCs). We found that DPP-4 is expressed in HDPCs. Interestingly, the expression of DPP-4 was increased in response to LPS treatment. We also found that saxagliptin ameliorated LPS-induced production of ROS and reduction of glutathione (GSH). Additionally, saxagliptin prevented LPS-induced mitochondrial dysfunction by increasing the levels of mitochondrial membrane potential (MMP) and the production of adenosine triphosphate (ATP). Importantly, saxagliptin ameliorated LPS-induced reduction of cell viability and lactate dehydrogenase (LDH) release. Our results indicate that saxagliptin significantly inhibited LPS-induced expression and secretions of tumour necrosis factor alpha (TNF-α), interleukin (IL)-1ß and IL-6 in HDPCs. Mechanistically, we found that saxagliptin inhibited the phosphorylation of p38 and the activation of NF-κB. Our findings suggest that saxagliptin might have a potential therapeutic capacity for the treatment of pulpitis through mitigating inflammatory signalling in dental pulp cells.


Assuntos
Adamantano/análogos & derivados , Citoproteção/efeitos dos fármacos , Polpa Dentária/citologia , Dipeptídeos/farmacologia , Lipopolissacarídeos/efeitos adversos , Adamantano/farmacologia , Polpa Dentária/patologia , Relação Dose-Resposta a Droga , Humanos , Inflamação/induzido quimicamente , Inflamação/patologia , Inflamação/prevenção & controle , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo
13.
Bull Exp Biol Med ; 166(6): 739-743, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31020587

RESUMO

Activities of noncompetitive NMDA receptor antagonists (aminoadamantane derivatives) were assessed in random-bred rats with modeled morphine withdrawal syndrome. A single intraperitoneal injection of hemantane (10 or 20 mg/kg) significantly and dose-dependently moderated some behavioral symptoms (teeth-chattering, ptosis, and vocalization) and reduced total score of morphine withdrawal syndrome. In morphine-abstinent rats, hemantane partially prevented the decrease in the thresholds of tactile sensitivity, but had no effect on locomotor activity and body weight loss. Under conditions of morphine withdrawal, intraperitoneal injection of amantadine (10 or 20 mg/kg) decreased motor activity and promoted body weight loss in parallel with the development of mechanical allodynia, but had no effect on the total withdrawal score. Comparison of aminoadamantane derivatives by behavioral and physiological parameters demonstrated the advantage of hemantane during morphine abstinence indicating the need of its study as a promising anti-addiction remedy.


Assuntos
Adamantano/análogos & derivados , Amantadina/farmacologia , Dependência de Morfina/fisiopatologia , Antagonistas de Entorpecentes/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Adamantano/farmacologia , Animais , Expressão Gênica , Hiperalgesia/induzido quimicamente , Hiperalgesia/fisiopatologia , Injeções Intraperitoneais , Masculino , Morfina/administração & dosagem , Dependência de Morfina/genética , Dependência de Morfina/metabolismo , Atividade Motora/efeitos dos fármacos , Ratos , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Síndrome de Abstinência a Substâncias/genética , Síndrome de Abstinência a Substâncias/metabolismo , Síndrome de Abstinência a Substâncias/fisiopatologia , Perda de Peso/efeitos dos fármacos
14.
Emerg Microbes Infect ; 8(1): 479-485, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30924394

RESUMO

In late 2016, an H7N6 low pathogenic avian influenza virus outbreak occurred in domestic turkeys in Central Chile. We characterized the genetic and antigenic properties of the outbreak virus and its experimental transmission in chickens. Our studies demonstrate that the outbreak virus is a reassortment of genes identified from Chilean wild bird viruses between 2013 and 2017 and displays molecular adaptations to poultry and antiviral resistance to adamantanes. Further, these wild bird viruses are also able to transmit in experimentally infected chickens highlighting the need for continued surveillance and improvement of biosecurity in poultry farms.


Assuntos
Surtos de Doenças , Vírus da Influenza A/classificação , Vírus da Influenza A/isolamento & purificação , Influenza Aviária/epidemiologia , Influenza Aviária/virologia , Vírus Reordenados/classificação , Vírus Reordenados/isolamento & purificação , Adamantano/farmacologia , Adaptação Biológica , Animais , Animais Domésticos , Antivirais/farmacologia , Chile/epidemiologia , Farmacorresistência Viral , Vírus da Influenza A/genética , Vírus da Influenza A/imunologia , Vírus Reordenados/genética , Vírus Reordenados/imunologia , Perus
15.
J Gen Virol ; 100(4): 629-641, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30869582

RESUMO

There is growing evidence of the influence of sphingosine kinase (SK) enzymes on viral infection. Here, the role of sphingosine kinase 2 (SK2), an isoform of SK prominent in the brain, was defined during dengue virus (DENV) infection. Chemical inhibition of SK2 activity using two different SK2 inhibitors, ABC294640 and K145, had no effect on DENV infection in human cells in vitro. In contrast, DENV infection was restricted in SK2-/- immortalized mouse embryonic fibroblasts (iMEFs) with reduced induction of IFN-ß mRNA and protein, and mRNA for the IFN-stimulated genes (ISGs) viperin, IFIT1, IRF7 and CXCL10 in DENV-infected SK2-/- compared to WT iMEFs. Intracranial (ic) DENV injection in C57BL/6 SK2-/- mice induced body weight loss earlier than in WT mice but DENV RNA levels were comparable in the brain. Neither SK1 mRNA or sphingosine-1-phosphate (S1P) levels were altered following ic DENV infection in WT or SK2-/- mice but brain S1P levels were reduced in all SK2-/- mice, independent of DENV infection. CD8 mRNA was induced in the brains of both DENV-infected WT and SK2-/- mice, suggesting normal CD8+ T-cell infiltration into the DENV-infected brain independent of SK2 or S1P. Thus, although SK2 may be important for replication of some viruses SK2 activity does not affect DENV infection in vitro and SK2 or S1P levels do not influence DENV infection or T-cell infiltration in the context of infection in the brain.


Assuntos
Vírus da Dengue/patogenicidade , Dengue/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Adamantano/análogos & derivados , Adamantano/farmacologia , Animais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/virologia , Linhagem Celular , Linhagem Celular Tumoral , Dengue/tratamento farmacológico , Vírus da Dengue/efeitos dos fármacos , Células HEK293 , Células Hep G2 , Humanos , Interferon beta/metabolismo , Lisofosfolipídeos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Piridinas/farmacologia , RNA Mensageiro/metabolismo , Esfingosina/análogos & derivados , Esfingosina/metabolismo , Tiazolidinedionas/farmacologia
16.
Mol Carcinog ; 58(7): 1208-1220, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30883933

RESUMO

Retinoids are vitamin A derivatives that regulate crucial biological processes such as cellular proliferation, apoptosis, and differentiation. The use of natural retinoids in cancer therapy is limited due to their toxicity and the acquired resistance by cancer cells. Therefore, synthetic retinoids were developed, such as the atypical adamantyl retinoid ST1926 that provides enhanced bioavailability and reduced toxicity. We have assessed the in vitro and in vivo antitumor properties and mechanism of action of ST1926 in targeting cancer stem-like cells population of human prostate cancer (PCa) cell lines, DU145 and PC3, and mouse PCa cell lines, PLum-AD and PLum-AI. We demonstrated that ST1926 substantially reduced proliferation of PCa cells and induced cell cycle arrest, p53-independent apoptosis, and early DNA damage. It also decreased migration and invasion of PCa cells and significantly reduced prostate spheres formation ability in vitro denoting sufficient eradication of the self-renewal ability of the highly androgen-resistant cancer stem cells. Importantly, ST1926 potently inhibited PCa tumor growth and progression in vivo. Our results highlight the potential of ST1926 in PCa therapy and warrant its clinical development.


Assuntos
Adamantano/análogos & derivados , Antineoplásicos/farmacologia , Carcinogênese/efeitos dos fármacos , Cinamatos/farmacologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Retinoides/farmacologia , Adamantano/farmacologia , Animais , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Humanos , Masculino , Camundongos , Invasividade Neoplásica/patologia , Próstata/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Chemistry ; 25(30): 7232-7242, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-30730065

RESUMO

Overuse and misuse of antibacterial drugs has resulted in bacteria resistance and in an increase in mortality rates due to bacterial infections. Therefore, there is an imperative necessity of new antibacterial drugs. Bio-organometallic derivatives of antibacterial agents offer an opportunity to discover new active antibacterial drugs. These compounds are well-characterized products and, in several examples, their antibacterial activities have been studied. Both inhibition of the antibacterial activity and strong increase in the antibiotic activity of the parent drug have been found. The synthesis of the main classes of bio-organometallic derivatives of these drugs, as well as examples of the use of structure-activity relation (SAR) studies to increase the activity and to understand the mode of action of bio-organometallic antimicrobial peptides (BOAMPs) and platensimicyn bio-organometallic mimics is presented in this article.


Assuntos
Antibacterianos/síntese química , Materiais Biocompatíveis/síntese química , Compostos Organometálicos/síntese química , Adamantano/síntese química , Adamantano/farmacologia , Aminobenzoatos/síntese química , Aminobenzoatos/farmacologia , Anilidas/síntese química , Anilidas/farmacologia , Antibacterianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/síntese química , Peptídeos Catiônicos Antimicrobianos/farmacologia , Materiais Biocompatíveis/farmacologia , Materiais Biomiméticos/síntese química , Materiais Biomiméticos/farmacologia , Humanos , Metais/química , Estrutura Molecular , Compostos Organometálicos/farmacologia , Relação Estrutura-Atividade
18.
Eur J Pharmacol ; 851: 186-193, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30639312

RESUMO

Diabetes-associated cardiovascular complications are the leading cause of death for diabetic patients. Dipeptidyl peptidase 4 (DPP-4) inhibitor agents, known as gliptins, are a class of potent anti-glycemic agents developed to treat diabetes. Recently, gliptins have been shown to have independent cardiovascular benefits. In this study, we revealed the protective role of saxagliptin in vascular endothelial cells. Our data show that saxagliptin suppresses oxidized low-density lipoprotein cholesterol (ox-LDL)-induced expression of its receptor lectin-like ox-LDL receptor-1 (LOX-1). Saxagliptin treatment reduces ox-LDL-induced production of cytokines and vascular adhesion molecules including tumor necrosis factor (TNF-α), interleukin-1ß (IL-1ß), vascular cell adhesion molecule 1 (VCAM-1), and intercellular cell adhesion molecule-1 (ICAM-1). The presence of saxagliptin suppressed ox-LDL-induced adhesion of monocytes to endothelial cells in co-culture adhesion experiments. Moreover, saxagliptin mitigated ox-LDL-induced production of reactive oxygen species and suppressed elevated expression of endothelial nicotinamide adenine dinucleotide phosphate oxidase subunit (NOX-4) induced by ox-LDL. Mechanistically, saxagliptin exerted inhibitory effects against ox-LDL-induced phosphorylation of JNK kinase, expression of the activator protein 1 (AP-1) subunits c-Jun/c-fos, and AP-1 promoter activity. Saxagliptin also suppressed nuclear factor κB (NF-κB) p65 accumulation and inhibited its promoter activity. Our data elaborate the molecular mechanism of saxagliptin-mediated endothelial protection and indicate that saxagliptin could have vascular benefits independent on its anti-glycemic function.


Assuntos
Adamantano/análogos & derivados , Dipeptídeos/farmacologia , Inibidores da Dipeptidil Peptidase IV/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Lipoproteínas LDL/farmacologia , NF-kappa B/metabolismo , Fator de Transcrição AP-1/metabolismo , Adamantano/farmacologia , Adesão Celular/efeitos dos fármacos , Citocinas/biossíntese , Regulação da Expressão Gênica/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/citologia , Humanos , MAP Quinase Quinase 4/metabolismo , Monócitos/citologia , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos
19.
Mol Cancer Res ; 17(4): 929-936, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30655325

RESUMO

Self-renewal maintains the long-term clonogenic growth that is required for cancer relapse and progression, but the cellular processes regulating this property are not fully understood. In many diseases, self-renewal is enhanced in cancer stem cells (CSC), and in pancreatic ductal adenocarcinoma (PDAC), CSCs are characterized by the surface expression of CD44. In addition to cell adhesion, CD44 impacts cell shape and morphology by modulating the actin cytoskeleton via Ezrin, a member of the Ezrin/Radixin/Moesin (ERM) family of linker proteins. We examined the expression of Ezrin in PDAC cells and found higher levels of both total and activated Ezrin in CSCs compared with bulk tumor cells. We also found that the knockdown of Ezrin in PDAC cells decreased clonogenic growth, self-renewal, cell migration, and CSC frequency in vitro as well as tumor initiation in vivo. These effects were associated with cytoskeletal changes that are similar to those occurring during the differentiation of normal stem cells, and the inhibition of actin remodeling reversed the impact of Ezrin loss. Finally, targeting Ezrin using a small-molecule inhibitor limited the self-renewal of clinically derived low-passage PDAC xenografts. Our findings demonstrate that Ezrin modulates CSCs properties and may represent a novel target for the treatment of PDAC. IMPLICATIONS: Our findings demonstrate that Ezrin modulates CSCs' properties and may represent a novel target for the treatment of PDAC.


Assuntos
Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Proteínas do Citoesqueleto/biossíntese , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Actinas/metabolismo , Adamantano/análogos & derivados , Adamantano/farmacologia , Animais , Linhagem Celular Tumoral , Proteínas do Citoesqueleto/antagonistas & inibidores , Proteínas do Citoesqueleto/metabolismo , Xenoenxertos , Humanos , Camundongos , Camundongos Nus , Quinolinas/farmacologia
20.
Fitoterapia ; 133: 43-50, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30576796

RESUMO

Hookeriones I-Q (1-9), nine new homo-adamantane type polycyclic polyprenylated acylphloroglucinols (PPAPs), were isolated from Hypericum hookerianum, along with twenty known analogues. These structures were determined on the basis of comprehensive NMR and MS spectroscopic data. Comprehensive analysis of the NMR data revealed the correlations between the configuration of H-18 and H-28 and the chemical shifts of related signals. The cytotoxicity and anti-allergic activities of the new isolates were evaluated, and several ones exhibited moderate cytotoxicity against ECA-109 cell lines.


Assuntos
Adamantano/farmacologia , Hypericum/química , Floroglucinol/farmacologia , Adamantano/isolamento & purificação , Animais , Linhagem Celular , Linhagem Celular Tumoral , China , Humanos , Estrutura Molecular , Floroglucinol/isolamento & purificação , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Componentes Aéreos da Planta/química , Ratos
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