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1.
Chem Biol Interact ; 315: 108864, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31629700

RESUMO

Type II diabetes is recognized as a major risk factor for death due to cardiovascular complications such as coronary heart disease (CHD), but the complex interplay between these two diseases remains poorly understood. Suppression of oxidative stress, apoptosis, and inflammation of endothelial cells is a valuable treatment strategy to prevent or halt the progression of CHD. In the present study, we used real-time polymerase chain reaction (PCR), Western blot analysis, and enzyme linked immunosorbent assay (ELISA) to investigate the effects of saxagliptin on hypoxia-inducible factors. Our findings demonstrate that saxagliptin can significantly improve cell viability in H9c2 cells as well as reduce hypoxia-induced oxidative damage and loss of mitochondrial membrane potential. Saxagliptin reduced hypoxia-induced NADPH oxidase 4 (NOX 4). We also show that saxagliptin can reduce the expression of matrix metallopeptidase-2 (MMP-2) and matrix metallopeptidase-9 (MMP-9), two important degradative enzymes. Saxagliptin also suppressed hypoxia-induced expression of high mobility group box-1 protein (HMGB1), a key inflammatory cytokine. Finally, we show that saxagliptin can exert atheroprotective effects by reducing the expression of myeloid differential protein-88 (MyD88) and increasing the expression of nuclear factor erythroid-2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). Thus, saxagliptin shows promise as a treatment against diabetes-associated CHD.


Assuntos
Adamantano/análogos & derivados , Dipeptídeos/farmacologia , Hipóxia/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Adamantano/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Proteína HMGB1/metabolismo , Heme Oxigenase-1/metabolismo , Hipóxia/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , NADPH Oxidase 4/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Ratos , Transdução de Sinais/efeitos dos fármacos
2.
Life Sci ; 241: 117119, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31794771

RESUMO

AIM: Mechanoelectric feedback (MEF) was related to malignant arrhythmias in heart failure (HF). Desmin is a cytoskeleton protein and could be involved in MEF as a mechanoelectrical transducer. In this study, we will discuss the role of desmin alterations in mechanical electrical feedback in heart failure and its mechanisms. METHODS: We used both an in vivo rat model and an in vitro cardiomyocyte model to address this issue. For the in vivo experiments, we establish a sham group, an HF group, streptomycin (SM) group, and an MDL-28170 group. The occurrence of ventricular arrhythmias (VA) was recorded in each group. For the in vitro cardiomyocyte model, we established an NC group, a si-desmin group, and a si-desmin + NBD IKK group. The expression of desmin, IKKß, p-IKKß, IKBα, p-NF-κB, and SERCA2 were detected in both in vivo and in vitro experiments. The content of Ca2+ in cytoplasm and sarcoplasmic were detected by confocal imaging in vitro experiments. RESULTS: An increased number of VAs were found in the HF group. SM and MDL-28170 can reduce desmin breakdown and the number of VAs in heart failure. The knockdown of desmin in the cardiomyocyte can activate the NF-κB pathway, decrease the level of SERCA2, and result in abnormal distribution of Ca2+. While treatment with NF-κB inhibitor can elevate the level of SERCA2 and alleviate the abnormal distribution of Ca2+. SIGNIFICANCE: Overall, desmin may participate in MEF through the NF-κB pathway. This study provides a potential therapeutic target for VA in HF.


Assuntos
Cálcio/metabolismo , Desmina/metabolismo , Insuficiência Cardíaca/etiologia , NF-kappa B/metabolismo , Animais , Calpaína/metabolismo , Células Cultivadas , Desmina/genética , Dipeptídeos/farmacologia , Modelos Animais de Doenças , Eletrocardiografia , Retroalimentação Fisiológica , Técnicas de Silenciamento de Genes , Masculino , Miócitos Cardíacos , NF-kappa B/genética , Ratos Sprague-Dawley , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Taquicardia Ventricular/complicações , Taquicardia Ventricular/fisiopatologia
3.
Chem Asian J ; 15(1): 51-55, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31686429

RESUMO

Monocyclic ß-lactams revive the research field on antibiotics, which are threatened by the emergence of resistant bacteria. A six-step synthetic route was developed, providing easy access to new 3-amino-1-carboxymethyl-4-phenyl-ß-lactams, of which the penicillin-binding protein (PBP) inhibitory potency was demonstrated biochemically.


Assuntos
Aminoácidos/farmacologia , Antibacterianos/farmacologia , Dipeptídeos/farmacologia , Iminas/farmacologia , Lactamas/farmacologia , Proteínas de Ligação às Penicilinas/antagonistas & inibidores , Aminoácidos/química , Antibacterianos/síntese química , Antibacterianos/química , Dipeptídeos/síntese química , Dipeptídeos/química , Iminas/química , Lactamas/síntese química , Lactamas/química , Estrutura Molecular , Proteínas de Ligação às Penicilinas/metabolismo
4.
Theriogenology ; 141: 82-90, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31518732

RESUMO

Relative to alanine and serine amino acid levels, glutamine is highly abundant in follicular fluid, and is an important source of energy required for oocyte maturation and embryo development. Thus, glutamine is an essential component of in vitro embryo culture media. However, glutamine has poor stability and degrades spontaneously in solution to form ammonia and pyrrolidonecarboxylic acid. In the present study, we aimed to explore the effect of substituting l-glutamine with glycine-glutamine, a more stable glutamine, on development of early parthenogenetic embryos and in vitro fertilization (IVF) embryos in bovine. Results revealed that glycine-glutamine can significantly increase cleavage rate (parthenogenetic embryos:87.24% vs. 72.61%, IVF embryos:89.33% vs. 83.79%, P < 0.01), blastocyst number (parthenogenetic embryos:24.98% vs. 18.07%, IVF embryos:33.53% vs. 27.29%, P < 0.01), and blastocyst number (parthenogenetic embryos:96 vs. 76, IVF embryos:114 vs. 109, P < 0.01), reduce blastocyst apoptosis (parthenogenetic embryos:3.72% vs. 6.65%, IVF embryos:2.53% vs.6.23%, P < 0.01), alleviate embryo ammonia toxicity, and reduce the content of reactive oxygen species (ROS) compared with the l-glutamine. In addition, glycine-glutamine can alter epigenetic reprogramming by increasing the expression of HDAC1 (Histone Deacetylase 1) and decreasing the relative expression levels of H3K9 acetylation in early parthenogenetic embryos and IVF embryos. From our present study, we concluded that glycine-glutamine is an effective substitute of glutamine in modified synthetic oviduct fluid with amino acids (mSOFaa).


Assuntos
Bovinos/embriologia , Técnicas de Cultura Embrionária/veterinária , Fertilização In Vitro/veterinária , Glutamina/química , Glicina/química , Partenogênese/fisiologia , Acetilação , Amônia/metabolismo , Animais , Apoptose , Meios de Cultura , Dipeptídeos/química , Dipeptídeos/farmacologia , Glutamina/farmacologia , Glicina/farmacologia , Histonas/metabolismo , Espécies Reativas de Oxigênio
5.
Eur J Med Chem ; 185: 111839, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31708185

RESUMO

The ligustrazine - betulin derivative (TB), TB amino acids derivatives (TB-01 - TB-09) and TB dipeptide derivatives (TB-10 - TB-18) were designed and synthesized. And their in vitro cytotoxic activities were evaluated against four cancer cell lines (Hela, HepG2, BGC-823 and HT-29) and normal cells MDCK by standard methylthiazol tetrazolium (MTT) assay. Most of them demonstrated better antitumor activity than the relevant material betulin. Among them, compound TB-01 showed the best anti-tumor effect on the cancer cells and the lowest toxicity on the normal cells. For example, the cytotoxicity of TB-01 against the cancer cells (mean IC50 = 4.86 ±â€¯1.16 µM) was 3-fold higher than that against the normal cells MDCK (IC50 = 16.11 ±â€¯2.29 µM). Moreover, TB-01 showed better cytotoxic than positive drug cisplatin (DDP) on tumor cells. Besides, the Zebrafish toxicity evaluation test showed that TB-01 demonstrated high biosafety. Subsequently, fluorescent staining, apoptosis detection and cell cycle analysis indicated that TB-01 induced early apoptosis in HepG2 cells and blocked the cell cycle in the G1 phase. In addition, the structure-activity relationships of these derivatives were briefly discussed.


Assuntos
Aminoácidos/farmacologia , Antineoplásicos/farmacologia , Dipeptídeos/farmacologia , Desenho de Drogas , Pirazinas/farmacologia , Triterpenos/farmacologia , Aminoácidos/química , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dipeptídeos/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Masculino , Estrutura Molecular , Pirazinas/química , Relação Estrutura-Atividade , Triterpenos/química , Peixe-Zebra
6.
BMC Infect Dis ; 19(1): 880, 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31640588

RESUMO

BACKGROUND: Antibiotic resistance is a leading cause of treatment failure in Helicobacter pylori infection. In Africa, there are very little data concerning the susceptibility of Helicobacter pylori isolates to antibiotics. The purpose of this study was to evaluate the resistance prevalence of Helicobacter pylori strains circulating in Cameroon, and to assess overexpression of efflux pump as a possible multi-drug resistance mechanisms. METHODS: A total of 140 H. pylori isolates were recovered from gastric biopsies of dyspeptic patients in two reference hospitals in Cameroon and analyzed for their antimicrobial susceptibility to amoxicillin, co-amoxiclav, ampicillin, penicillin, imipenem, metronidazole, rifabutin, erythromycin, clarithromycin, azithromycin, levofloxacin, ciprofloxacin, norfloxacin, tetracycline, doxycycline and minocycline. Antibiotic sensitivity was tested by disk diffusion method. Phe-Arg-naphthylamide (PAßN) was used as efflux pump inhibitor. INT broth microdilution method in supplemented Brain Heart Infusion broth was used to determine the MIC of ampicillin, amoxicillin, metronidazole, erythromycin, clarithromycin and doxycycline in the absence and the presence of PAßN against 32 selected MDR isolates. RESULTS: Overall H. pylori resistance rate was 100% to ampicillin, penicillin and co-amoxiclav; 97.14% to amoxicillin, 97.85% to metronidazole, 47.85% to erythromycin, 13.57% to clarithromycin; 5, 2.86 and 0.71% to doxycycline, tetracycline and minocycline respectively. No resistance to azithromycin, rifabutin, imipenem, ciprofloxacin, norfloxacin and levofloxacin was detected among H. pylori isolates. Seventy percent (70%) of the tested isolates elicited a multiple drugs resistance pattern; 42.57% double, 15.71% triple and 5.71% quadruple drugs resistance. Metronidazole and amoxicillin were more concerned with double resistance pattern (86.76%). The spectrum of activity recorded with metronidazole, doxycycline, clarithromycin and erythromycin ranged from 0 to 100% in the absence to the presence of PAßN against the tested MDR isolates. An 8 to 128-fold increase in potency was also noticed with these antibiotics in the presence of PAßN. CONCLUSION: With regard to the high resistance rate to both amoxicillin and metronidazole, these drugs should be avoided as components of triple therapy in our milieu. In contrast, ciprofloxacin, norfloxacin, levofloxacin and tetracyclines could be used to achieve a better eradication rate and to reduce the risk of selection of H. pylori resistant strains.


Assuntos
Antibacterianos/farmacologia , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Dispepsia/microbiologia , Infecções por Helicobacter/microbiologia , Helicobacter pylori/efeitos dos fármacos , Adulto , Antibacterianos/uso terapêutico , Biópsia , Camarões , Estudos Transversais , Dipeptídeos/farmacologia , Feminino , Infecções por Helicobacter/tratamento farmacológico , Helicobacter pylori/isolamento & purificação , Humanos , Masculino , Testes de Sensibilidade Microbiana
7.
BMC Cancer ; 19(1): 958, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31619190

RESUMO

BACKGROUND: We analyzed the changes in permeability of endothelial cell layers after photon irradiation, with a focus on the metalloproteases ADAM10 and ADAM17, and on VE-cadherin, components crucial for the integrity of endothelial intercellular junctions, and their roles in the transmigration of cancer cells through endothelial cell monolayers. METHODS: Primary HUVEC were irradiated with 2 or 4 Gy photons at a dose rate of 5 Gy/min. The permeability of an irradiated endothelial monolayer for macromolecules and tumor cells was analyzed in the presence or absence of the ADAM10/17 inhibitors GI254023X and GW280264X. Expression of ADAM10, ADAM17 and VE-Cadherin in endothelial cells was quantified by immunoblotting and qRT. VE-Cadherin was additionally analyzed by immunofluorescence microscopy and ELISA. RESULTS: Ionizing radiation increased the permeability of endothelial monolayers and the transendothelial migration of tumor cells. This was effectively blocked by a selective inhibition (GI254023X) of ADAM10. Irradiation increased both, the expression and activity of ADAM10, which led to increased degradation of VE-cadherin, but also led to higher rates of VE-cadherin internalization. Increased degradation of VE-cadherin was also observed when endothelial monolayers were exposed to tumor-cell conditioned medium, similar to when exposed to recombinant VEGF. CONCLUSIONS: Our results suggest a mechanism of irradiation-induced increased permeability and transendothelial migration of tumor cells based on the activation of ADAM10 and the subsequent change of endothelial permeability through the degradation and internalization of VE-cadherin.


Assuntos
Proteína ADAM10/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Antígenos CD/metabolismo , Caderinas/metabolismo , Células Endoteliais/efeitos da radiação , Células Endoteliais da Veia Umbilical Humana/efeitos da radiação , Proteínas de Membrana/metabolismo , Proteólise/efeitos da radiação , Radiação Ionizante , Migração Transendotelial e Transepitelial/efeitos da radiação , Proteína ADAM10/antagonistas & inibidores , Proteína ADAM10/genética , Proteína ADAM17/antagonistas & inibidores , Proteína ADAM17/genética , Proteína ADAM17/metabolismo , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/genética , Linhagem Celular Tumoral , Dipeptídeos/farmacologia , Células Endoteliais/metabolismo , Humanos , Ácidos Hidroxâmicos/farmacologia , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Permeabilidade/efeitos da radiação , Radioterapia/efeitos adversos , Transdução de Sinais/efeitos da radiação , Migração Transendotelial e Transepitelial/efeitos dos fármacos , Fator de Necrose Tumoral alfa/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/farmacologia
8.
Carbohydr Res ; 485: 107815, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31622943

RESUMO

Tripodal nonameric mannoside glycodendrimer 1 with carbohydrate tethered triazole linked with the TRIS-glycine-ß-alanine dipeptidic aromatic centered core was synthesized. Glycodendrimer 1 demonstrated potential in vitro anti-leishmanial activity. The bio-activity data was substantiated with molecular modelling and docking studies of 1 with the three-dimensional protein structure of Leishmanolysin.


Assuntos
Dipeptídeos/síntese química , Dipeptídeos/farmacologia , Glicina/química , Leishmania/efeitos dos fármacos , Manosídeos/química , Triazóis/química , beta-Alanina/química , Antiprotozoários/síntese química , Antiprotozoários/química , Antiprotozoários/metabolismo , Antiprotozoários/farmacologia , Técnicas de Química Sintética , Dendrímeros/química , Dipeptídeos/química , Dipeptídeos/metabolismo , Metaloendopeptidases/química , Metaloendopeptidases/metabolismo , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Conformação Proteica
9.
ACS Appl Mater Interfaces ; 11(40): 37147-37155, 2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31513742

RESUMO

Drug-loading hydrogels are promising candidates in the bioengineering research field; nevertheless, hydrophobic drug loading into a hydrophilic carrier system remains unsolved and is full of challenges. In this work, following the potential dual interactions between peptides and aromatic drugs, we developed a potent hybrid hydrogel formation method, namely, "peptide-/drug-directed self-assembly". The hybrid hydrogels were synthesized using polyethylene glycol (PEG)-based Fmoc-FF peptide hybrid polyurethane, in which curcumin could be encapsulated through self-assembly with Fmoc-FF peptide via π-π stacking. On the basis of this, curcumin loading capacity could be improved to as high as 3.3 wt % with sustained release. In addition, the curcumin loading enhanced the hydrogel mechanical properties from 4 kPa to over 10 kPa, similar to that of natural soft tissues. Furthermore, the hydrogels were injectable with self-healing properties since the Fmoc-FF peptide/curcumin coassembly was noncovalent and reversible. Spectroscopy results confirmed the existence of the coassembly of Fmoc-FF peptide/curcumin. Further in vivo experiments effectively demonstrated that the hydrogels could improve the cutaneous wound healing in a full-thickness skin defected model. This peptide-/drug-directed self-assembly of hybrid polyurethane hydrogel could be used as a promising platform for tissue-engineering scaffold and biomedical application.


Assuntos
Hidrogéis/farmacologia , Peptídeos/farmacologia , Poliuretanos/farmacologia , Cicatrização/efeitos dos fármacos , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Curcumina/farmacologia , Dipeptídeos/farmacologia , Liberação Controlada de Fármacos , Fluorenos/farmacologia , Tecido de Granulação/patologia , Hidrogéis/química , Peso Molecular , Peptídeos/química , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Poliuretanos/química , Ratos Sprague-Dawley , Pele/efeitos dos fármacos , Pele/patologia
10.
Mem Inst Oswaldo Cruz ; 114: e190147, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31553371

RESUMO

BACKGROUND: Calpains are proteins belonging to the multi-gene family of calcium-dependent cysteine peptidases that undergo tight on/off regulation, and uncontrolled proteolysis of calpains is associated with severe human pathologies. Calpain orthologues are expanded and diversified in the trypanosomatids genome. OBJECTIVES: Here, we characterised calpains in Leishmania braziliensis, the main causative agent of cutaneous leishmaniasis in Brazil. METHODS/FINDINGS: In total, 34 predicted calpain-like genes were identified. After domain structure evaluation, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) during in vitro metacyclogenesis revealed (i) five genes with enhanced expression in the procyclic stage, (ii) one augmented gene in the metacyclic stage, and (iii) one procyclic-exclusive transcript. Western blot analysis revealed that an antibody against a consensus-conserved peptide reacted with multiple calpain-like proteins, which is consistent with the multi-gene family characteristic. Flow cytometry and immunocytochemistry analyses revealed the presence of calpain-like molecules mainly in the cytoplasm, to a lesser extent in the plasma membrane, and negligible levels in the nucleus, which are all consistent with calpain localisation. Eventually, the calpain inhibitor MDL28170 was used for functional studies revealing (i) a leishmaniostatic effect, (ii) a reduction in the association index in mouse macrophages, (iii) ultra-structural alterations conceivable with autophagy, and (iv) an enhanced expression of the virulence factor GP63. CONCLUSION: This report adds novel insights into the domain structure, expression, and localisation of L. braziliensis calpain-like molecules.


Assuntos
Calpaína/genética , Genoma de Protozoário/genética , Leishmania braziliensis/química , Macrófagos Peritoneais/metabolismo , Animais , Western Blotting , Calpaína/efeitos dos fármacos , Calpaína/metabolismo , Calpaína/ultraestrutura , Inibidores de Cisteína Proteinase/farmacologia , Dipeptídeos/farmacologia , Citometria de Fluxo , Regulação da Expressão Gênica , Imuno-Histoquímica , Leishmania braziliensis/genética , Leishmania braziliensis/metabolismo , Leishmania braziliensis/ultraestrutura , Camundongos , Camundongos Endogâmicos BALB C , Microscopia Eletrônica de Transmissão , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Virulência
11.
J Enzyme Inhib Med Chem ; 34(1): 1388-1399, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31392901

RESUMO

Fourteen novel dipeptide carboxamide derivatives bearing benzensulphonamoyl propanamide were synthesized and characterized using 1H NMR, 13C NMR, FTIR and MS spectroscopic techniques. In vivo antimalarial and in vitro antimicrobial studies were carried out on these synthesized compounds. Molecular docking, haematological analysis, liver and kidney function tests were also evaluated to assess the effect of the compounds on the organs. At 200 mg/kg body weight, 7i inhibited the multiplication of the parasite by 81.38% on day 12 of post-treatment exposure. This was comparable to the 82.34% reduction with artemisinin. The minimum inhibitory concentration (MIC) in µM ranged from 0.03 to 2.34 with 7h having MIC of 0.03 µM against Plasmodium falciparium. The in vitro antibacterial activity of the compounds against some clinically isolated bacteria strains showed varied activities with some of the new compounds showing better activities against the bacteria and the fungi more than the reference drug ciprofloxacin and fluconazole.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Antimaláricos/química , Antimaláricos/farmacologia , Dipeptídeos/química , Dipeptídeos/farmacologia , Sulfonamidas/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Antimaláricos/síntese química , Bactérias/efeitos dos fármacos , Dipeptídeos/síntese química , Fungos/efeitos dos fármacos , Camundongos , Testes de Sensibilidade Microbiana , Testes de Sensibilidade Parasitária , Plasmodium falciparum/efeitos dos fármacos , Ratos , Sulfonamidas/química
12.
Tissue Cell ; 59: 1-9, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31383283

RESUMO

The effect of the GM6001 metalloproteinase inhibitor on the regeneration of ambulacral structures in Eupentacta fraudatrix has been investigated. Inhibition of proteinase activity exerts a marked effect on regeneration, being dependent on the time when GM6001 is injected. When administration of the inhibitor begins on day 3 post-injury, regeneration is completely abolished, and the animals die. This means that early activation of proteinases is crucial for triggering the regenerative process in holothurians. When GM6001 in first injected on day 7 post-injury, the regeneration rate decreases. However, this effect has proven to be reversible: when inhibition ceases, the regeneration resumes. The effect of the inhibitor is manifested as a retarded degradation of the extracellular matrix, the lack of cell dedifferentiation, and, probably, a slower cell migration. The gelatinase activity is detected in all the regenerating organs of E. fraudatrix. In the holothurian Cucumaria japonica, which is not capable of healing skin wounds and ambulacrum reparation, no gelatinase activity was observed at the site of damage. A suggestion is made that proteinases play an important role in regeneration in holothurians. The most probable morphogenesis regulators are matrix metalloproteinases with gelatinase activity.


Assuntos
Dipeptídeos/farmacologia , Gelatinases/antagonistas & inibidores , Holothuria/fisiologia , Inibidores de Metaloproteinases de Matriz/farmacologia , Regeneração/efeitos dos fármacos , Animais , Gelatinases/metabolismo , Regeneração/fisiologia
13.
Eur J Pharmacol ; 861: 172620, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31437429

RESUMO

The reno-protective effects of antidiabetic dipeptidyl peptidase (DPP)-4 inhibitors have been studied regarding their antioxidant and anti-inflammatory properties. However, the potential ability of saxagliptin to ameliorate renal injury by enhancing neovascularization has not been elucidated. To address this issue, saxagliptin (10 and 30 mg/kg) was administered to Wistar rats after the induction of renal ischaemia/reperfusion (I/R). Our results showed that saxagliptin operated through different axes to ameliorate I/R injury. By inhibiting DPP-4, saxagliptin maintained stromal cell-derived factor-1α expression and upregulated its chemokine receptor CXCR4 to trigger vasculogenesis through the enhanced migration of endothelial progenitor cells (EPCs). Additionally, this compound rescued the levels of glucagon-like peptide-1 and its downstream mediator cAMP to increase vascular endothelial growth factor (VEGF) and CXCR4 levels. Moreover, saxagliptin stimulated atrial natriuretic peptide/endothelial nitric oxide synthase to increase nitric oxide levels and provoke angiogenesis and renal vasodilation. In addition to inhibiting DPP-4, saxagliptin increased the renal kidney injury molecule-1/pY705-STAT3/hypoxia-inducible factor-1α/VEGF pathway to enhance angiogenesis. Similar to other gliptins, saxagliptin exerted its anti-inflammatory and antioxidant effects by suppressing the renal contents of p (S536)-nuclear factor-κB p65, tumour necrosis factor-α, monocyte chemoattractant protein-1, myeloperoxidase, and malondialdehyde while boosting the glutathione content. These events improved the histological structure and function of the kidney, as evidenced by decreased serum creatinine, blood urea nitrogen, and cystatin C and increased serum albumin. Accordingly, in addition to its anti-inflammatory and antioxidant activities, saxagliptin dose-dependently ameliorated I/R-induced renal damage by enhancing neovascularization through improved tissue perfusion and homing of bone marrow-derived EPCs to mediate repair processes.


Assuntos
Adamantano/análogos & derivados , Dipeptídeos/farmacologia , Rim/irrigação sanguínea , Rim/efeitos dos fármacos , Neovascularização Fisiológica/efeitos dos fármacos , Traumatismo por Reperfusão/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Adamantano/farmacologia , Adamantano/uso terapêutico , Animais , Fator Natriurético Atrial/metabolismo , Moléculas de Adesão Celular/metabolismo , Quimiocina CXCL12/metabolismo , AMP Cíclico/metabolismo , Dipeptídeos/uso terapêutico , Modelos Animais de Doenças , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Glutationa/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Rim/patologia , Rim/fisiopatologia , Masculino , Malondialdeído/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Peroxidase/metabolismo , Ratos , Ratos Wistar , Receptores CXCR4/metabolismo , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/fisiopatologia , Fator de Transcrição STAT3/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
14.
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
15.
Org Biomol Chem ; 17(28): 6782-6785, 2019 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-31276151

RESUMO

Gliocladiosin A (1) and B (2), two dipeptides conjugated with macrolides, were identified from a verM disruption mutant of the Cordycep-colonizing fungus Clonostachys rogersoniana. The structures and absolute configurations of 1 and 2 were determined on the basis of spectroscopic data analysis, including MS, NMR, CD and X-ray diffraction. A biogenetic pathway for 1 and 2 was proposed. These two compounds showed moderate antibacterial effects.


Assuntos
Antibacterianos/farmacologia , Bacillus subtilis/efeitos dos fármacos , Dipeptídeos/farmacologia , Hypocreales/química , Klebsiella pneumoniae/efeitos dos fármacos , Antibacterianos/biossíntese , Antibacterianos/química , Cristalografia por Raios X , Dipeptídeos/biossíntese , Dipeptídeos/química , Testes de Sensibilidade Microbiana , Modelos Moleculares , Conformação Molecular
16.
Int J Mol Sci ; 20(13)2019 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-31261895

RESUMO

Preventive approaches for age-related memory decline and dementia have become a high priority in the aging society because of the lack of therapeutic approaches. Recent epidemiological studies have reported that fermented dairy products can help prevent dementia. Previously, we identified tryptophan-tyrosine (WY) and tryptophan-methionine (WM) peptides as the suppressants of activation of the primary microglia and showed that WY peptide consumption suppresses inflammation in the brains of Alzheimer's disease model mice. However, the effects of the WM peptide on inflammation in the brain and Alzheimer's pathology have not been investigated. Here, we evaluated the effect of WM peptide consumption on Alzheimer's disease model (5×FAD) mice. In 5×FAD mice, intake of WM peptide suppressed the production of inflammatory cytokines, activation of microglia, and infiltration of activated microglia around ß amyloid (Aß) depositions. WM peptide intake reduced Aß deposition in the cortex and hippocampus and then improved the object recognition memory. Taken together with previous reports, the current findings indicate that ingestion of tryptophan-related peptides or food material rich in tryptophan-related peptides, thereby regulating microglial activity, represents a potential preventive approach for cognitive decline and dementia related to inflammation.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Anti-Inflamatórios/farmacologia , Dipeptídeos/farmacologia , Doença de Alzheimer/prevenção & controle , Peptídeos beta-Amiloides/metabolismo , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/uso terapêutico , Citocinas/metabolismo , Suplementos Nutricionais , Dipeptídeos/administração & dosagem , Dipeptídeos/química , Dipeptídeos/uso terapêutico , Feminino , Metionina/química , Camundongos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Proteínas do Leite/química , Triptofano/química
17.
Biosci Biotechnol Biochem ; 83(11): 2027-2033, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31322484

RESUMO

Collagen-derived dipeptide prolyl hydroxyproline (Pro-Hyp) is involved in the proliferation and differentiation of various types of cultured cells. To elucidate the mechanism underlying Pro-Hyp actions during osteoblast differentiation, we hypothesized that proteins binding to Pro-Hyp serve to mediate cellular signaling, affecting Runx2 expression. Recently, we performed the characterization of Foxg1, that it enhances Runx2 expression in the presence of Pro-Hyp. Our findings indicate that Pro-Hyp directly binds to the Foxg1 recombinant protein, which leads to the structural alteration of the Foxg1 protein. In addition, Foxg1 appears to interact with Runx2 in the absence of Pro-Hyp, with Pro-Hyp disrupting the interaction between Foxg1 and Runx2. Collectively, our results indicate that the Pro-Hyp bound Foxg1 alters the structured conformation of Foxg1, resulting in conformational changes that lead to dissociation from Runx2. These novel findings suggest that during osteoblast differentiation, Pro-Hyp mediates Runx2 activity though directly binding to Foxg1 and increases Runx2 expression. Abbreviations: CPT: collagen peptide; GST: Glutathione S-transferase; PAGE: Polyacrylamide gel electrophoresis; PCR: Polymerase chain reaction; prolyl hydroxyproline: Pro-Hyp.


Assuntos
Colágeno/química , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Dipeptídeos/metabolismo , Dipeptídeos/farmacologia , Fatores de Transcrição Forkhead/química , Fatores de Transcrição Forkhead/metabolismo , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Camundongos , Osteoblastos/citologia , Osteoblastos/efeitos dos fármacos , Ligação Proteica/efeitos dos fármacos , Conformação Proteica/efeitos dos fármacos
18.
J Agric Food Chem ; 67(30): 8361-8369, 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31339708

RESUMO

The calcium-sensing receptor (CaSR), a G-protein receptor, is well recognized for its role in the regulation of adipocyte proliferation, in modulating adipose tissue dysfunction, and as a potential target for therapeutic intervention. In the present study, we investigate the anti-inflammatory effect of γ-glutamylvaline (γ-EV) on mouse adipocytes and explore the role of γ-EV-activated CaSR in the regulation of cellular homeostasis using the mouse 3T3-L1 cell line in vitro model. Our results indicate that the 3T3-L1 adipocyte-like cells accumulated lipids and expressed CaSR after 2 days of differentiation and 7 days of maturation period. The pretreatment with γ-EV (10 µM) suppressed the production of TNF-α-induced pro-inflammatory cytokines, i.e., IL-6 (23.92 ± 5.45 ng/mL, p < 0.05)) and MCP-1 (101.17 ± 39.93 ng/mL, p < 0.05), while enhancing the expression of PPARγ (1.249 ± 0.109, p < 0.001) and adiponectin (7.37 ± 0.59 ng/mL, p < 0.05). Elevated expression of Wnt5a was detected in γ-EV-treated cells (115.90 ± 45.50, p < 0.001), suggesting the involvement of the Wnt/ß-catenin pathway. Also, phosphorylation of ß-catenin was shown to be significantly inhibited (0.442 ± 0.034) by TNF-α but restored when cells were pretreated with γ-EV (0.765 ± 0.048, p < 0.05). These findings suggest that γ-EV-induced CaSR activation not only prevents TNF-α-induced inflammation in adipocytes but also modulates the cross-talk between Wnt and PPARγ pathways. Concentrations of serine phosphorylated IRS-1 were shown to be lower in γ-EV-treated cells, indicating γ-EV may also prevent inflammation in the context of insulin resistance. Thus, γ-EV-activated CaSR plays a significant role in the cross-talk between adipocyte inflammatory and metabolic pathways through the regulation of extracellular sensing.


Assuntos
Adipócitos/efeitos dos fármacos , Dipeptídeos/farmacologia , Receptores de Detecção de Cálcio/imunologia , Células 3T3-L1 , Adipócitos/imunologia , Animais , Interleucina-6/genética , Interleucina-6/imunologia , Camundongos , PPAR gama/genética , PPAR gama/imunologia , Fosforilação , Receptores de Detecção de Cálcio/genética , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
19.
Eur J Med Chem ; 179: 591-607, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31279293

RESUMO

Antibody-drug conjugates (ADCs) containing pyrrolobenzodiazepine (PBD) dimers are currently being evaluated in human oncology clinical trials with encouraging results. To further improve the therapeutic window, next-generation PBD drug-linker design has focused on the inclusion of additional tumor-selective triggers and use of lower-potency PBDs. ß-Glucuronidase is a well-known target for discovery prodrugs due to increased presence in tumor cells and microenvironment. In this study, a ß-glucuronidase cleavable cap was investigated at the PBD N10-position and compared with corresponding free imine ADCs. SG3600 (glucuronide) ADCs showed in vitro and in vivo efficacy/tolerability comparable to SG3400 (imine) ADCs, and good 50% inhibitory concentration differentials were observed in vitro between control non-antigen-targeted ADCs and targeted ADCs. Dependence on ß-glucuronidase for SG3600 activity was demonstrated through CRISPRCas9 knockdown studies and addition of exogenous ß-glucuronidase. SG3600 showed better serum stability, improved conjugation efficiency and was able to reach high drug-to-antibody ratio without aggregation.


Assuntos
Benzodiazepinas/farmacologia , Dipeptídeos/farmacologia , Glucuronídeos/farmacologia , Imunoconjugados/farmacologia , Pirróis/farmacologia , Benzodiazepinas/síntese química , Benzodiazepinas/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dipeptídeos/química , Relação Dose-Resposta a Droga , Glucuronídeos/química , Humanos , Imunoconjugados/química , Estrutura Molecular , Pirróis/síntese química , Pirróis/química , Relação Estrutura-Atividade
20.
Life Sci ; 233: 116698, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31356906

RESUMO

AIM: Type 1 diabetes (T1DM) is a common chronic disease in childhood. Increasing insulin resistance in puberty gives rise to higher doses of insulin usage in treatment. Of this reason new approaches in treatment are needed. Noopept researches suggest it to have anti-diabetic properties. We tried to determine the effects of noopept on pubertal diabetes. MAIN METHOD: The research was made with 60 prepubertal, 28 day-old, male, Sprague Dawley rats. The rats were divided into randomised 6 groups (n = 10/group). i) Control, ii) Diabetes Control, iii) Noopept Control, iv) Diabetes + Noopept, v) Diabetes + Insulin, vi) Diabetes + Insulin + Noopept. T1DM model was induced by streptozotocin on postnatal 28th day. 0.5 mg/kg noopept and 1 IU insulin were administered intraperitoneally for 14 days. Blood glucose and body weight measurements, puberty follow-up and MWM tests were performed. Hippocampus, hypothalamus and testis were evaluated histologically. Hypothalamic GnRH and kisspeptin were studied immunohistochemically. Serum LH, FSH and insulin, hippocampal homogenate NGF and BDNF levels were determined by ELISA. KEY FINDINGS: Delayed puberty was normalized by noopept (p < 0.05). Blood glucose levels were lower in noopept-administered diabetic groups (p < 0.05). Noopept decreased HOMA-IR in insulin administered diabetic group (p < 0.05). Number of degenerated cells in hippocampus and testis were higher in diabetes control group when compared with other groups (p < 0.05). GnRH immunoreactivity in Diabetes + Noopept group was increased when compared to insulin + noopept group (p = 0.018). There was no difference in kisspeptin, serum LH, FSH, hippocampal NGF-BDNF levels and spatial learning assessment among groups (p > 0.05). SIGNIFICANCE: Noopept may have positive effect in treatment of pubertal diabetes.


Assuntos
Cognição/fisiologia , Diabetes Mellitus Experimental/tratamento farmacológico , Dipeptídeos/farmacologia , Resistência à Insulina , Fármacos Neuroprotetores/farmacologia , Puberdade/fisiologia , Animais , Glicemia/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Cognição/efeitos dos fármacos , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Insulina/metabolismo , Masculino , Fator de Crescimento Neural/metabolismo , Puberdade/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
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