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1.
Biomed Khim ; 65(5): 366-373, 2019 Aug.
Artigo em Russo | MEDLINE | ID: mdl-31666407

RESUMO

Neurogenesis is a complex process which governs embryonic brain development and is importants for brain plasticity throughout the whole life. Postnatal neurogenesis occurs in neurogenic niches that regulate the processes of proliferation and differentiation of stem and progenitor cells under the action of stimuli that trigger the mechanisms of neuroplasticity. Cells of glial and endothelial origin are the key regulators of neurogenesis. It is known that physiological neurogeneses is crucial for memory formation, whereas reparative neurogenesis provides partial repair of altered brain structure and compensation of neurological deficits caused by brain injury. Dysregulation of neurogenesis is a characteristics of various neurodevelopmental and neurodegenerative diseases, particularly, Alzheimer's disease which is very important medical and social problem. In the in vitro model of the neurogenic niche using hippocampal neurospheres as a source of stem/progenitor cells and astrocytes, we studied effects of astrocyte activation on the expression of markers of different stages of cell proliferation and differentiation. We found that aberrant mechanisms of development of stem and progenitor cells, caused by the beta-amyloid (Aß1-42), can be partially restored by targeted activation of GFAP-expressing cells in the neurogenic niche.


Assuntos
Peptídeos beta-Amiloides/farmacologia , Astrócitos/citologia , Células-Tronco Neurais/citologia , Neurogênese , Fragmentos de Peptídeos/farmacologia , Diferenciação Celular , Células Cultivadas , Hipocampo/citologia , Humanos
2.
Life Sci ; 235: 116840, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31494171

RESUMO

AIMS: Ovarian ischemia as a consequence of torsion constitutes a gynecologic emergency affecting females during reproductive age. Its management by detorsion results in ovarian ischemia-reperfusion (IR) injury. Thus, a conservative treatment with detorsion is highly recommended. Therefore, we attempted to investigate the effect and underlying mechanisms of angiotensin 1-7 (Ang-(1-7)) treatment against ovarian IR injury. MAIN METHODS: Female rats were included into: Sham group; Ang-(1-7) (300 µg/kg, i.p.) group; ovarian IR groups with and without Ang-(1-7) treatment. We determined ovarian Ang-(1-7), malondialdehyde (MDA) and nitric oxide (NO) in addition to serum total anti-oxidant capacity (TAC) levels. Ovarian gene expressions of angiotensin converting enzyme 2 (ACE2), Mas receptor, tumor necrosis factor alpha (TNF-α) and B-cell leukemia/lymphoma-2 (BCL-2) were estimated. Furthermore, histopathological changes and ovarian expressions of nuclear factor kappa B (NF-κB), inducible and endothelial nitric oxide synthases (iNOS and eNOS) were done. KEY FINDINGS: Treatment of ovarian IR rats with Ang-(1-7) led to marked improvement of ovarian damage through histological examination which was accompanied with marked increase in ovarian Ang-(1-7) level and expressions of ACE2 and Mas receptor, decrease in MDA and NO levels and expressions of NF-kB, iNOS and TNF-α with increase in serum TAC levels and ovarian expressions of eNOS and BCL-2. SIGNIFICANCE: Our results proved the protective effect of Ang-(1-7) against ovarian IR injury in rats and this may be attributed to ACE2/Ang (1-7)/Mas axis which showed anti-oxidant, anti-inflammatory and anti-apoptotic effects. Therefore, Ang-(1-7) can be used in the future for treatment of ovarian IR injury.


Assuntos
Angiotensina I/farmacologia , Ovário/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Animais , Antioxidantes/metabolismo , Feminino , Expressão Gênica/efeitos dos fármacos , Malondialdeído/metabolismo , NF-kappa B/biossíntese , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/biossíntese , Óxido Nítrico Sintase Tipo III/biossíntese , Ovário/lesões , Ovário/metabolismo , Peptidil Dipeptidase A/biossíntese , Proteínas Proto-Oncogênicas/biossíntese , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Ratos , Receptores Acoplados a Proteínas-G/biossíntese , Soro/metabolismo , Fator de Necrose Tumoral alfa/biossíntese
3.
Pharm Res ; 36(10): 146, 2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31396727

RESUMO

PURPOSE: CTB-001, a recently developed generic version of bivalirudin, an FDA-approved anticoagulant used for prophylaxis and treatment of cardiovascular diseases, has shown good efficacy and safety in clinical trials. We characterized the pharmacokinetics (PK) and pharmacodynamics (PD) of CTB-001 by modeling and simulation analysis. METHODS: PK/PD data were collected from a randomized, double-blind, placebo-controlled, single-dose, dose-escalation phase 1 study conducted in 24 healthy Korean male subjects. PK/PD analysis was conducted sequentially by nonlinear mixed-effects modeling implemented in NONMEM®. Monte-Carlo simulations were conducted for PK, activated partial thromboplastin time (aPTT), prothrombin time (PT), and thrombin time (TT). RESULTS: The CTB-101 PK was best described by a three-compartment linear model with a saturable binding peripheral compartment. All PD endpoints showed dose-response relationship, and their changes over time paralleled those of CTB-101 concentrations. A simple maximum effect model best described the aPTT, PT in INR, PT in seconds, and TT, whereas an inhibitory simple maximum effect model best described PT in percentages. The maximum duration of effect of CTB-001 on aPTT prolongation was 52.1 s. CONCLUSIONS: The modeling and simulation analysis well-characterized the PK and PD of CTB-001 in healthy Koreans, which will be valuable for identifying optimal dosing regimens of CBT-001.


Assuntos
Anticoagulantes/farmacologia , Hirudinas/farmacologia , Modelos Biológicos , Fragmentos de Peptídeos/farmacologia , Adulto , Anticoagulantes/farmacocinética , Simulação por Computador , Relação Dose-Resposta a Droga , Método Duplo-Cego , Medicamentos Genéricos , Hirudinas/farmacocinética , Humanos , Masculino , Método de Monte Carlo , Fragmentos de Peptídeos/farmacocinética , Tempo de Protrombina , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/farmacologia , Resultado do Tratamento , Adulto Jovem
4.
Food Chem ; 299: 124985, 2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31279127

RESUMO

Dietary protein peptides from quinoa yoghurt beverage (QYB) fermented with probiotic lactic acid bacteria strains play a protective role against diabetes and hypertension. In this study, the α-glucosidase and ACE inhibitory activities of germination-based protein hydrolysates of QYB were investigated. All protein hydrolysates exhibited a dose and strain-dependent inhibition on the enzymes. The inhibition of α-glucosidase was the highest in QLCSY13 (IC50 = 8.86 mg/mL), while ACE inhibition was the highest in QLCZ (IC50 = 0.03 mg/mL). Overall, QLCSY13 had the highest inhibitory activities, which was ascribed to its relatively higher amino acid contents and hydrophobicity. In addition, the ACE and α-glucosidase inhibitory activities of peptide fractions identified by RP-HPLC were 127 ±â€¯4.29 mg/mL and 10.39 ±â€¯4.73 mg/mL respectively. Among the potent inhibitory peptide sequences identified, both LAHMIVAGA and VAHPVF significantly had α-glucosidase and ACE inhibitory activities. Consequently, dietary protein peptides present in QYB had anti-hypertensive and anti-diabetic potentials.


Assuntos
Bebidas/microbiologia , Lactobacillus casei/metabolismo , Peptidil Dipeptidase A/metabolismo , Hidrolisados de Proteína/farmacologia , Iogurte/microbiologia , alfa-Glucosidases/metabolismo , Sequência de Aminoácidos , Inibidores da Enzima Conversora de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Fermentação , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/farmacologia , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/farmacologia , Hidrolisados de Proteína/química
5.
Biomed Environ Sci ; 32(6): 419-426, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31262387

RESUMO

OBJECTIVE: Silicosis, caused by inhalation of silica dust, is the most serious occupational disease in China and the aim of present study was to explore the protective effect of Ang (1-7) on silicotic fibrosis and myofibroblast differentiation induced by Ang II. METHODS: HOPE-MED 8050 exposure control apparatus was used to establish the rat silicosis model. Pathological changes and collagen deposition of the lung tissue were examined by H.E. and VG staining, respectively. The localizations of ACE2 and α-smooth muscle actin (α-SMA) in the lung were detected by immunohistochemistry. Expression levels of collagen type I, α-SMA, ACE2, and Mas in the lung tissue and fibroblasts were examined by western blot. Levels of ACE2, Ang (1-7), and Ang II in serum were determined by ELISA. Co-localization of ACE2 and α-SMA in fibroblasts was detected by immunofluorescence. RESULTS: Ang (1-7) induced pathological changes and enhanced collagen deposition in vivo. Ang (1-7) decreased the expressions of collagen type I and α-SMA and increased the expressions of ACE2 and Mas in the silicotic rat lung tissue and fibroblasts stimulated by Ang II. Ang (1-7) increased the levels of ACE2 and Ang (1-7) and decreased the level of Ang II in silicotic rat serum. A779 enhanced the protective effect of Ang (1-7) in fibroblasts stimulated by Ang II. CONCLUSION: Ang (1-7) exerted protective effect on silicotic fibrosis and myofibroblast differentiation induced by Ang II by regulating ACE2-Ang (1-7)-Mas axis.


Assuntos
Angiotensina II/sangue , Angiotensina I/uso terapêutico , Pulmão/metabolismo , Miofibroblastos/efeitos dos fármacos , Fragmentos de Peptídeos/uso terapêutico , Silicose/prevenção & controle , Actinas/metabolismo , Angiotensina I/sangue , Angiotensina I/farmacologia , Animais , Animais Recém-Nascidos , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Colágeno Tipo I/metabolismo , Modelos Animais de Doenças , Pulmão/patologia , Fragmentos de Peptídeos/sangue , Fragmentos de Peptídeos/farmacologia , Peptidil Dipeptidase A/metabolismo , Ratos Wistar , Silicose/metabolismo , Silicose/patologia
6.
Chem Biol Interact ; 309: 108707, 2019 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-31194956

RESUMO

Alzheimer's disease (AD) is a slow but progressive neurodegenerative disease. One of the pathological hallmarks of AD is the progressive accumulation of ß-amyloid (Aß) in the form of senile plaques, and Aß insult to neuronal cells has been identified as one of the major causes of AD onset. In the present study, we investigated the anti-AD potential of four flavonoids, naringenin, didymin, prunin, and poncirin, by evaluating their ability to inhibit acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and ß-site amyloid precursor protein cleaving enzyme 1 (BACE1). All four flavonoids displayed promising inhibitory activity against AChE, BChE, and BACE1. Structure-activity relationships suggested that glycosylation of naringenin at sugar moieties, and at different positions of the glycosidic linkage, might be closely associated with anti-AD potential. Kinetic and docking studies showed the lowest binding energy and highest affinity for the mixed, competitive, and non-competitive type inhibitors didymin, prunin, and poncirin. Hydrophobic interactions and the number of hydrogen bonds determined the strength of the protein-inhibitor interaction. We also examined the neuroprotective mechanisms by which flavonoids act against Aß25-35-induced toxicity in PC12 cells. Exposure of PC12 cells to 10 µM Aß25-35 for 24 h resulted in a significant decrease in cell viability. In addition, pretreatment of PC12 cells with different concentrations of flavonoids for 1 h significantly reversed the effects of Aß. Furthermore, treatment with the most active flavonoid, didymin, significantly reduced BACE1, APPsß, and C99 expression levels in a dose-dependent manner, without affecting amyloid precursor protein (APP) levels in the amyloidogenic pathway. Together, our results indicate that flavonoids, and in particular didymin, exhibit inhibitory activity in vitro, and may be useful in the development of therapeutic modalities for the treatment of AD.


Assuntos
Acetilcolinesterase/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Butirilcolinesterase/metabolismo , Flavanonas/química , Glicosídeos/farmacologia , Agregados Proteicos/efeitos dos fármacos , Acetilcolinesterase/química , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/farmacologia , Animais , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Sítios de Ligação , Butirilcolinesterase/química , Domínio Catalítico , Sobrevivência Celular/efeitos dos fármacos , Glicosídeos/química , Cinética , Simulação de Acoplamento Molecular , Células PC12 , Fragmentos de Peptídeos/farmacologia , Substâncias Protetoras/química , Substâncias Protetoras/farmacologia , Ratos , Relação Estrutura-Atividade
7.
J Appl Microbiol ; 127(3): 856-866, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31161702

RESUMO

AIMS: We developed a strategy for localized delivery of the LFCA (lactoferricinlactoferrampin), which is actively synthesized in situ by Lactococcus lactis (pAMJ399-LFCA/LLMG1363), and explored the possibility of using pAMJ399-LFCA/LLMG1363 as an alternative additive diet to antibiotics. METHODS AND RESULTS: The antimicrobial activities of the LFCA derived from pAMJ399-LFCA/LLMG1363 were tested in vitro. The results showed that LFCA had an inhibitory effect on Staphylococcus aureus, Escherichia coli and Salmonella enteritidis. Then, the pAMJ399-LFCA/LLMG1363 was used as an additive diet for piglets. Our data demonstrated that oral administration of pAMJ399-LFCA/LLMG1363 significantly improved the average daily gain, feed-to-gain ratio, intestinal mucosal integrity and decreased the serum endotoxin and d-lactic acid levels. The mRNA expression levels of intestinal tight junction proteins (including occludin, Claudin-1 and ZO-1) were significantly upregulated by pAMJ399-LFCA/LLMG1363 administration. The serum immunoglobulin G (IgG) levels, intestinal secretory immunoglobulin A (sIgA) levels, IL-2, IL-10 and TGF-ß levels were significantly increased by pAMJ399-LFCA/LLMG1363. Furthermore, our data revealed that oral administration of pAMJ399-LFCA/LLMG1363 significantly increased the number of general Lactobacillus, and decreased the total viable E. coli counts in the ileum and cecum contents. CONCLUSIONS: We developed a novel pAMJ399-LFCA/LLMG1363 secreting LFCA, which had probiotic effects on the growth performance, intestinal morphology, intestinal barrier function and immunological indices of weaned piglets. SIGNIFICANCE AND IMPACT OF THE STUDY: pAMJ399-LFCA/LLMG1363, with probiotic effects on the health of weaned piglets, may be a promising feed additive for weaned piglets.


Assuntos
Antibacterianos/farmacologia , Lactococcus lactis/metabolismo , Lactoferrina/farmacologia , Fragmentos de Peptídeos/farmacologia , Suínos/imunologia , Animais , Bovinos , Escherichia coli/efeitos dos fármacos , Interleucina-10/metabolismo , Interleucina-2/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Intestinos/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Probióticos/farmacologia , Salmonella enteritidis/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Fator de Crescimento Transformador beta/metabolismo
8.
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
9.
Mol Med Rep ; 19(6): 4897-4905, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059028

RESUMO

Amyloid ß (Aß) has been reported to have an important role in the cognitive deficits of Alzheimer's disease (AD), as oligomeric Aß promotes synaptic dysfunction and triggers neuronal death. Recent evidence has associated an endocytosis protein, endophilin 1, with AD, as endophilin 1 levels have been reported to be markedly increased in the AD brain. The increase in endophilin 1 levels in neurons is associated with an increase in the activation of the stress kinase JNK, with subsequent neuronal death. In the present study, whole­cell patch­clamp recording demonstrated that oligomeric Aß caused synaptic dysfunction and western blotting revealed that endophilin 1 was highly expressed prior to neuronal death of cultured hippocampal neurons. Furthermore, RNA interference and electrophysiological recording techniques in cultured hippocampal neurons demonstrated that knockdown of endophilin 1 prevented synaptic dysfunction induced by Aß. Thus, a potential role for endophilin 1 in Aß­induced postsynaptic dysfunction has been identified, indicating a possible direction for the prevention of postsynaptic dysfunction in cognitive impairment and suggesting that endophilin may be a potential target for the clinical treatment of AD.


Assuntos
Aciltransferases/metabolismo , Peptídeos beta-Amiloides/farmacologia , Neurônios/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Sinapses/efeitos dos fármacos , Aciltransferases/antagonistas & inibidores , Aciltransferases/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Células HEK293 , Humanos , Masculino , Camundongos , Neurônios/citologia , Neurônios/metabolismo , Polímeros/química , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Sprague-Dawley , Sinapses/fisiologia
10.
Cell Biol Int ; 43(7): 809-819, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31050073

RESUMO

Our research group has developed a cell-penetrating peptide-based delivery system that includes the Asn194Lys mutation in the rabies virus glycoprotein-9R peptide (mRVG-9R). This system has the capacity to deliver DNA in astrocytes and SH-SY5Y cells. The aim of this study was to evaluate the ability of the mRVG-9R peptide to deliver DNA molecules to murine brain cells. The mRVG-9R peptide, a karyophilic peptide (KP) and a plasmid encoding green fluorescent protein (GFP) were bound by electrostatic charges to form the mRVG-9R complex. mRVG-9R complex was injected into the cerebral cortex, striatum and hippocampus of C57BL/6 mice by stereotactic surgery. After 2, 4, and 20 days, the animals were sacrificed and their brains were prepared for quantitative reverse-transcription polymerase chain reaction and histological analysis. We detected the GFP expression in neurons and glial cells in the cerebral cortex, striatum, and hippocampus of the murine brain. The results suggest that the mRVG-9R peptide has the ability to deliver DNA molecules to murine brain cells. Also, the expression of the reporter gene is maintained at least up to 20 days after injection in neurons, astrocytes, oligodendrocytes, and microglia cells. Thus, the in vivo transfection ability of the mRVG-9R peptide, makes it a promising candidate as a therapeutic gene delivery vector to the central nervous system cells.


Assuntos
Peptídeos Penetradores de Células/farmacologia , Corpo Estriado/efeitos dos fármacos , Portadores de Fármacos/farmacologia , Glicoproteínas/farmacologia , Proteínas de Fluorescência Verde/metabolismo , Hipocampo/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Proteínas Virais/farmacologia , Animais , Astrócitos/citologia , Astrócitos/efeitos dos fármacos , Corpo Estriado/citologia , Genes Reporter , Vetores Genéticos/uso terapêutico , Proteínas de Fluorescência Verde/genética , Hipocampo/citologia , Camundongos , Camundongos Endogâmicos C57BL , Microglia/citologia , Neurônios/citologia , Neurônios/efeitos dos fármacos , Oligodendroglia/citologia , Oligodendroglia/efeitos dos fármacos , Transfecção/métodos
11.
Life Sci ; 229: 200-209, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31047894

RESUMO

AIMS: The rapeseed protein derived peptide DHNNPQIR (named as RAP-8) has been previously reported to possess antioxidant activity and alleviate liver fibrosis. The purpose of the present study was to investigate the potential crucial pathways involved in ameliorating liver fibrosis of RAP-8. MAIN METHODS: Next-generation sequencing of messenger RNA (RNA-Seq) analysis of the fibrotic and RAP-8 treated mice was performed. Western blot, qPCR and flow cytometry detection analysis were conducted to measure cell cycle and oxidative stress in LX-2 cells and liver samples. KEY FINDINGS: 588 overlapped differentially expressed genes were obtained from a batch of genes RAP-8 altered. Gene Ontology enrichment analysis revealed that changes in the most significant modules were mainly enriched in cell division, nuclear division and mitotic cell cycle process, while alterations in Kyoto Encyclopedia of Genes and Genomes were mainly enriched in cell cycle. Thereafter, according to the co-expression network analysis, the regulations of three core genes (Cenpp, Cyp2c55, Serpinh1) were verified that might be targets for treating liver fibrosis. Furthermore, through experimental verification, we demonstrated that RAP-8 induced cell cycle arrest and prevents oxidation stress. SIGNIFICANCE: As a promising therapeutic candidate for hepatic fibrosis treating, RAP-8 exhibited anti-fibrotic effects via exerting cell cycle arrest and inhibiting oxidative stress.


Assuntos
Brassica rapa/química , Ciclo Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Cirrose Hepática/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Proteínas de Plantas/farmacologia , Animais , Perfilação da Expressão Gênica , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
12.
Bull Exp Biol Med ; 166(6): 754-758, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31028579

RESUMO

We studied immunocorrecting effects of Semax (Met-Glu-His-Phe-Pro-Gly-Pro) on the model of "social" stress caused by sensory contact and intermale confrontation. Functional activity of the immune system of laboratory animals was evaluated in standard immunopharmacological tests: delayed-type hypersensitivity reaction, direct agglutination test, latex test for studying phagocytic activity of peripheral blood neutrophils, changes in differential leukocyte count, and weight of immunocompetent organs. It was found that changes in the immune response caused by "social" stress are multidirectional, which confirms the theory of stress-induced "immune imbalance". Semax acted as effective immune corrector restoring cellular and humoral immunogenesis reactions and phagocytic activity of neutrophils. This attested to the presence of immunomodulating properties in Semax and necessitates further studies in this field.


Assuntos
Hormônio Adrenocorticotrópico/análogos & derivados , Fatores Imunológicos/farmacologia , Fármacos Neuroprotetores/farmacologia , Nootrópicos/farmacologia , Fragmentos de Peptídeos/farmacologia , Estresse Psicológico/tratamento farmacológico , Hormônio Adrenocorticotrópico/farmacologia , Agressão , Animais , Animais não Endogâmicos , Hipersensibilidade Tardia/tratamento farmacológico , Hipersensibilidade Tardia/imunologia , Imunidade Inata/efeitos dos fármacos , Testes de Fixação do Látex , Contagem de Leucócitos , Masculino , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Fagocitose/efeitos dos fármacos , Estresse Psicológico/imunologia , Estresse Psicológico/fisiopatologia
13.
Cell Mol Life Sci ; 76(15): 3005-3018, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31006037

RESUMO

The accumulation of intracellular ß-amyloid peptide (Aß) is important pathological characteristic of Alzheimer's disease (AD). However, the exact underlying molecular mechanism remains to be elucidated. Here, we reported that Nuclear Paraspeckle Assembly Transcript 1 (NEAT1), a long n on-coding RNA, exhibits repressed expression in the early stage of AD and its down-regulation declines neuroglial cell mediating Aß clearance via inhibiting expression of endocytosis-related genes. We find that NEAT1 is associated with P300/CBP complex and its inhibition affects H3K27 acetylation (H3K27Ac) and H3K27 crotonylation (H3K27Cro) located nearby to the transcription start site of many genes, including endocytosis-related genes. Interestingly, NEAT1 inhibition down-regulates H3K27Ac but up-regulates H3K27Cro through repression of acetyl-CoA generation. NEAT1 also mediates the binding between STAT3 and H3K27Ac but not H3K27Cro. Therefore, the decrease of H3K27Ac and/or the increase of H3K27Cro declines expression of multiple related genes. Collectively, this study first reveals the different roles of H3K27Ac and H3K27Cro in regulation of gene expression and provides the insight of the epigenetic regulatory mechanism of NEAT1 in gene expression and AD pathology.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Fragmentos de Peptídeos/metabolismo , RNA Longo não Codificante/metabolismo , Acetilcoenzima A/metabolismo , Acetilação/efeitos dos fármacos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/farmacologia , Animais , Caveolina 2/antagonistas & inibidores , Caveolina 2/genética , Caveolina 2/metabolismo , Modelos Animais de Doenças , Epigênese Genética , Expressão Gênica/efeitos dos fármacos , Histonas/metabolismo , Camundongos , Camundongos Transgênicos , Neuroglia/citologia , Neuroglia/metabolismo , Fragmentos de Peptídeos/farmacologia , Interferência de RNA , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/genética , RNA Interferente Pequeno/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I/antagonistas & inibidores , Receptor do Fator de Crescimento Transformador beta Tipo I/genética , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Fator de Transcrição STAT3/metabolismo , Fator de Crescimento Transformador beta2/antagonistas & inibidores , Fator de Crescimento Transformador beta2/genética , Fator de Crescimento Transformador beta2/metabolismo , Fatores de Transcrição de p300-CBP/metabolismo
14.
Neurochem Res ; 44(7): 1636-1652, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31006091

RESUMO

HIV-1 gp120, an important subunit of the envelope spikes that decorate the surface of virions, is known to play a vital role in neuronal injury during HIV-1-associated neurocognitive disorder (HAND), although the pathological mechanism is not fully understood. Our previous studies have suggested that the V3 loop of HIV-1 gp120 (HIV-1 gp120 V3 loop) can induce neuronal apoptosis in the hippocampus, resulting in impairment in spatial learning and memory in Sprague-Dawley (SD) rats. In this study, we demonstrated that autophagy was significantly increased in rat primary hippocampal neurons in response to treatment of HIV-1 gp120 V3 loop. Importantly, HIV-1 gp120 V3 loop-induced autophagy played a dual role in the cell survival and death. An increase in autophagy for a short period inhibited apoptosis of neurons, while persistent autophagy over an extended period of time played a detrimental role by augmenting the apoptotic cascade in rat primary hippocampal neurons. In addition, we found that the HIV-1 gp120 V3 loop induced autophagy via AMPK/mTOR-dependent and calpain/mTOR-independent pathways, and the ERK/mTOR pathway plays a partial role. These findings provide evidence that HIV-1-induced autophagy plays a dual role in the survival and apoptosis of the primary rat hippocampal neurons and persistent autophagy may contribute to the pathogenesis of HAND, and autophagy modulation may represent a potential therapeutic strategy for reducing neuronal damage in HAND.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Proteína gp120 do Envelope de HIV/farmacologia , HIV-1/química , Hipocampo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Proteínas Quinases Ativadas por AMP/fisiologia , Adenina/análogos & derivados , Adenina/farmacologia , Sequência de Aminoácidos , Animais , Apoptose/fisiologia , Autofagia/fisiologia , Calpaína/antagonistas & inibidores , Calpaína/fisiologia , Inibidores de Cisteína Proteinase/farmacologia , Dipeptídeos/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , MAP Quinases Reguladas por Sinal Extracelular/fisiologia , Flavonoides/farmacologia , Proteína gp120 do Envelope de HIV/química , Proteína gp120 do Envelope de HIV/toxicidade , Hipocampo/patologia , Masculino , Neurônios/patologia , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/toxicidade , Inibidores de Proteínas Quinases/farmacologia , Ratos Sprague-Dawley
15.
Methods Mol Biol ; 1944: 229-252, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30840247

RESUMO

The triple-helical structure of collagen has been accurately reproduced in numerous chemical and recombinant model systems. Triple-helical peptides have found application for dissecting collagen-stabilizing forces, isolating receptor and protein binding sites in collagen, evaluating collagen-mediated cell signaling activities, mechanistic examination of collagenolytic proteases, and developing novel biomaterials and drug delivery vehicles. Due to their inherent stability to general proteolysis, triple-helical peptides present an opportunity as in vivo inhibitory agents. The present chapter provides methods for the construction of collagen-based triple-helical peptides designed as matrix metalloproteinase inhibitors.


Assuntos
Colágeno/química , Inibidores de Metaloproteinases de Matriz/química , Inibidores de Metaloproteinases de Matriz/farmacologia , Metaloproteinases da Matriz/química , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/farmacologia , Sequência de Aminoácidos , Animais , Humanos
16.
BMC Neurosci ; 20(1): 11, 2019 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-30885137

RESUMO

BACKGROUND: Pre-treatment with the corticotropin-releasing factor antagonist α-helical CRF9-41 prevents inhibition of gastric emptying by cocaine-and amphetamine-regulated transcript peptide at a dorsal hindbrain level, but its inhibition of sucrose intake is not affected. This is suggestive of separable underlying mechanisms of action in the caudal brainstem for cocaine-and amphetamine-regulated transcript peptide with regard to food intake and gastrointestinal functions. Here we further examine cocaine-and amphetamine-regulated transcript peptide-corticotropin-releasing factor receptor interactions in caudal brainstem controls of solid food intake. Injections of combinations of vehicle, cocaine-and amphetamine-regulated transcript peptide (0.5 µg or 1 µg) or α-helical CRF9-41 were given into the fourth cerebral ventricle of rats. Nocturnal solid food intake was recorded over 22 h. RESULTS: Pre-treatment with α-helical CRF9-41 into the fourth ventricle significantly increased the responsivity to cocaine-and amphetamine-regulated transcript peptide on hypophagia. In a separate control experiment, α-helical CRF9-41 pre-treatment blocked CRF-induced food intake inhibition indicative of its antagonistic effectiveness. CONCLUSIONS: We conclude that an endogenous Corticotropin-releasing factor agonist may modulate suppression of food intake caused by cocaine-and amphetamine-regulated transcript peptide at a dorsal hindbrain level in the absence of stress. A potential caudal brainstem mechanism whereby cocaine-and amphetamine-regulated transcript peptide effects on food intake is attenuated via corticotropin-releasing factor receptor activity causing tonic inhibition, is suggested.


Assuntos
Fármacos do Sistema Nervoso Central/farmacologia , Hormônio Liberador da Corticotropina/antagonistas & inibidores , Ingestão de Alimentos/efeitos dos fármacos , Proteínas do Tecido Nervoso/farmacologia , Fragmentos de Peptídeos/farmacologia , Rombencéfalo/efeitos dos fármacos , Animais , Hormônio Liberador da Corticotropina/metabolismo , Hormônio Liberador da Corticotropina/farmacologia , Ingestão de Alimentos/fisiologia , Quarto Ventrículo , Injeções Intraventriculares , Masculino , Proteínas do Tecido Nervoso/metabolismo , Fragmentos de Peptídeos/metabolismo , Ratos Sprague-Dawley , Rombencéfalo/metabolismo
17.
J Pept Sci ; 25(5): e3161, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30912242

RESUMO

Inflammation of intestinal tissue in patients affected by celiac disease (CD) originates from the adaptive and innate immune responses elicited by the undigested gliadin fragments through molecular mechanisms not yet completely described. Undigested A-gliadin peptide P31-43 is central to CD pathogenesis, entering enterocytes in vesicular compartments by endocytosis and inducing an innate immune response in CD intestinal mucosa. This study focused on the reasons why P31-43 does not behave as adaptive immunogenic agent. Once obtained by NMR analysis, the three-dimensional model of P31-43 was used to implement a series of in silico experiments aimed to explore the ability of the peptide to interact with HLA-DQ2 and the corresponding receptor onto T cells. Our results show that P31-43 is a poor ligand for DQ2 and/or T-cell receptor. This study was also aimed to investigate, from a structural point of view, the previous experimental findings by which P31-43 is able to enhance the phosphorylation level of the protein ERK2, while some P31-43 Ala-mutants decrease or totally inhibit that process. The molecular models of P31-43, P31-43 P36A, and F37A mutants were used for in silico docking experiments onto the ERK2 structure. The experiments support the hypothesis that P31-43 F37A works as an ERK2 phosphorylation inhibitor because it binds to the ERK2 phosphorylation site. This study reports on the structural properties of so far never NMR characterized gliadin peptides relevant in CD and explores details about their mechanisms of action.


Assuntos
Doença Celíaca/imunologia , Gliadina/farmacologia , Imunidade Inata/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Gliadina/química , Humanos , Imunidade Inata/imunologia , Mucosa Intestinal/imunologia , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Simulação de Acoplamento Molecular , Ressonância Magnética Nuclear Biomolecular , Fragmentos de Peptídeos/química , Fosforilação
18.
Nutrients ; 11(3)2019 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-30823411

RESUMO

Introduction: In phenylketonuria (PKU), evidence suggests that casein glycomacropeptide supplemented with rate-limiting amino acids (CGMP-AA) is associated with better protein utilisation and less blood phenylalanine (Phe) variability. Aim: To study the impact of CGMP-AA on blood Phe variability using 3 different dietary regimens in children with PKU. Methods: This was a 6-week randomised controlled cross-over study comparing CGMP-AA vs. Phe-free l-amino acids (l-AA) assessing blood Phe and tyrosine (Tyr) variability over 24 h in 19 children (7 boys) with PKU, with a median age of 10 years (6⁻16). Subjects were randomised to 3 dietary regimens: (1) R1, CGMP-AA and usual dietary Phe (CGMP + Phe); (2) R2, CGMP-AA - Phe content of CGMP-AA from usual diet (CGMP - Phe); and (3) R3, l-AA and usual dietary Phe. Each regimen was administered for 14 days. Over the last 48 h on days 13 and 14, blood spots were collected every 4 h at 08 h, 12 h, 16 h, 20 h, 24 h, and 04 h. Isocaloric intake and the same meal plan and protein substitute dosage at standardised times were maintained when blood spots were collected. Results: Eighteen children completed the study. Median Phe concentrations over 24 h for each group were (range) R1, 290 (30⁻580), R2, 220 (10⁻670), R3, 165 (10⁻640) µmol/L. R1 vs. R2 and R1 vs. R3 p < 0.0001; R2 vs. R3 p = 0.0009. There was a significant difference in median Phe at each time point between R1 vs. R2, p = 0.0027 and R1 vs. R3, p < 0.0001, but not between any time points for R2 vs. R3. Tyr was significantly higher in both R1 and R2 [70 (20⁻240 µmol/L] compared to R3 [60 (10⁻200) µmol/L]. In children < 12 years, blood Phe remained in the target range (120⁻360 µmol/L), over 24 h, for 75% of the time in R1, 72% in R2 and 64% in R3; for children aged ≥ 12 years, blood Phe was in target range (120⁻600 µmol/L) in R1 and R2 for 100% of the time, but 64% in R3. Conclusions: The residual Phe in CGMP-AA increased blood Phe concentration in children. CGMP-AA appears to give less blood Phe variability compared to l-AA, but this effect may be masked by the increased blood Phe concentrations associated with its Phe contribution. Reducing dietary Phe intake to compensate for CGMP-AA Phe content may help.


Assuntos
Caseínas/administração & dosagem , Caseínas/farmacologia , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/farmacologia , Fenilalanina/sangue , Tirosina/sangue , Criança , Suplementos Nutricionais , Feminino , Humanos , Masculino , Fenilalanina/metabolismo , Fenilcetonúrias , Tirosina/metabolismo
19.
Nutrients ; 11(3)2019 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-30870995

RESUMO

Food-derived bioactive peptides are reported as beneficial and safe for human health. Glycomacropeptide (GMP) is a milk-protein-derived peptide that, in addition to its nutritional value, retains many biological properties and has therapeutic effects in several inflammatory disorders. GMP was shown under in vitro and in vivo conditions to exert a number of activities that regulate the physiology of important body systems, namely the gastrointestinal, endocrine, and immune systems. This review represents a comprehensive compilation summarizing the current knowledge and updated information on the major biological properties associated with GMP. GMP bioactivity is addressed with special attention on mechanisms of action, signaling pathways involved, and structural characteristics implicated. In addition, the results of various studies dealing with the effects of GMP on models of inflammatory diseases are reviewed and discussed.


Assuntos
Caseínas/administração & dosagem , Caseínas/farmacologia , Redes e Vias Metabólicas/efeitos dos fármacos , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/farmacologia , Caseínas/química , Análise de Alimentos , Humanos , Fragmentos de Peptídeos/química
20.
Mol Brain ; 12(1): 27, 2019 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-30922360

RESUMO

AIM: The amyloid precursor protein (APP) is endoproteolytically processed to generate either the neurotoxic beta-amyloid peptide (Aß) or the secreted ectodomain APP alpha (sAPPα). While neurotrophic properties of sAPPα were suggested in several studies, it is still unclear if and how sAPPα counteracts pathogenic effects of Aß. Direct comparisons with sAPPß, produced in the Aß-generating pathway, are missing in order to determine the role of sAPPα's carbonyl-terminal end in its possible neuroprotective activity. METHODS: Mouse neuronal primary cultures and hippocampal slices were treated with oligomeric Aß42. The effects on tau phosphorylation and dendritic spine densities were assessed by western blot and confocal imaging, respectively. Co-administration of either sAPPα or sAPPß was used to determine activity on Aß-induced toxicity. RESULTS/DISCUSSION: We found that oligomeric Aß strongly increased AT8 and AT180 phosphorylation of tau and caused a loss of dendritic spines. SAPPα completely abolished Aß effects whereas sAPPß had no such rescue activity. Interestingly, sAPPα or sAPPß alone neither affected tau phosphorylation nor dendritic spine numbers. Together, our data suggest that sAPPα specifically protects neurons against Aß-dependent toxicity supporting the strategy of activating α-secretase-dependent endoproteolytic APP processing to increase sAPPα shedding from the neuronal plasma membrane as a therapeutic intervention for the protection of dendritic spines and phospho-tau-dependent toxicity in Alzheimer's disease.


Assuntos
Peptídeos beta-Amiloides/toxicidade , Espinhas Dendríticas/metabolismo , Neuroproteção/efeitos dos fármacos , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/farmacologia , Proteínas tau/metabolismo , Espinhas Dendríticas/efeitos dos fármacos , Humanos , Fosforilação/efeitos dos fármacos , Domínios Proteicos
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