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1.
Int J Nanomedicine ; 14: 6135-6150, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31447556

RESUMO

Background: Nanostructured lipid carriers (NLCs) are emerging as attractive drug carriers in transdermal drug delivery. The surface modification of NLCs with cell-penetrating peptides (CPPs) can enhance the skin permeation of drugs. Purpose: The objective of the current study was to evaluate the ability of the cell-penetrating peptide (CPP) polyarginine to translocate NLCs loaded with lornoxicam (LN) into the skin layers and to evaluate its anti-inflammatory effect. Methods: The NLCs were prepared using an emulsion evaporation and low temperature solidification technique using glyceryl monostearates, triglycerides, DOGS-NTA-Ni lipids and surfactants, and then six histidine-tagged polyarginine containing 11 arginine (R11) peptides was modified on the surface of NLCs. Results: The developed NLCs formulated with LN and R11 (LN-NLC-R11) were incorporated into 2% HPMC gels. NLCs were prepared with a particle size of (121.81±3.61)-(145.72±4.78) nm, and the zeta potential decreased from (-30.30±2.07) to (-14.66±0.74) mV after the modification of R11 peptides. The encapsulation efficiency and drug loading were (74.61±1.13) % and (7.92±0.33) %, respectively, regardless of the surface modification. Cellular uptake assays using HaCaT cells suggested that the NLC modified with R11 (0.02%, w/w) significantly enhanced the cell internalization of nanoparticles relative to unmodified NLCs (P<0.05 or P<0.01). An in vitro skin permeation study showed better permeation-enhancing ability of R11 (0.02%, w/w) than that of other content (0.01% or 0.04%). In carrageenan-induced rat paw edema models, LN-NLC-R11 gels inhibited rat paw edema and the production of inflammatory cytokines compared with LN-NLC gels and LN gels (P<0.01). Conclusion: In our investigation, it was strongly demonstrated that the surface modification of NLC with R11 enhanced the translocation of LN across the skin, thereby alleviating inflammation.


Assuntos
Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Edema/tratamento farmacológico , Lipídeos/química , Nanoestruturas/química , Peptídeos/farmacologia , Piroxicam/análogos & derivados , Administração Cutânea , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Carragenina , Morte Celular/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Peptídeos Penetradores de Células/farmacologia , Edema/induzido quimicamente , Edema/metabolismo , Emulsões/química , Endocitose/efeitos dos fármacos , Géis/química , Humanos , Camundongos Endogâmicos BALB C , Nanopartículas/química , Nanopartículas/ultraestrutura , Oligopeptídeos/farmacologia , Oligopeptídeos/uso terapêutico , Piroxicam/administração & dosagem , Piroxicam/farmacologia , Piroxicam/uso terapêutico , Coelhos , Ratos Sprague-Dawley , Pele/efeitos dos fármacos , Absorção Cutânea/efeitos dos fármacos , Testes de Irritação da Pele
2.
Cell Prolif ; 52(5): e12665, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31332862

RESUMO

OBJECTIVES: Abnormal activation of NF-κB signalling is a major mechanism of apoptosis resistance in glioblastoma multiforme (GBM). Therefore, better understanding of the regulation of NF-κB signalling has a significant impact for GBM therapy. Here, we uncovered a critical role of the small GTPase RND3 in regulating the p65 subunit of NF-κB and NF-κB signalling in GBM. MATERIALS AND METHODS: Human GBM samples, GBM cells and a human orthotopic GBM-xenografted animal model were used. The mechanisms of RND3 in regulation of NF-κB signalling and GBM cell apoptosis were examined by luciferase assay, quantitative PCR, immunostaining, immunoblotting, immunofluorescence, coimmunoprecipitation, TUNEL staining, JC-1 analysis and flow cytometry. RESULTS: Overexpression of RND3 led to reduced p65 activity in GBM-cultured cells and a GBM animal model, indicating that the NF-κB pathway is negatively regulated by RND3 in GBM. Mechanistically, we found that RND3 bound p65 and promoted p65 ubiquitination, leading to decreased p65 protein levels. Furthermore, RND3 enhanced cleaved caspase 3 levels and promoted apoptosis in GBM cells, and RND3 expression was positively correlated with cleaved caspase 3 and IL-8 in human GBM samples. The effect of RND3 on promoting apoptosis disappeared when p65 ubiquitination was blocked by protease inhibitor carfilzomib or upon co-expression of ectopic p65. CONCLUSIONS: RND3 binds p65 protein and promotes its ubiquitination, resulting in reduced p65 protein expression and inhibition of NF-κB signalling to induce GBM cell apoptosis.


Assuntos
Neoplasias Encefálicas/patologia , Glioblastoma/patologia , Transdução de Sinais , Proteínas rho de Ligação ao GTP/metabolismo , Animais , Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/metabolismo , Caspase 3/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/metabolismo , Humanos , Interleucina-8/metabolismo , Camundongos , Camundongos Nus , Oligopeptídeos/farmacologia , Ligação Proteica , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo , Transplante Heterólogo , Ubiquitinação/efeitos dos fármacos , Proteínas rho de Ligação ao GTP/genética
3.
Eur J Med Chem ; 179: 527-536, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31276897

RESUMO

New analogs of the endogenous opioid agonist endomorphin-2 (EM-2, H-Tyr-Pro-Phe-Phe-NH2) have been obtained by introducing modified tyrosines at the position 1 of the sequence. For all analogs, the cis/trans conformation ratio about the tyramine-Pro amide bond, lipophilicity, receptor affinities, and functional activities, have been determined. Among the novel derivatives, [Dmt(3'-Cl)]1EM-2 (4) stood out for its subnanomolar µ-opioid receptor affinity and potent agonist activity, superior to that of the parent peptide EM-2. Hybrid quantum mechanics/molecular mechanics docking computations supported the cis tyramine-Pro bioactive conformation, and allowed us to analyze the contribution of the substituents of the "message" tyramine to binding, highlighting the role of halogen-bonding in the higher receptor affinity of peptide 4.


Assuntos
Analgésicos Opioides/farmacologia , Teoria da Densidade Funcional , Oligopeptídeos/farmacologia , Receptores Opioides/agonistas , Tirosina/farmacologia , Analgésicos Opioides/síntese química , Analgésicos Opioides/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Conformação Molecular , Oligopeptídeos/síntese química , Oligopeptídeos/química , Relação Estrutura-Atividade , Tirosina/química
4.
Bratisl Lek Listy ; 120(6): 468-475, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31223029

RESUMO

BACKGROUND: Previous studies on the efficacy of platinum-based drugs and selective inhibitors of proteasome have revealed promising outcomes. This study is aimed to evaluate the effects of the combination of cisplatin and carfilzomib on the cell death induction and drug efflux transporters expression in cisplatin-sensitive (A2780s) and cisplatin-resistant (A2780cp) ovarian cancer cells lines. METHODS: MTT cytotoxic assay was conducted to determine the cytotoxicity. Drug interactions were analyzed based on Chou-Talalay's principles and real-time PCR analysis was performed to determine possible alterations in mRNA levels of MRP1 and BCRP. RESULTS: A2780s cells were more susceptible to both cisplatin and carfilzomib while analyses of drug interactions between the two agents showed synergistic effects in all affected fractions of drug-treated A2780s and A2780cp cells (CI<0.9) with the combination indices being significantly lower in A2780cp cells (p < 0.01). We also found that although mRNA levels of BCRP and MRP1 were significantly altered in both cells exposed to each drug alone, only the combination regimen was able to significantly reduce the mRNA levels of these genes in A2780cp cells (p<0.001). CONCLUSION: This combination might be a potential strategy for suppressing cell growth via downregulating the drug efflux transporters expression, especially in cisplatin-resistant ovarian cancer cells (Fig. 3, Ref. 45).


Assuntos
Antineoplásicos , Cisplatino , Oligopeptídeos , Neoplasias Ovarianas , Antineoplásicos/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cisplatino/farmacologia , Regulação para Baixo , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Oligopeptídeos/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia
5.
Arch Insect Biochem Physiol ; 101(4): e21586, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31180597

RESUMO

This study examined the effect of two natural toxins (a venom from the parasitic wasp Habrobracon hebetor and destruxin A from the entomopathogenic fungus Metarhizium anisopliae), and one pathogen (the entomopathogenic fungus Isaria fumosorosea) on the activity of basic digestive enzymes in the midgut of the cockroach Periplaneta americana. Simultaneously, the role of adipokinetic hormones (AKH) in the digestive processes was evaluated. The results showed that all tested toxins/pathogens elicited stress responses when applied into the cockroach body, as documented by an increase of AKH level in the central nervous system. The venom from H. hebetor showed no effect on digestive enzyme activities in the ceca and midgut in vitro. In addition, infection by I. fumosorosea caused a decrease in activity of all enzymes in the midgut and a variable decrease in activity in the ceca; application of AKHs did not reverse the inhibition. Destruxin A inhibited the activity of all enzymes in the midgut but none in the ceca in vitro; application of AKHs did reverse this inhibition, and no differences between both cockroach AKHs were found. Overall, the results demonstrated the variable effect of the tested toxins/pathogens on the digestive processes of cockroaches as well as the variable ability of AKH to counteract these effects.


Assuntos
Depsipeptídeos/toxicidade , Hormônios de Inseto/farmacologia , Oligopeptídeos/farmacologia , Periplaneta/efeitos dos fármacos , Ácido Pirrolidonocarboxílico/análogos & derivados , Venenos de Vespas/toxicidade , Animais , Ativação Enzimática , Trato Gastrointestinal/enzimologia , Periplaneta/enzimologia , Ácido Pirrolidonocarboxílico/farmacologia
6.
Toxicol Lett ; 313: 30-41, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31181250

RESUMO

The hedgehog (HH) signaling pathway plays an important role in lung development, but its significance in silicosis is unclear. We showed that in human coal pneumoconiosis autopsy specimens, Sonic Hedgehog (SHH) and the Glioma-associated oncogene homolog transcription factors family (GLI) 1 proteins were up-regulated, whereas Patch-1 (PTC) was down-regulated. The protein levels of SHH, smoothened (SMO), GLI1, GLI2, α-smooth muscle actin (α-SMA) and collagen type Ⅰ (Col Ⅰ) were also elevated gradually in the bronchoalveolar lavage fluid (BALF) of different stages of coal pneumoconiosis patients, dynamic silica-inhalation rat lung tissue and MRC-5 cells induced by Ang II at different time points, whereas the PTC and GLI3 levels were diminished gradually. Ac-SDKP, an active peptide of renin-angiotensin system (RAS), is an anti-fibrotic tetrapeptide. Targeting RAS axis also has anti-silicotic fibrosis effects. However, their roles on the HH pathway are still unknown. Here, we reported that Ac-SDKP + Captopril, Ac-SDKP, Captopril, or Ang (1-7) could alleviate silicotic fibrosis and collagen deposition, as well as improve the lung functions of silicotic rat. These treatments decreased the expression of SHH, SMO, GLI1, GLI2, α-SMA, and Col Ⅰ and increased the expression of PTC and GLI3 on both the silicotic rat lung tissue and MRC-5 cells induced by Ang II. We also reported that Ang II may promote myofibroblast differentiation via the GLI1 transcription factor and independently of the SMO receptor.


Assuntos
Angiotensina II/farmacologia , Angiotensina I/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Captopril/farmacologia , Diferenciação Celular/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Miofibroblastos/efeitos dos fármacos , Oligopeptídeos/farmacologia , Fragmentos de Peptídeos/farmacologia , Fibrose Pulmonar/prevenção & controle , Sistema Renina-Angiotensina/efeitos dos fármacos , Silicose/prevenção & controle , Adulto , Idoso , Animais , Antracose/metabolismo , Antracose/patologia , Linhagem Celular , Colágeno/metabolismo , Modelos Animais de Doenças , Feminino , Proteínas Hedgehog/metabolismo , Humanos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Silicose/metabolismo , Silicose/patologia
7.
Eur J Med Chem ; 177: 235-246, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31152989

RESUMO

Culicinin D is a 10 amino acid peptaibol containing a rare and synthetically challenging (2S,4S,6R)-AHMOD residue, that exhibits potent antiproliferative activity against MDA-MB-468 cells. An SAR study focusing on replacement of the AHMOD residue was undertaken, culminating in the revelation that a 6-hydroxy or 6-keto substituent was essential to retain potent low nanomolar antiproliferative activity.


Assuntos
Antineoplásicos/farmacologia , Oligopeptídeos/farmacologia , Peptaibols/farmacologia , Substituição de Aminoácidos , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Ácidos Decanoicos/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Oligopeptídeos/síntese química , Oligopeptídeos/química , Peptaibols/síntese química , Peptaibols/química , Estereoisomerismo , Relação Estrutura-Atividade
8.
Mol Med Rep ; 19(6): 4553-4560, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059021

RESUMO

Cardiac fibrosis secondary to long­term hypertension is known to promote cardiac dysfunction; however, few therapeutic agents are available for the treatment of this condition in clinical practice. The heptapeptide alamandine (Ala) has recently been identified as a component of the renin­angiotensin system (RAS), which exerts a protective effect against cardiac hypertrophy; however, it is unknown whether Ala may also be useful for the treatment of cardiac fibrosis. In the present study, the potential therapeutic effects of Ala on long­term hypertension­induced cardiac fibrosis were investigated in an aged, spontaneous hypertensive rat model. Weekly blood pressure (BP) measurements revealed that daily Ala treatment significantly decreased the systolic, diastolic and mean arterial BP compared with the control. Of note, the observed reduction in BP in Ala­treated animals markedly differed to that observed in rats treated with hydralazine (Hyd). Echocardiography further demonstrated that Ala treatment decreased the ratio of left ventricle mass to body weight, and alleviated structural and functional parameters associated with cardiac fibrosis, including left ventricular volume, ejection fraction and fractional shortening compared with the control and Hyd­treated groups. Furthermore, Ala deceased the density of cardiac fibrosis, as assessed by Masson and Sirius red staining; reduced expression of fibrotic proteins, including connective tissue growth factor, collagen I (COL1A1) and matrix metalloproteinase 9, was also observed. In addition, Ala treatment further decreased the expression of angiotensin II­induced fibrotic markers at the mRNA and protein levels in cultured cardiac fibroblasts; Ala­mediated inhibition of COL1A1 expression and Akt phosphorylation was inhibited via the Mas­related G protein receptor antagonist, PD123319. Collectively, the findings of the present study suggest that Ala is an effective anti­hypertensive peptide that can attenuate cardiac dysfunction and fibrosis induced by chronic hypertension, independent of BP.


Assuntos
Cardiomegalia/tratamento farmacológico , Fibrose/tratamento farmacológico , Hipertensão/tratamento farmacológico , Oligopeptídeos/farmacologia , Angiotensina II/genética , Angiotensina II/metabolismo , Animais , Anti-Hipertensivos/farmacologia , Pressão Sanguínea , Cardiomegalia/etiologia , Colágeno Tipo I/antagonistas & inibidores , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Fibrose/etiologia , Ventrículos do Coração/metabolismo , Hipertensão/complicações , Imidazóis/farmacologia , Masculino , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Piridinas/farmacologia , Ratos , Ratos Endogâmicos SHR , Sistema Renina-Angiotensina
9.
Mar Drugs ; 17(5)2019 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-31086041

RESUMO

The peptide QAGLSPVR, which features high angiotensin-I-converting enzyme (ACE) inhibitory activity, was identified in our previous study. In this study, the in vivo antihypertensive effect of QAGLSPVR was evaluated. Results showed that QAGLSPVR exerts a clear antihypertensive effect on spontaneously hypertensive rats (SHRs), and the systolic and diastolic blood pressures of the rats remarkably decreased by 41.86 and 40.40 mm Hg, respectively, 3 h after peptide administration. The serum ACE activities of SHRs were determined at different times, and QAGLSPVR was found to decrease ACE activities in serum; specifically, minimal ACE activity was found 3 h after administration. QAGLSPVR could be completely absorbed by the Caco-2 cell monolayer, and its transport percentage was 3.5% after 2 h. The transport route results of QAGLSPVR showed that Gly-Sar and wortmannin exert minimal effects on the transport percentage of the peptide (p> 0.05), thus indicating that QAGLSPVR transport through the Caco-2 cell monolayer is not mediated by peptide transporter 1 or transcytosis. By contrast, cytochalasin D significantly increased QAGLSPVR transport (p< 0.05); thus, QAGLSPVR may be transported through the Caco-2 cell monolayer via the paracellular pathway.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Oligopeptídeos/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacocinética , Animais , Anti-Hipertensivos/farmacocinética , Células CACO-2 , Captopril/farmacologia , Humanos , Hipertensão/sangue , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Masculino , Oligopeptídeos/farmacocinética , Peptidil Dipeptidase A/sangue , Ratos Endogâmicos SHR
10.
Cell Physiol Biochem ; 52(6): 1339-1360, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31050282

RESUMO

BACKGROUND/AIMS: Melanocortin receptors (MCRs) belong to a hormonal signalling pathway with multiple homeostatic and protective actions. Microvascular and umbilical vein endothelial cells (ECs) express components of the melanocortin system, including the type 1 receptor (MC1R), playing a role in modulating inflammation and vascular tone. Since ECs exhibit a remarkable heterogeneity, we investigated whether human artery ECs express any functional MCR and whether its activation affects cell migration. METHODS: We used reverse transcription real-time PCR to examine the expression of melanocortin system components in primary human artery ECs. We assessed MC1R protein expression and activity by western blot, immunohistochemistry, cAMP production, and intracellular Ca²âº mobilization assays. We performed gap closure and scratch tests to examine cell migration after stimulation with alpha-melanocyte-stimulating hormone (α-MSH), the receptor highest-affinity natural ligand. We assessed differential time-dependent transcriptional changes in migrating cells by microarray analysis. RESULTS: We showed that human aortic ECs (HAoECs) express a functionally active MC1R. Unlike microvascular ECs, arterial cells did not express the α-MSH precursor proopiomelanocortin, nor produced the hormone. MC1R engagement with a single pulse of α-MSH accelerated HAoEC migration both in the directional migration assay and in the scratch wound healing test. This was associated with an enhancement in Ca²âº signalling and inhibition of cAMP elevation. Time-course genome-wide expression analysis in HAoECs undergoing directional migration allowed identifying dynamic co-regulation of genes involved in extracellular matrix-receptor interaction, vesicle-mediated trafficking, and metal sensing - which have all well-established influences on EC motility -, without affecting the balance between pro- and anticoagulant genes. CONCLUSION: Our work broadens the knowledge on peripherally expressed MC1R. These results indicate that the receptor is constitutively expressed by arterial ECs and provide evidence of a novel homeostatic function for MC1R, whose activation may participate in preventing/healing endothelial dysfunction or denudation in macrovascular arteries.


Assuntos
Receptor Tipo 1 de Melanocortina/metabolismo , Aorta/citologia , Sinalização do Cálcio/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , AMP Cíclico/metabolismo , Ácido Egtázico/análogos & derivados , Ácido Egtázico/farmacologia , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Antígeno Ki-67/metabolismo , Oligopeptídeos/farmacologia , Receptor Tipo 1 de Melanocortina/genética , alfa-MSH/farmacologia
11.
Mar Drugs ; 17(4)2019 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-30935056

RESUMO

A protein extract was generated from the macroalga Ulva lactuca, which was subsequently hydrolysed using the food-grade enzyme papain and angiotensin-converting Enzyme I and renin inhibitory peptides identified using a combination of enrichment strategies employing molecular weight cutoff filtration and mass spectrometry analysis. The generated hydrolysates with the most promising in vitro activity were further purified using preparative RP-HPLC and characterised. The 1 kDa hydrolysate (1 kDa-UFH), purified and collected by preparative RP-HPLC at minutes 41‒44 (Fr41‒44), displayed statistically higher ACE-I inhibitory activities ranging from 96.91% to 98.06%. A total of 48 novel peptides were identified from these four fractions by LC-MS/MS. A simulated gastrointestinal digestion of the identified peptide sequences was carried out using in silico enzyme cleavage simulation tools, resulting in 86 peptide sequences that were further assessed for their potential activity, toxicity and allergenicity using multiple predictive approaches. All the peptides obtained in this study were predicted to be non-toxic. However, 28 out of the 86 novel peptides released after the in silico gastrointestinal digestion were identified as potential allergens. The potential allergenicity of these peptides should be further explored to comply with the current labelling regulations in formulated food products containing U. lactuca protein hydrolysates.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/metabolismo , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Oligopeptídeos/metabolismo , Oligopeptídeos/farmacologia , Hidrolisados de Proteína/farmacologia , Ulva/metabolismo , Alérgenos/farmacologia , Sequência de Aminoácidos , Inibidores da Enzima Conversora de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/isolamento & purificação , Anti-Hipertensivos/farmacologia , Simulação por Computador , Humanos , Hidrólise , Oligopeptídeos/química , Oligopeptídeos/isolamento & purificação , Hidrolisados de Proteína/química , Hidrolisados de Proteína/isolamento & purificação , Alga Marinha/química , Ulva/química , Ulva/citologia
12.
Nutrients ; 11(4)2019 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-30987324

RESUMO

Alcalase- generated potato protein hydrolysate (APPH) is a potential bioactive peptide against diabetes mellitus (DM) and DM-associated secondary effects in animal models. The aim of the present study was to find the efficiency of a deca-peptide DIKTNKPVIF (DF) from APPH against DM. Six-week-old male ICR mice were divided into the following groups: Control, Control+DF (received 50 mg/kg DF), streptozotocin (STZ)-induced DM group, DM+Acarbose group (20 mg/kg of acarbose), DM+DF-L (25 mg/kg of DF), DM+DF-H (50 mg/kg of DF), and DM+APPH (50 mg/kg of APPH). Comparable to APPH, treatment with DF effectively regulated blood glucose level and also controlled plasma total glycerol (TG), total cholesterol (TC), insulin, and HbA1c levels in DM animals. DF treatment also showed evidence of ameliorating DM-associated damages in the pancreatic islets and in the liver, heart, and kidney tissues. Therefore, the results demonstrate that the short synthetic peptide-DF may effectively provide protection against DM-associated damages.


Assuntos
Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental/prevenção & controle , Hipoglicemiantes/farmacologia , Ilhotas Pancreáticas/efeitos dos fármacos , Oligopeptídeos/farmacologia , Proteínas de Plantas/metabolismo , Hidrolisados de Proteína/metabolismo , Solanum tuberosum/metabolismo , Animais , Biomarcadores/sangue , Glicemia/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/patologia , Hemoglobina A Glicada/metabolismo , Hipoglicemiantes/metabolismo , Insulina/sangue , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/patologia , Lipídeos/sangue , Masculino , Camundongos Endogâmicos ICR , Oligopeptídeos/metabolismo , Estreptozocina , Subtilisinas/metabolismo
13.
Molecules ; 24(8)2019 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-31013889

RESUMO

The five melanocortin receptors (MC1R-MC5R) are involved in numerous biological pathways, including steroidogenesis, pigmentation, and food intake. In particular, MC3R and MC4R knockout mice suggest that the MC3R and MC4R regulate energy homeostasis in a non-redundant manner. While MC4R-selective agonists have been utilized as appetite modulating agents, the lack of MC3R-selective agonists has impeded progress in modulating this receptor in vivo. In this study, the (pI)DPhe position of the tetrapeptide Ac-His-Arg-(pI)DPhe-Tic-NH2 (an MC3R agonist/MC4R antagonist ligand) was investigated with a library of 12 compounds. The compounds in this library were found to have higher agonist efficacy and potency at the mouse (m) MC3R compared to the MC4R, indicating that the Arg-DPhe motif preferentially activates the mMC3R over the mMC4R. This observation may be used in the design of new MC3R-selective ligands, leading to novel probe and therapeutic lead compounds that will be useful for treating metabolic disorders.


Assuntos
Oligopeptídeos , Receptores de Melanocortina/agonistas , Animais , Células HEK293 , Humanos , Camundongos , Camundongos Knockout , Oligopeptídeos/síntese química , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Receptores de Melanocortina/genética , Receptores de Melanocortina/metabolismo , Relação Estrutura-Atividade
14.
Molecules ; 24(8)2019 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-31013611

RESUMO

Walnut oligopeptides (WOPs) intake is associated with the augment of the antioxidant defense system and immune system. The chief object of this study is to evaluate the radioprotective effect of walnut oligopeptides extracted from walnut seed protein against 60Coγ-irradiation induced damage in mice. Female BALB/c mice were administered WOPs through drinking water for 14 days until a single dose of whole-body 60Coγ-irradiation. The 30-day survival test was carried out in the first group (8 Gy), and the other two groups (3.5 Gy) were sacrificed at 3 days and 14 days post-irradiation. Blood and organ samples of mice in the three groups were collected, the histopathological analysis and immunohistochemistry were conducted. The number of peripheral blood leukocytes, bone marrow DNA content, inflammatory cytokines, antioxidant capacity, and intestinal permeability were measured. We found that the administration of WOPs augmented antioxidant defense system, accelerated hematopoietic recovery and showed the significant trend toward higher survival rate and less weight loss compared with non-administrated control mice. In addition, WOPs administration appeared to be important to limit IR-induced splenocyte apoptosis and inflammatory cascade as well as reduce intestine epithelial barrier dysfunction and promote epithelial integrity. These results suggest that pre and post-treatment of WOPs may help to ameliorate acute damage, which is induced by ionizing radiation in mice and accelerate its recovery.


Assuntos
Apoptose , Raios gama/efeitos adversos , Intestinos/lesões , Juglans/química , Oligopeptídeos , Proteínas de Plantas , Lesões Experimentais por Radiação , Protetores contra Radiação , Baço/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Feminino , Intestinos/patologia , Camundongos , Camundongos Endogâmicos BALB C , Oligopeptídeos/química , Oligopeptídeos/isolamento & purificação , Oligopeptídeos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/efeitos da radiação , Proteínas de Plantas/química , Proteínas de Plantas/isolamento & purificação , Proteínas de Plantas/farmacologia , Lesões Experimentais por Radiação/metabolismo , Lesões Experimentais por Radiação/patologia , Lesões Experimentais por Radiação/prevenção & controle , Protetores contra Radiação/química , Protetores contra Radiação/isolamento & purificação , Protetores contra Radiação/farmacologia , Baço/patologia
15.
Food Chem Toxicol ; 129: 30-37, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31009737

RESUMO

Rambutan peel phenolics (RPP) have high antioxidant and anti-inflammatory activities. Leu-Ser-Gly-Tyr-Gly-Pro (LSGYGP) possesses good radical scavenging activity and matrix metalloproteinase (MMPs) inhibitory ability. These underlying mechanisms indicated that RPP and LSGYGP may be used for antiphotoaging. Few data on the effects of RPP and LSGYGP on in vivo photoaging are available. We evaluated the effects of RPP and/or LSGYGP on ultraviolet (UV)-induced hairless mice skin photoaging. In particular, we analyzed the additive effect of RPP and LSGYGP. The biochemical indices of mice skin, including composition (collagen and hyaluronic acid [HA] contents), oxidant stress (antioxidant enzyme activities and glutathione and malondialdehyde contents), MMPs (MMP-1, MMP-3, and MMP-9 levels), inflammatory cytokines (interleukin (IL)-1α, tumor nuclear factor-α, and IL-6 levels) and the phosphorylation of the mitogen-activated protein kinase pathway, were determined. Results showed a protective effect of RPP and/or LSGYGP on photoaging skin. LSGYGP showed considerable effects on skin collagen and HA contents. RPP showed improved effects on the regulation of the oxidant stress and inflammatory cytokine levels. RPP and LSGYGP exerted an additive effect on the amelioration of the biochemical indices of UV-induced photoaging skin. The histological changes showed that RPP and LSGYGP recovered the changes in skin tissue and endogenous collagen.


Assuntos
Oligopeptídeos/farmacologia , Fenóis/farmacologia , Protetores contra Radiação/farmacologia , Sapindaceae/química , Envelhecimento da Pele/efeitos dos fármacos , Envelhecimento da Pele/efeitos da radiação , Pele/efeitos dos fármacos , Pele/efeitos da radiação , Raios Ultravioleta , Sequência de Aminoácidos , Animais , Citocinas/metabolismo , Ácido Hialurônico/metabolismo , Mediadores da Inflamação/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Metaloproteinases da Matriz/metabolismo , Camundongos , Camundongos Pelados , Camundongos Endogâmicos BALB C , Camundongos Nus , Oligopeptídeos/química , Fosforilação , Pele/metabolismo , Pele/patologia
16.
J Biochem ; 166(3): 223-230, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31004484

RESUMO

Vinegar soaked black soybean is a traditional Chinese food widely used for the treatment of hypertension. While its pharmacodynamic substance was not fully unveiled. It contained abundant glutelin, thus the purpose of this study was to obtain potent antihypertensive peptides from vinegar soaked black soybean. Black soybean was soaked with vinegar and then glutelin was first catalyzed by alcalase. Ultrafiltration, ion exchange chromatography and reversed-phase high performance liquid chromatography were sequentially applied to separate and purify the angiotensin-I converting enzyme (ACE) inhibitory peptides from glutelin hydrolysates. As a result, the fraction L1-4 with the highest ACE inhibitory activity (83.41%) at the final concentration of 0.01 mg/ml was obtained and five peptides were then identified. These peptides were further optimized by virtual screening combining with in silico proteolysis. Finally, a novel tetrapeptide Phe-Gly-Ser-Phe (FGSF) was obtained. FGSF exhibited high in vitro ACE inhibitory activity (IC50 = 117.11 µM) and in vivo hypotensive effect which maximally reduced systolic blood pressure of 21.95 mmHg at 20 mg/kg body weight in spontaneously hypertensive rats. Our study demonstrated that FGSF derived from vinegar soaked black soybean might be used as a promising ingredient for pharmaceuticals against hypertension and its related diseases.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Anti-Hipertensivos/farmacologia , Glutens/química , Hipertensão/tratamento farmacológico , Oligopeptídeos/farmacologia , Soja/química , Ácido Acético/química , Inibidores da Enzima Conversora de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/isolamento & purificação , Animais , Anti-Hipertensivos/química , Anti-Hipertensivos/isolamento & purificação , Relação Dose-Resposta a Droga , Glutens/isolamento & purificação , Hipertensão/metabolismo , Masculino , Simulação de Acoplamento Molecular , Oligopeptídeos/química , Oligopeptídeos/isolamento & purificação , Peptidil Dipeptidase A/metabolismo , Ratos , Ratos Endogâmicos SHR , Relação Estrutura-Atividade
17.
Talanta ; 199: 32-39, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30952265

RESUMO

The majority of eukaryotic regulated protein turnover is performed by the proteasome, a multi-catalytic enzyme. Due to the fact that proteasome enzyme abnormal functioning was observed in different malignant cells, the proteasome is becoming a target for medical treatment. In order to evaluate the mechanisms of action of pharmaceutical compounds on proteasome enzyme inhibition, detecting and characterizing its activity is essential. An electrochemical assay that allows the monitoring of the chymotrypsin-like activity and inhibition of the 20S proteasome enzyme, based on the electrochemical detection of an electroactive compound released upon proteolysis of an adequate chymotrypsin-substrate is described. By employing differential pulse voltammetric measurement, the activity of the 20S proteasome enzyme was investigated for different incubation times of 20S with oligopeptide substrate as well as for different concentrations of substrate. Enzyme kinetic parameters were determined by voltammetry and the electrochemical assay compared with fluorescence spectroscopy. Electrochemical quartz crystal microbalance and atomic force microscopy were also used to investigate substrate interaction with the 20S proteasome and their adsorption at the electrode surface. Finally, the new electrochemical assay allowed to investigate the mechanisms of two different proteasome inhibitor drugs, bortezomib and oprozomib, underlying the applicability of the assay for understanding proteasome inhibitor action.


Assuntos
Antineoplásicos/farmacologia , Bortezomib/farmacologia , Técnicas Eletroquímicas , Ensaios Enzimáticos/métodos , Inibidores Enzimáticos/farmacologia , Oligopeptídeos/farmacologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/farmacologia , Antineoplásicos/química , Bortezomib/química , Inibidores Enzimáticos/química , Humanos , Microscopia de Força Atômica , Estrutura Molecular , Oligopeptídeos/química , Inibidores de Proteassoma/química , Técnicas de Microbalança de Cristal de Quartzo
18.
Hum Cell ; 32(3): 360-366, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31020605

RESUMO

Gefitinib is the first-generation EGFR tyrosine kinase inhibitor (EGFR-TKI), which is used in the treatment of NCSLC patients through interrupting EGFR signaling pathway. Although gefitinib prolongs patients' progression-free survival (PFS), acquired resistance occurs in advanced NSCLC patients. In this study, we mainly investigated the effects of antagonist for ghrelin-R (D-lys-3-GHRP-6) on conquering acquired gefitinib resistance in human lung cancer cells. We found that GHSR was overexpressed in our established HCC827/GR cells compared with parental cells, accompanied with increase of p-AKT and p-ERK1/2. Treatment of D-lys-3-GHRP-6 significantly decreased p-AKT and p-ERK1/2 expression in HCC827/GR cells. H1650 cells and HCC827/GR cells were treated with control, gefitinib, D-lys-3-GHRP-6 and D-lys-3-GHRP-6 + gefitinib, respectively. In H1650 and HCC827/GR cells, combination of D-lys-3-GHRP-6 and gefitinib significantly inhibited cell proliferation and Bcl2 protein level, induced the cell apoptosis and cleaved-caspase3 protein level compared with control group, while there was no significant difference between control and gefitinib group.


Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Gefitinibe/administração & dosagem , Gefitinibe/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Oligopeptídeos/administração & dosagem , Oligopeptídeos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Receptores de Grelina/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/genética , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quimioterapia Combinada , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transdução de Sinais/efeitos dos fármacos
19.
Chemistry ; 25(37): 8894-8902, 2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31012978

RESUMO

Cyclomarins are highly potent antimycobacterial and antiplasmodial cyclopeptides isolated from a marine bacterium (Streptomyces sp.). Previous studies have identified the target proteins and elucidated a novel mode of action, however there are currently only a few studies examining the structure-activity relationship (SAR) for both pathogens. Herein, we report the synthesis and biological evaluation of 17 novel desoxycyclomarin-inspired analogues. Optimization via side chain modifications of the non-canonical amino acids led to potent lead structures for each pathogen.


Assuntos
Antibacterianos/síntese química , Antimaláricos/síntese química , Mycobacterium tuberculosis/efeitos dos fármacos , Peptídeos Cíclicos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Antibacterianos/farmacologia , Antimaláricos/farmacologia , Concentração Inibidora 50 , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Peptídeos Cíclicos/química , Estereoisomerismo , Relação Estrutura-Atividade
20.
FEBS Open Bio ; 9(5): 1029-1038, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30972974

RESUMO

Endothelial-mesenchymal transition (EndMT) has emerged as an essential bioprocess responsible for the development of organ fibrosis. We have previously reported that fibroblast growth factor receptor 1 (FGFR1) is involved in the anti-EndMT effect of N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP). FGFR1 is expressed on the cell membrane and performs its biological function through interaction with co-receptors, including ßklotho (KLB). However, it remains unknown whether KLB is involved in the anti-EndMT effects of AcSDKP. Here, we demonstrated that AcSDKP increased KLB expression in an FGFR1-dependent manner and that KLB deficiency induced AcSDKP-resistant EndMT via the induction of the mitogen-activated protein kinase (MAPK) pathway. In cultured endothelial cells, AcSDKP increased KLB protein level in an FGFR1-dependent manner through induction of the FGFR1-KLB complex. KLB suppression by small interfering RNA transfection did not affect FGFR1 levels and resulted in the induction of EndMT. In contrast to the EndMT observed under FGFR1 deficiency, the EndMT induced by KLB suppression was not accompanied by the induction of Smad3 phosphorylation; instead, KLB-deficient cells exhibited induced activation of the MAPK/extracellular signal-regulated kinase (ERK) kinase (MEK) and ERK pathways. Treatment with the specific MEK inhibitor U0126 diminished KLB deficiency-induced EndMT. Consistent with this finding, AcSDKP did not suppress either EndMT or MEK/ERK activation induced by KLB deficiency. Application of either FGF19 or FGF21 synergistically augmented the anti-EndMT effects of AcSDKP. Taken together, these results indicate that endogenous peptide AcSDKP exerts its activity through induction of the FGFR1-KLB complex in vascular endothelial cells.


Assuntos
Transição Epitelial-Mesenquimal/efeitos dos fármacos , Inibidores do Crescimento/farmacologia , Proteínas de Membrana/genética , Oligopeptídeos/farmacologia , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Camundongos
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