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1.
Acta Cir Bras ; 35(2): e202000204, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32294688

RESUMO

PURPOSE: To investigate the effect of growth arrest-specific protein 6 (Gas6) on acute liver injury in mice and related mechanisms. METHODS: Thirty C57BL/6 (6-8 weeks old) mice were randomly divided into control, LPS/D-GalN, and LPS/D-GalN+Gas6 groups (10 mice in each group). The LPS/D-GalN group was intraperitoneally administered with LPS (0.25 mg/Kg) and D-GalN (400 mg/Kg) for 5h. The LPS/D-GalN+Gas6 group was intraperitoneally administered with rmGas6 one hour before intraperitoneal application of LPS/D-GalN. All subjects were sacrificed at 5 h for blood and tissue analysis. The expression of protein and mRNA was assessed by western blotting and RT-PCR, respectively. RESULTS: Compared with the control group, AST, ALT, IL-1ß, TNF-α, IL-6 IL-10, MPO activity were increased in the LPS/D-GalN group. However, they were significantly inhibited by Gas6. Gas6 markedly suppressed the expression of apoptosis-related protein induced by LPS/D-GalN. Moreover, Gas6 attenuated the activation of the NF-κB signaling pathway in acute liver injury induced by LPS/D-GalN. CONCLUSIONS: Gas6 alleviates acute liver injury in mice through regulating NF-κB signaling pathways. Gas6 can be a potential therapeutic agent in treating LPS/D-GalN-induced acute liver injury in the future.


Assuntos
Anti-Inflamatórios/farmacologia , Apoptose/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Lipopolissacarídeos/efeitos adversos , Fígado/efeitos dos fármacos , Animais , Anti-Inflamatórios/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Peptídeos e Proteínas de Sinalização Intercelular/uso terapêutico , Masculino , Camundongos
2.
Am J Physiol Heart Circ Physiol ; 318(4): H747-H755, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32108522

RESUMO

This study tested the hypothesis that (pyr)apelin-13 dose-dependently augments myocardial contractility and coronary blood flow, irrespective of changes in systemic hemodynamics. Acute effects of intravenous (pyr)apelin-13 administration (10 to 1,000 nM) on blood pressure, heart rate, left ventricular pressure and volume, and coronary parameters were measured in dogs and pigs. Administration of (pyr)apelin-13 did not influence blood pressure (P = 0.59), dP/dtmax (P = 0.26), or dP/dtmin (P = 0.85) in dogs. However, heart rate dose-dependently increased > 70% (P < 0.01), which was accompanied by a significant increase in coronary blood flow (P < 0.05) and reductions in left ventricular end-diastolic volume and stroke volume (P < 0.001). In contrast, (pyr)apelin-13 did not significantly affect hemodynamics, coronary blood flow, or indexes of contractile function in pigs. Furthermore, swine studies found no effect of intracoronary (pyr)apelin-13 administration on coronary blood flow (P = 0.83) or vasorelaxation in isolated, endothelium-intact (P = 0.89) or denuded (P = 0.38) coronary artery rings. Examination of all data across (pyr)apelin-13 concentrations revealed an exponential increase in cardiac output as peripheral resistance decreased across pigs and dogs (P < 0.001; R2 = 0.78). Assessment of the Frank-Starling relationship demonstrated a significant linear relationship between left ventricular end-diastolic volume and stroke volume across species (P < 0.001; R2 = 0.70). Taken together, these findings demonstrate that (pyr)apelin-13 does not directly influence myocardial contractility or coronary blood flow in either dogs or pigs.NEW & NOTEWORTHY Our findings provide much needed insight regarding the pharmacological cardiac and coronary effects of (pyr)apelin-13 in larger animal preparations. In particular, data highlight distinct hemodynamic responses of apelin across species, which are independent of any direct effect on myocardial contractility or perfusion.


Assuntos
Circulação Coronária/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Contração Miocárdica/efeitos dos fármacos , Animais , Pressão Sanguínea , Vasos Coronários/efeitos dos fármacos , Cães , Frequência Cardíaca , Masculino , Volume Sistólico , Suínos , Vasodilatação
3.
Eur J Ophthalmol ; 30(1): 94-103, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30585084

RESUMO

PURPOSE: To evaluate the efficacy and safety of plasma rich in growth factors eye drops for the treatment of corneal and ocular surface disorders in patients with graft versus host disease. METHODS: This retrospective and longitudinal study included graft versus host disease patients with ocular disorders. The resolution of corneal ulcers (area and density staining) was evaluated as primary outcome. Best corrected visual acuity, intraocular pressure, tear film breakup time, Schirmer test, ocular surface disease index, and visual analog score were evaluated as secondary outcomes. All variables were analyzed before and after plasma rich in growth factors treatment. The safety of plasma rich in growth factors treatment was also assessed. RESULTS: Twelve patients (23 eyes) with ocular graft versus host disease were evaluated. Statistically significant improvement in the area (75.7%) and density (73.3%) of the corneal staining, in best corrected visual acuity (74.7%), in ocular surface disease index scale (75.4%), visual analog score frequency (81.4%) and visual analog score severity (81.9%), and an increase of 3.8 s in tear film breakup time and 6 mm in Schirmer test was observed after plasma rich in growth factors treatment (p < 0.001). Some potential modifiers of the therapeutic effect were identified. All patients achieved corneal stability without perforation risk. No adverse events associated with the plasma rich in growth factors were observed. CONCLUSION: Immunosafe plasma rich in growth factors eye drops for the treatment of patients with ocular graft versus host disease could be safe and effective, showing a high rate of corneal ulcer resolution and dry eye disease control. Plasma rich in growth factors eye drops may help to maintain corneal stability and prevent it against higher ocular complications.


Assuntos
Síndromes do Olho Seco/terapia , Doença Enxerto-Hospedeiro/complicações , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Plasma Rico em Plaquetas , Adulto , Idoso , Síndromes do Olho Seco/etiologia , Síndromes do Olho Seco/metabolismo , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Soluções Oftálmicas/uso terapêutico , Estudos Retrospectivos , Lágrimas/metabolismo
4.
Clin Sports Med ; 39(1): 125-163, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31767102

RESUMO

Meniscus injuries are among the most common athletic injuries and result in functional impairment in the knee. Repair is crucial for pain relief and prevention of degenerative joint diseases like osteoarthritis. Current treatments, however, do not produce long-term improvements. Thus, recent research has been investigating new therapeutic options for regenerating injured meniscal tissue. This review comprehensively details the current methodologies being explored in the basic sciences to stimulate better meniscus injury repair. Furthermore, it describes how these preclinical strategies may improve current paradigms of how meniscal injuries are clinically treated through a unique and alternative perspective to traditional clinical methodology.


Assuntos
Meniscos Tibiais/fisiologia , Regeneração , Lesões do Menisco Tibial/cirurgia , Engenharia Tecidual , Tecidos Suporte , Tecido Adiposo/citologia , Fenômenos Biomecânicos , Células da Medula Óssea , Cartilagem/citologia , Condrócitos/transplante , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Meniscos Tibiais/citologia , Fibrina Rica em Plaquetas , Plasma Rico em Plaquetas , Transplante de Células-Tronco , Membrana Sinovial/citologia
5.
J Craniofac Surg ; 31(1): 158-161, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31842076

RESUMO

The aim of this study was to evaluate the effect of Concentrated Growth Factor (CGF) on bone healing in diabetic rat model. Experimental diabetes was induced in 24 male Sprague-Dawley rats by streptozotocin. Twenty-four animals served as healthy controls. The animals were divided into 4 subgroups; empty bone defect, grafting with xenogenous graft (Geno-os, OsteoBiol, Turin-Italy), CGF administration, and combined application of the CGF with the xenogenous graft in critical-sized defects in the calvaria of the rats. The diabetic group was given 4 units of Neutral Protamin Hagedorn per day. After 6 weeks, all animals were sacrificed and bone healing was histologically and histomorphometrically analyzed, and the evaluation revealed that the new bone formation in diabetic animals was significantly lower than in healthy group (P: 0.001, P: 0.023). In both groups, the highest rate of ossification was observed in the combined use of xenogenous graft and CGF. When the new bone formation was examined in the graft and CGF group, no significant difference was found between control and diabetic group (P = 0.562; P > 0.05). In conclusion, in patients with diabetes mellitus, combination therapy of CGF with graft is expected to contribute positively to the healing of bone defect.


Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Crânio/efeitos dos fármacos , Animais , Masculino , Osteogênese/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Crânio/patologia , Cicatrização/efeitos dos fármacos
7.
Cell Physiol Biochem ; 53(4): 687-700, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31577078

RESUMO

BACKGROUND/AIMS: Apelin and its G protein-coupled receptor APJ (gene symbol Aplnr) are strongly expressed in magnocellular vasopressinergic neurons suggesting that the apelin/APJ system plays a key role at the central level in regulating salt and water balance by counteracting the antiduretic action of vasopressin (AVP). Likewise, recent studies revealed that apelin exerts opposite effects to those of vasopressin induced on water reabsorption via a direct action on the kidney collecting duct. However, the underlying mechanisms of the peripheral action of apelin are not clearly understood. Here, we thus investigated the role of the apelin/APJ system in the regulation of water balance in the kidney, and more specifically its involvement in modulating the function of aquaporin-2 (AQP2) in the collecting duct. METHODS: Mouse cortical collecting duct cells (mpkCCD) were incubated in the presence of dDAVP and treated with or without apelin-13. Changes in AQP2 expression and localization were determined by immunoblotting and confocal immunofluorescence staining. RESULTS: Herein, we showed that the APJ was present in mpkCCD cells. Treatment of mpkCCD with apelin-13 reduced the cAMP production and antagonized the AVP-induced increase in AQP2 mRNA and protein expressions. Immunofluorescent experiments also revealed that the AVP-induced apical cell surface expression of AQP2, and notably its phosphorylated isoform AQP2-pS269, was considerably reduced following apelin-13 application to mpkCCD cells. CONCLUSION: Our data reinforce the aquaretic role of the apelin/APJ system in the fine regulation of body fluid homeostasis at the kidney level and its physiological opposite action to the antiduretic activity of AVP.


Assuntos
Aquaporina 2/metabolismo , Desamino Arginina Vasopressina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Transporte Proteico/efeitos dos fármacos , Animais , Receptores de Apelina/metabolismo , Aquaporina 2/genética , Linhagem Celular , AMP Cíclico/metabolismo , Células HEK293 , Humanos , Túbulos Renais Coletores/citologia , Túbulos Renais Coletores/metabolismo , Camundongos , Fosforilação/efeitos dos fármacos
8.
J Biol Regul Homeost Agents ; 33(5): 1369-1376, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31637897

RESUMO

The objective of this paper was to study the effects of PYR-ARG-PRO-ARG-LEU-SER-HIS-YSGLY-PRO-MET-PRO-PHE-OH (APELIN-13) on the expression of inflammatory factors interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) in rats with experimental autoimmune neuritis (EAN). A total of 30 rats were divided into a control group, an EAN group, and an APELIN-13 group. Enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of IL-6, TNF-α, and IFN-γ in rat plasma. Real-time quantitative Polymerase Chain Reaction (PCR) and Western blot were used to detect the protein and mRNA expression of IL-6, TNF-α, and IFN-γ in rat lymph nodes. In the EAN group, the infiltration of various types of inflammatory cells and focal demyelination were observed near the nerve fascicles of sciatic nerves. Compared with the EAN group, the infiltration of inflammatory cells and demyelination in the APELIN-13 group decreased significantly. The levels of plasma IL-6, TNF-α, and IFN-γ in the EAN group were significantly higher than those in the control group (P < 0.05) but significantly lower than those in the APELIN-13 group (P < 0.05). Compared with the control group, the mRNA and protein expression of IL-6, TNF-α, and IFN-γ increased significantly (P < 0.05) in the EAN group but decreased significantly in the APELIN-13 group (P < 0.05). In conclusion, APELIN-13 exerted a protective effect against EAN in rats.


Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Interferon gama/metabolismo , Interleucina-6/metabolismo , Neurite Autoimune Experimental/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Ratos
9.
Molecules ; 24(18)2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31527407

RESUMO

Most growth factors are naturally occurring proteins, which are signaling molecules implicated in cellular multiple functions such as proliferation, migration and differentiation under patho/physiological conditions by interacting with cell surface receptors and other ligands in the extracellular microenvironment. Many of the growth factors are heparin-binding proteins (HBPs) that have a high affinity for cell surface heparan sulfate proteoglycans (HSPG). In the present study, we report the binding kinetics and affinity of heparin interacting with different growth factors, including fibroblast growth factor (FGF) 2,7,10, hepatocyte growth factor (HGF) and transforming growth factor (TGF ß-1), using a heparin chip. Surface plasmon resonance studies revealed that all the tested growth factors bind to heparin with high affinity (with KD ranging from ~0.1 to 59 nM) and all the interactions are oligosaccharide size dependent except those involving TGF ß-1. These heparin-binding growth factors also interact with other glycosaminoglycans (GAGs), as well as various chemically modified heparins. Other GAGs, including heparan sulfate, chondroitin sulfates A, B, C, D, E and keratan sulfate, showed different inhibition activities for the growth factor-heparin interactions. FGF2, FGF7, FGF10 and HGF bind heparin but the 2-O-sulfo and 6-O-sulfo groups on heparin have less impact on these interactions than do the N-sulfo groups. All the three sulfo groups (N-, 2-O and 6-O) on heparin are important for TGFß-1-heparin interaction.


Assuntos
Glicosaminoglicanos/química , Peptídeos e Proteínas de Sinalização Intercelular/química , Glicosaminoglicanos/farmacologia , Heparina/química , Heparina/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Cinética , Estrutura Molecular , Oligossacarídeos/química , Oligossacarídeos/farmacologia , Ligação Proteica , Ressonância de Plasmônio de Superfície
10.
Future Microbiol ; 14: 1087-1097, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31512522

RESUMO

Aim: In this work, mastoparan analog peptides from wasp venom were tested against Candida albicans and safety assays were performed using cell culture and model zebrafish. Materials & methods: Minimal inhibitory concentration was determined and toxicity was performed using human skin keratinocyte and embryo zebrafish. Also, permeation of peptides through embryo chorion was performed. Results: The peptides demonstrated anti-C. albicans activity, with low cytotoxicity and nonteratogenicity in Danio rerio. The compounds had different permeation through chorion, suggesting that this occurs due to modifications in their amino acid sequence. Conclusion: The results showed that the studied peptides can be used as structural study models for novel potential antifungal agents.


Assuntos
Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Peptídeos/farmacologia , Venenos de Vespas/farmacologia , Animais , Antifúngicos/administração & dosagem , Antifúngicos/efeitos adversos , Antifúngicos/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/administração & dosagem , Peptídeos e Proteínas de Sinalização Intercelular/efeitos adversos , Peptídeos e Proteínas de Sinalização Intercelular/toxicidade , Queratinócitos/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Peptídeos/administração & dosagem , Peptídeos/efeitos adversos , Peptídeos/toxicidade , Venenos de Vespas/administração & dosagem , Venenos de Vespas/efeitos adversos , Venenos de Vespas/toxicidade , Peixe-Zebra
11.
Gene ; 716: 144032, 2019 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-31377316

RESUMO

Mitochondrial folate metabolism is central to the generation of nucleotides, fuelling methylation reactions, and redox homeostasis. Uniquely among the reactions of the mitochondrial folate pathway, the key step of the oxidation of 5,10-methylene-tetrahydrofolate (CH2-THF) can be catalysed by two isozymes, MTHFD2 and MTHFD2L. The MTHFD2 enzyme has recently received considerable attention as an oncogenic enzyme upregulated in several tumour types, which is additionally required by cancer cells in vitro and in vivo. However, much less is currently known about MTHFD2L and its expression in cancer. In this study, we examine and compare the expression and regulation of the two mitochondrial MTHFD isozymes in normal human and cancer cells. We found that normal and cancer cells express both enzymes, although MTHFD2 has a much higher baseline expression. Unlike MTHFD2, the MTHFD2L isozyme does not show an association with proliferation and growth factor stimulation. In addition, we did not find evidence of a compensatory increase of MTHFD2L following suppression of its isozyme. This study supports that MTHFD2L is unlikely to have an important function in increased proliferation or cancer. Furthermore, therapeutic strategies aiming to block the mitochondrial folate pathway in cancer should focus on MTHFD2, with MTHFD2L being unlikely to be involved in the development of chemoresistance to targeting of its mitochondrial isozyme.


Assuntos
Aminoidrolases/metabolismo , Metilenotetra-Hidrofolato Desidrogenase (NADP)/metabolismo , Enzimas Multifuncionais/metabolismo , Neoplasias/enzimologia , Aminoidrolases/genética , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Isoenzimas/genética , Isoenzimas/metabolismo , Células MCF-7 , Metilenotetra-Hidrofolato Desidrogenase (NADP)/genética , Enzimas Multifuncionais/genética , Neoplasias/genética , Regulação para Cima
12.
Neurochem Res ; 44(9): 2103-2112, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31385138

RESUMO

Methamphetamine (METH) is a potent psychomotor stimulant that has a high potential for abuse in humans. In addition, it is neurotoxic, especially in dopaminergic neurons. Long-lasting exposure to METH causes psychosis and increases the risk of Parkinson's disease. Apelin-13 is a novel endogenous ligand which studies have shown that may have a neuroprotective effect. Therefore, we hypothesized that Apelin-13 might adequately prevent METH-induced neurotoxicity via the inhibition of apoptotic, autophagy, and ROS responses. In this study, PC12 cells were exposed to both METH (0.5, 1, 2, 3, 4, 6 mmol/L) and Apelin-13 (0.5, 1.0, 2.0, 4.0, 8.0 µmol/L) in vitro for 24 h to measure determined dose, and then downstream pathways were measured to investigate apoptosis, autophagy, and ROS responses. The results have indicated that Apelin-13 decreased the apoptotic response post-METH exposure in PC12 cells by increasing cell viability, reducing apoptotic rates. In addition, the study has revealed Apelin-13 decreased gene expression of Beclin-1 by Real-Time PCR and LC3-II by western blotting in METH-induced PC12 cells, which demonstrated autophagy is reduced. In addition, this study has shown that Apelin-13 reduces intracellular ROS of METH-induced PC12 cells. These results support Apelin-13 to be investigated as a potential drug for treatment of neurodegenerative diseases. It is suggested that Apelin-13 is beneficial in reducing oxidative stress, which may also play an important role in the regulation of METH-triggered apoptotic response. Hence, these data indicate that Apelin-13 could potentially alleviate METH-induced neurotoxicity via the reduction of oxidative damages, apoptotic, and autophagy cell death.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Metanfetamina/efeitos adversos , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Proteína Beclina-1/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Proteínas Associadas aos Microtúbulos/metabolismo , Células PC12 , Ratos , Espécies Reativas de Oxigênio/metabolismo
13.
Int J Nanomedicine ; 14: 5449-5475, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31409998

RESUMO

Purpose: We created and evaluated an enhanced topical delivery system featuring a combination of highly skin-permeable growth factors (GFs), quercetin (QCN), and oxygen; these synergistically accelerated re-epithelialization and granulation tissue formation of/in diabetic wounds by increasing the levels of GFs and antioxidants, and the oxygen partial pressure, at the wound site. Methods: To enhance the therapeutic effects of exogenous administration of GFs for the treatment of diabetic wounds, we prepared highly skin-permeable GF complexes comprised of epidermal growth factor (EGF), insulin-like growth factor-I (IGF-I), platelet-derived growth factor-A (PDGF-A), and basic fibroblast growth factor (bFGF), genetically attached, via the N-termini, to a low-molecular-weight protamine (LMWP) to form LMWP-EGF, LMWP-IGF-I, LMWP-PDGF-A, and LMWP-bFGF, respectively. Furthermore, quercetin (QCN)- and oxygen-carrying 1-bromoperfluorooctane (PFOB)-loaded nanoemulsions (QCN-NE and OXY-PFOB-NE) were developed to improve the topical delivery of QCN and oxygen, respectively. After confirming the enhanced penetration of LMWP-GFs, QCN-NE, and oxygen delivered from OXY-PFOB-NE across human epidermis, we evaluated the effects of combining LMWP-GFs, QCN-NE, and OXY-PFOB-NE on proliferation of keratinocytes and fibroblasts, and the chronic wound closure rate of a diabetic mouse model. Results: The optimal ratios of LMWP-EGF, LMWP-IGF-I, LMWP-PDGF-A, LMWP-bFGF, QCN-NE, and OXY-PFOB-NE were 1, 1, 0.02, 0.02, 0.2, and 60, respectively. Moreover, a Carbopol hydrogel containing LMWP-GFs, QCN-NE, and OXY-PFOB-NE (LMWP-GFs/QCN-NE/OXY-PFOB-NE-GEL) significantly improved scratch-wound recovery of keratinocytes and fibroblasts in vitro compared to that afforded by hydrogels containing each component alone. LMWP-GFs/QCN-NE/OXY-PFOB-NE-GEL significantly accelerated wound-healing in a diabetic mouse model, decreasing wound size by 54 and 35% compared to the vehicle and LMWP-GFs, respectively. Conclusion: LMWP-GFs/QCN-NE/OXY-PFOB-NE-GEL synergistically accelerated the healing of chronic wounds, exerting both rapid and prolonged effects.


Assuntos
Diabetes Mellitus/patologia , Hidrogéis/química , Fator de Crescimento Insulin-Like I/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Oxigênio/metabolismo , Quercetina/farmacologia , Absorção Cutânea , Cicatrização/efeitos dos fármacos , Animais , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Colágeno/biossíntese , Modelos Animais de Doenças , Emulsões/química , Fator de Crescimento Epidérmico/farmacologia , Epiderme/efeitos dos fármacos , Fator 2 de Crescimento de Fibroblastos/farmacologia , Humanos , Queratinócitos/citologia , Queratinócitos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Peso Molecular , Nanopartículas/química , Nanopartículas/ultraestrutura , Octanos/química , Fator de Crescimento Derivado de Plaquetas/farmacologia , Protaminas/química , Absorção Cutânea/efeitos dos fármacos
14.
Zool Res ; 40(4): 317-323, 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31310065

RESUMO

Leukocyte cell-derived chemotaxin 2 (LECT2), a multifunctional hepatokine, is involved in many pathological conditions. However, its role in atherosclerosis remains undefined. In this study, we administered vehicle or LECT2 to male Apoe-/- mice fed a Western diet for 15 weeks. Atherosclerotic lesions were visualized and quantified with Oil-red O and hematoxylin staining. The mRNA expression levels of MCP-1, MMP-1, IL-8, IL-1ß, and TNF-α were analyzed by quantitative real-time polymerase chain reaction. Serum TNF-α, IL-1ß, IL-8, MCP-1, and MMP-1 concentrations were measured by enzyme-linked immunosorbent assay. CD68, CD31, and α-SMA, markers of macrophages, endothelial cells, and smooth muscle cells, respectively, were detected by immunostaining. Results showed that LECT2 reduced total cholesterol and low-density lipoprotein concentrations in serum and inhibited the development of atherosclerotic lesions, accompanied by reductions in inflammatory cytokines and lower MCP-1, MMP-1, TNF-α, IL-8, and IL-1ß mRNA abundance. Furthermore, LECT2 decreased CD68, but increased α-SMA in atherosclerotic lesions, suggesting an increase in smooth muscle cells and reduction in macrophages. In summary, LECT2 inhibited the development of atherosclerosis in mice, accompanied by reduced serum total cholesterol concentration and lower inflammatory responses.


Assuntos
Aterosclerose/prevenção & controle , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Animais , Citocinas/genética , Citocinas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/metabolismo , Inflamação/prevenção & controle , Peptídeos e Proteínas de Sinalização Intercelular/química , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Distribuição Aleatória
15.
Transfus Apher Sci ; 58(4): 498-504, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31311752

RESUMO

Diabetic foot ulcer is a major complication of diabetes mellitus with negative effects on the life quality. Management of diabetic foot ulcers is a big challenge with poor and low sufficient outcome management. Therefore, achievement to effective treatments may treat these ulcers. Nowdays, platelet products are used as an effective and safe agent for promotion of healing proposes in regenerative medicine. Serum rich in growth factors (SRGF) is a source of released growth factors from the platelets. In the present study, effect of allogenous SRGF was investigated on the streptozotocin (STZ)-induced diabetic wounds in rats. STZ (50 mg/kh, SC) caused significant increase in blood glucose and weight loss in rats. Full thickness cutaneous wounds (8 mm diameter) were created bilaterally on the dorsal of the diabetic rats. SRGF was injected at the edges of the wounds of one side only on the first day, and the contrary sides were considered as the control group. The percentage of wound contraction was demonstrared on day 3, 7, 11 after surgery. Tissue specimens were collected for microscopic study on days 7 and 14. Results showed a significant higher rate of wound contraction on days 5 and 7 in the treated group. Histopathologic findings displayed acceleration of re-epithelialization, increased angiogenesis and dense collagen fibers with better organization in the treated group. Current study suggests that SRGF was efficient because facilate wound healing and showed rapid re-epithelialization and increased angiogenesis.


Assuntos
Diabetes Mellitus Experimental , Angiopatias Diabéticas , Peptídeos e Proteínas de Sinalização Intercelular , Soro/química , Pele , Cicatrização/efeitos dos fármacos , Ferimentos e Lesões , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Angiopatias Diabéticas/tratamento farmacológico , Angiopatias Diabéticas/metabolismo , Angiopatias Diabéticas/patologia , Peptídeos e Proteínas de Sinalização Intercelular/química , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Masculino , Ratos , Pele/metabolismo , Pele/patologia , Ferimentos e Lesões/tratamento farmacológico , Ferimentos e Lesões/metabolismo , Ferimentos e Lesões/patologia
17.
Mater Sci Eng C Mater Biol Appl ; 103: 109761, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31349418

RESUMO

Bone fracture healing is a multistep and overlapping process of inflammation, angiogenesis and osteogenesis. It is initiated by inflammation, causing the release of various cytokines and growth factors. It leads to the recruitment of stem cells and formation of vasculature resulting in the functional bone formation. This combined phenomenon is used by bone tissue engineers from past few years to address the problem of vasculature and osteogenic differentiation during bone regeneration. In this review, we have discussed all major studies reporting the dual functioning approach to promote osteogenesis coupled angiogenesis using various scaffolds. These scaffolds are broadly classified into four types based on the nature of their structural and functional components. The functionality of the scaffold is either due to the structural components or the loaded cargo which conducts or induces the coupled functionality. Dual delivery system for osteoinductive and angioinductive factors ensures the co-delivery of two different types of molecules to induce osteogenesis and angiogenesis. Single delivery scaffold for angioinductive and osteoinductive molecule releases single type of molecules which could induce both angiogenesis and osteogenesis. Osteoconductive scaffold consisted of bone constituents releases angioinductive factors. Osteoconductive and angioconductive scaffold composed of components which provide the native substrate features for osteogenesis and angiogenesis. This review article also discusses the studies highlighting the synergism of physico-chemical stimuli as dual functioning feature to enhance angiogenesis and osteogenesis simultaneously. In addition, this article covers one of the least discussed area of the bone regeneration i.e. 'cartilage formation as a median between angiogenesis and osteogenesis'.


Assuntos
Regeneração Óssea/fisiologia , Neovascularização Fisiológica , Osteogênese , Engenharia Tecidual/métodos , Animais , Materiais Biocompatíveis , Osso e Ossos/fisiologia , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Osteogênese/efeitos dos fármacos , Osteogênese/fisiologia , Tecidos Suporte , Oligoelementos/farmacologia
18.
Mater Sci Eng C Mater Biol Appl ; 103: 109778, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31349506

RESUMO

Herein, we electrospun ultrathin core-shell fibers based on polycaprolactone (PCL), polyethylene glycol (PEG), gelatin and osteogenic growth peptide (OGP), and evaluated their potential to upregulate human osteoblast cells (hFOB) and to reduce Gram-positive and Gram-negative bacteria. We also evaluated the fiber morphology, chemical structure and peptide delivery efficacy. The employment of core-shell fibers compared to fibers without a core-shell showed improved mechanical strength, comparable to the strength of pure PCL, as well as improved hydrophilicity and wettability. The careful selection of polymer combination and core-shell strategy promoted a controlled and sustained release of OGP. Moreover, increased calcium deposition (CD) (1.3-fold) and alkaline phosphate (ALP) activity was observed when hFOBs were cultivated onto core-shell fibers loaded with OGP after 21 days of culture. Our developed scaffolds were also able to reduce the amount of Pseudomonas aeruginosa (ATCC 25668) bacteria by a factor of two compared to raw PCL without the use of any antibiotics. All of these results demonstrate a promising potential of the developed core-shell electrospun scaffolds based on PCL:PEG:Gelatin:OGP for numerous bone tissue applications.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Histonas , Peptídeos e Proteínas de Sinalização Intercelular , Staphylococcus aureus Resistente à Meticilina/crescimento & desenvolvimento , Osteoblastos/metabolismo , Pseudomonas aeruginosa/crescimento & desenvolvimento , Engenharia Tecidual , Tecidos Suporte/química , Linhagem Celular , Histonas/química , Histonas/farmacologia , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/química , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia
19.
Metabolism ; 98: 37-48, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31202835

RESUMO

BACKGROUND: Impaired cardiac insulin signalling and high cardiac fatty acid oxidation rates are characteristics of conditions of insulin resistance and diabetic cardiomyopathies. The potential role of liver-derived peptides such as adropin in mediating these changes in cardiac energy metabolism is unclear, despite the fact that in skeletal muscle adropin can preferentially promote glucose metabolism and improve insulin sensitivity. OBJECTIVES: To determine the influence of adropin on cardiac energy metabolism, insulin signalling and cardiac efficiency. METHODS: C57Bl/6 mice were injected with either vehicle or a secretable form of adropin (450 nmol/kg, i.p.) three times over a 24-h period. The mice were fasted to accentuate the differences between animals in adropin plasma levels before their hearts were isolated and perfused using a working heart system. In addition, direct addition of adropin to the perfusate of ex vivo hearts isolated from non-fasting mice was utilized to investigate the acute effects of the peptide on heart metabolism and ex vivo function. RESULTS: In contrast to the observed fasting-induced predominance of fatty acid oxidation as a source of ATP production in control hearts, insulin inhibition of fatty acid oxidation was preserved by adropin treatment. Adropin-treated mouse hearts also showed a higher cardiac work, which was accompanied by improved cardiac efficiency and enhanced insulin signalling compared to control hearts. Interestingly, acute adropin administration to isolated working hearts also resulted in an inhibition of fatty acid oxidation, accompanied by a robust stimulation of glucose oxidation compared to vehicle-treated hearts. Adropin also increased activation of downstream cardiac insulin signalling. Moreover, both in vivo and ex vivo treatment protocols induced a reduction in the inhibitory phosphorylation of pyruvate dehydrogenase (PDH), the major enzyme of glucose oxidation, and the protein levels of the responsible kinase PDH kinase 4 and the insulin-signalling inhibitory phosphorylation of JNK (p-T183/Y185) and IRS-1 (p-S307), suggesting acute receptor- and/or post-translational modification-mediated mechanisms. CONCLUSIONS: These results demonstrate that adropin has important effects on energy metabolism in the heart and may be a putative candidate for the treatment of cardiac disease associated with impaired insulin sensitivity.


Assuntos
Metabolismo Energético/efeitos dos fármacos , Coração/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Miocárdio/metabolismo , Animais , Ácidos Graxos/metabolismo , Glucose/metabolismo , Técnicas In Vitro , Insulina/fisiologia , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oxirredução , Transdução de Sinais/efeitos dos fármacos
20.
Drug Metab Rev ; 51(3): 266-292, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31203666

RESUMO

Currently, there are no established adjuvant drugs for the acceleration of peripheral nerve regeneration. In this paper, we reviewed the literature from the last 10 years and described the drugs proved to accelerate the functional and histological regeneration of the peripheral nerves, either after trauma or in neuropathy experimental models. The vast majority of the studies were experimental with very few small clinical studies, which indicates the need for prospective randomized studies to identify the best drugs to use as adjuvants for nerve regeneration.


Assuntos
Regeneração Nervosa/efeitos dos fármacos , Nervos Periféricos/efeitos dos fármacos , Nervos Periféricos/fisiologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Humanos , Imunossupressores/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia
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