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1.
J Surg Res ; 257: 294-305, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32871430

RESUMO

BACKGROUND: Drug-eluting stents impair post-angioplasty re-endothelialization thus compromising restenosis prevention while heightening thrombotic risks. We recently found that inhibition of protein kinase RNA-like endoplasmic reticulum kinase (PERK) effectively mitigated both restenosis and thrombosis in rodent models. This motivated us to determine how PERK inhibition impacts re-endothelialization. METHODS: Re-endothelialization was evaluated in endothelial-denuded rat carotid arteries after balloon angioplasty and periadventitial administration of PERK inhibitor in a hydrogel. To study whether PERK in smooth muscle cells (SMCs) regulates re-endothelialization by paracrinally influencing endothelial cells (ECs), denuded arteries exposing SMCs were lentiviral-infected to silence PERK; in vitro, the extracellular vesicles isolated from the medium of PDGF-activated, PERK-upregulating human primary SMCs were transferred to human primary ECs. RESULTS: Treatment with PERK inhibitor versus vehicle control accelerated re-endothelialization in denuded arteries. PERK-specific silencing in the denuded arterial wall (mainly SMCs) also enhanced re-endothelialization compared to scrambled shRNA control. In vitro, while medium transfer from PDGF-activated SMCs impaired EC viability and increased the mRNA levels of dysfunctional EC markers, either PERK inhibition or silencing in donor SMCs mitigated these EC changes. Furthermore, CXCL10, a paracrine cytokine detrimental to ECs, was increased by PDGF activation and decreased after PERK inhibition or silencing in SMCs. CONCLUSIONS: Attenuating PERK activity pharmacologically or genetically provides an approach to accelerating post-angioplasty re-endothelialization in rats. The mechanism may involve paracrine factors regulated by PERK in SMCs that impact neighboring ECs. This study rationalizes future development of PERK-targeted endothelium-friendly vascular interventions.


Assuntos
Angioplastia com Balão/efeitos adversos , Reestenose Coronária/prevenção & controle , Miócitos de Músculo Liso/efeitos dos fármacos , Inibidores de Proteínas Quinases/administração & dosagem , Reepitelização/efeitos dos fármacos , eIF-2 Quinase/antagonistas & inibidores , Angioplastia com Balão/instrumentação , Animais , Artérias Carótidas/efeitos dos fármacos , Artérias Carótidas/patologia , Artérias Carótidas/cirurgia , Reestenose Coronária/etiologia , Modelos Animais de Doenças , Stents Farmacológicos/efeitos adversos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/patologia , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Humanos , Masculino , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Comunicação Parácrina/efeitos dos fármacos , Comunicação Parácrina/genética , RNA Interferente Pequeno/metabolismo , Ratos , Reepitelização/genética , eIF-2 Quinase/genética
2.
Vascul Pharmacol ; 131: 106764, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32629143

RESUMO

The effects of angiotensin converting enzyme inhibitors and angiotensin receptor blockers (ACEI/ARBs) on angiogenesis, myocardial remodeling and intermittent claudication have been studied. Clinical studies have shown reduced re-intervention after cardiac stenting with the use of ACEI/ARBs. We hypothesized that the use of ACEI/ARBs decreases re-interventions after endovascular revascularization in tibial artery disease (TAD) patients. This is a retrospective study comparing the effects of ACEI/ARBs on the outcomes after endovascular revascularization for TAD. We divided all patients that underwent endovascular revascularization into Angiotensin converting enzyme inhibitor/Angiotensin receptor blockers (ACEI/ARBs) and No Angiotensin converting enzyme inhibitor/Angiotensin receptor blockers (NoACEI/ARBs) groups. A total of 360 patients underwent endovascular intervention for TAD. One hundred and ninety-six (54%) patients, 124 (57%) males, were on ACEI/ARBs after endovascular intervention for TAD, whereas 164(46%) patients, 87 (53%) males were not. The groups were well matched in the demographic variables except higher incidence of congestive heart failure, coronary artery disease and dialysis in the ACEI/ARBs group (p = .001, 0.02, 0.01 respectively). Reintervention rates were not associated with ACEI/ARBs use (p = .097). Even when corrected for statin use and antiplatelet therapy, no difference was seen in the reintervention rates in the two groups (p = .535, 0.547 respectively). Primary patency, assisted primary patency and secondary patency did not differ with the use of ACEI/ARBs (p = .244 0.096,0.060 respectively). No difference was seen in overall survival between the two groups (p = .690). ACEI/ARBs do not appear to affect the patency and reintervention rates for patients undergoing endovascular revascularization for TAD.


Assuntos
Angioplastia com Balão , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Aterectomia , Células Endoteliais/efeitos dos fármacos , Doença Arterial Periférica/terapia , Reepitelização/efeitos dos fármacos , Artérias da Tíbia/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Angioplastia com Balão/efeitos adversos , Antagonistas de Receptores de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Aterectomia/efeitos adversos , Células Endoteliais/patologia , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Doença Arterial Periférica/diagnóstico , Doença Arterial Periférica/fisiopatologia , Retratamento , Estudos Retrospectivos , Artérias da Tíbia/patologia , Artérias da Tíbia/fisiopatologia , Fatores de Tempo , Resultado do Tratamento , Grau de Desobstrução Vascular/efeitos dos fármacos
3.
Arterioscler Thromb Vasc Biol ; 40(9): 2143-2158, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32640903

RESUMO

OBJECTIVE: ERα (estrogen receptor alpha) exerts nuclear genomic actions and also rapid membrane-initiated steroid signaling. The mutation of the cysteine 451 into alanine in vivo has recently revealed the key role of this ERα palmitoylation site on some vasculoprotective actions of 17ß-estradiol (E2) and fertility. Here, we studied the in vivo role of the arginine 260 of ERα which has also been described to be involved in its E2-induced rapid signaling with PI-3K (phosphoinositide 3-kinase) as well as G protein in cultured cell lines. Approach and Results: We generated a mouse model harboring a point mutation of the murine counterpart of this arginine into alanine (R264A-ERα). In contrast to the C451A-ERα, the R264A-ERα females are fertile with standard hormonal serum levels and normal control of hypothalamus-pituitary ovarian axis. Although R264A-ERα protein abundance was normal, the well-described membrane ERα-dependent actions of estradiol, such as the rapid dilation of mesenteric arteries and the acceleration of endothelial repair of carotid, were abrogated in R264A-ERα mice. In striking contrast, E2-regulated gene expression was highly preserved in the uterus and the aorta, revealing intact nuclear/genomic actions in response to E2. Consistently, 2 recognized nuclear ERα-dependent actions of E2, namely atheroma prevention and flow-mediated arterial remodeling were totally preserved. CONCLUSIONS: These data underline the exquisite role of arginine 264 of ERα for endothelial membrane-initiated steroid signaling effects of E2 but not for nuclear/genomic actions. This provides the first model of fertile mouse with no overt endocrine abnormalities with specific loss-of-function of rapid ERα signaling in vascular functions.


Assuntos
Lesões das Artérias Carótidas/tratamento farmacológico , Endotélio Vascular/efeitos dos fármacos , Estradiol/farmacologia , Receptor alfa de Estrogênio/agonistas , Terapia de Reposição de Estrogênios , Estrogênios/farmacologia , Fertilidade/efeitos dos fármacos , Artérias Mesentéricas/efeitos dos fármacos , Mutação Puntual , Animais , Aterosclerose/metabolismo , Aterosclerose/patologia , Aterosclerose/prevenção & controle , Lesões das Artérias Carótidas/metabolismo , Lesões das Artérias Carótidas/patologia , Lesões das Artérias Carótidas/fisiopatologia , Proliferação de Células/efeitos dos fármacos , Endotélio Vascular/lesões , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Ativação Enzimática , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Ciclo Estral/efeitos dos fármacos , Feminino , Masculino , Artérias Mesentéricas/metabolismo , Artérias Mesentéricas/fisiopatologia , Camundongos Endogâmicos C57BL , Óxido Nítrico Sintase Tipo III/metabolismo , Ovariectomia , Reepitelização/efeitos dos fármacos , Transdução de Sinais , Fatores de Tempo , Útero/efeitos dos fármacos , Útero/metabolismo , Remodelação Vascular/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos
4.
Adv Wound Care (New Rochelle) ; 9(4): 199-210, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32117583

RESUMO

Objective: Skin graft donor site management is a concern particularly for elderly patients and patients with poor wound healing competence, and also because donor sites are a source of pain and discomfort. Although different types of dressings exist, there is no consensus regarding optimal dressing type on donor site care to promote healing, reduce pain, and improve patients' comfort. Approach: This prospective, single-center clinical trial evaluated the performance of nanofibrillar cellulose (NFC) wound dressing (FibDex® by UPM-Kymmene Corporation) for treatment of donor sites compared with a polylactide-based copolymer dressing. The study enrolled 24 patients requiring skin grafting with mean age of 49 ± 18. The primary outcome measure was wound healing time. Secondary outcomes, the epithelialization, subjective pain, the scar appearance assessed using the Patient and Observer Scar Assessment Scale (POSAS), and skin elasticity and transepidermal water loss (TEWL), were evaluated at 1 and 6 months postoperatively. Results: No statistically significant differences were observed between NFC and copolymer dressings regarding wound healing time, epithelialization, experience of pain, or TEWL. Significant differences were observed in the POSAS results for thickness and vascularity in the Observer score, in the favor of NFC over copolymer dressing. Moreover, skin elasticity was significantly improved with NFC dressing in terms of viscoelasticity and elastic modulus at 1 month postoperatively. Innovation: NFC dressing is a new, green sustainable product for wound treatment without animal or human-origin components. Conclusion: NFC dressing provides efficient wound healing at skin graft donor sites and is comparable or even preferable compared with the copolymer dressing.


Assuntos
Bandagens , Queimaduras/cirurgia , Celulose/uso terapêutico , Hidrogéis/uso terapêutico , Reepitelização/efeitos dos fármacos , Transplante de Pele/métodos , Sítio Doador de Transplante , Adulto , Idoso , Feminino , Humanos , Hidrogéis/química , Masculino , Membranas Artificiais , Pessoa de Meia-Idade , Poliésteres/uso terapêutico , Estudos Prospectivos , Resultado do Tratamento
5.
Int J Nanomedicine ; 15: 1349-1361, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32184590

RESUMO

Background: Impaired wound healing might be associated with many issues, especially overactive of reactive oxygen species (ROS), deficiency of blood vessels and immature of epidermis. N-acetylcysteine (NAC), as an antioxidant, could solve these problems by inhibiting overreactive of ROS, promoting revascularization and accelerating re-epithelialization. How to deliver NAC in situ with a controllable releasing speed still remain a challenge. Materials and Methods: In this study, we combined collagen (Col) with N-acetylcysteine to perform the characteristics of sustained release and chemically crosslinked Col/NAC composite with polyamide (PA) nanofibers to enhance the mechanical property of collagen and fabricated this multi-layered scaffold (PA-Col/NAC scaffold). The physical properties of the scaffolds such as surface characteristics, water absorption and tensile modulus were tested. Meanwhile, the ability to promote wound healing in vitro and in vivo were investigated. Results: These scaffolds were porous and performed great water absorption. The PA-Col/NAC scaffold could sustainably release NAC for at least 14 days. After cell implantation, PA-Col/NAC scaffold showed better cell proliferation and cell migration than the other groups. In vivo, PA-Col/NAC scaffolds could promote wound healing best among all the groups. Conclusion: The multi-layered scaffolds could obviously accelerate the process of wound healing and exert better and prolonged effects.


Assuntos
Acetilcisteína/farmacologia , Colágeno/química , Depuradores de Radicais Livres/farmacologia , Nylons/química , Reepitelização/efeitos dos fármacos , Tecidos Suporte/química , Cicatrização/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Preparações de Ação Retardada , Masculino , Nanofibras/química , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo
6.
Sci Rep ; 10(1): 3008, 2020 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-32080300

RESUMO

Several proteins and peptides in saliva were shown to stimulate gingival wound repair, but the role of salivary metabolites in this process remains unexplored. In vitro gingival re-epithelialization kinetics were determined using unstimulated saliva samples from healthy individuals collected during an experimental gingivitis study. Elastic net regression with stability selection identified a specific metabolite signature in a training dataset that was associated with the observed re-epithelialization kinetics and enabled its prediction for all saliva samples obtained in the clinical study. This signature encompassed ten metabolites, including plasmalogens, diacylglycerol and amino acid derivatives, which reflect enhanced host-microbe interactions. This association is in agreement with the positive correlation of the metabolite signature with the individual's gingival bleeding index. Remarkably, intra-individual signature-variation over time was associated with elevated risk for gingivitis development. Unravelling how these metabolites stimulate wound repair could provide novel avenues towards therapeutic approaches in patients with impaired wound healing capacity.


Assuntos
Eritritol/uso terapêutico , Gengiva/efeitos dos fármacos , Gengivite/metabolismo , Hemorragia/metabolismo , Metaboloma , Saliva/metabolismo , Adolescente , Adulto , Aminoácidos/metabolismo , Aminoácidos/farmacologia , Bioensaio , Estudos de Casos e Controles , Linhagem Celular , Diglicerídeos/metabolismo , Diglicerídeos/farmacologia , Suscetibilidade a Doenças , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Feminino , Gengiva/metabolismo , Gengiva/microbiologia , Gengiva/patologia , Gengivite/tratamento farmacológico , Gengivite/microbiologia , Gengivite/patologia , Hemorragia/tratamento farmacológico , Hemorragia/microbiologia , Hemorragia/patologia , Interações Hospedeiro-Patógeno , Humanos , Masculino , Pessoa de Meia-Idade , Plasmalogênios/metabolismo , Plasmalogênios/farmacologia , Reepitelização/efeitos dos fármacos , Reepitelização/fisiologia , Saliva/química , Saliva/microbiologia , Índice de Gravidade de Doença , Streptococcus mutans/crescimento & desenvolvimento , Streptococcus mutans/patogenicidade
7.
Int Wound J ; 17(1): 158-166, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31661727

RESUMO

Treating chronic skin wounds in patients with diabetes, bed sores, or stasis dermatitis is typically a time-consuming and costly process, and the outcome is not always promising. Concentrated growth factor (CGF) obtained from the autologous venous blood of patients via fractional centrifugation is employed for producing a CGF gel or membrane that can be applied to expedite self-regeneration of skin wounds. In this case report, we presented the results from 18 patients with chronic skin wounds treated with a CGF gel or membrane produced from autologous venous blood. Noticeable granulation tissue and regenerated epidermal coverage were observed in 16 patients who received CGF treatment over various time courses, thereby demonstrating the significant therapeutic effects of CGF treatment in overall wound healing. The other two patients with stasis ulcers in their calves failed to respond to the treatment because of the comorbidity of iliac vein thrombosis. In addition, by culturing HaCaT keratinocytes using CGF membrane as the foundation, we observed that HaCaT cells attached to the CGF membrane migrated and proliferated to form an epithelium-like structure. Comprehensively, the clinical results infer that CGF gel can expedite the regeneration of the soft tissue at the wound, whereas CGF membrane may facilitate its marginal re-epithelialisation. The combination of the two can promote autologous regeneration of both deep and superficial wounds effectively and safely.


Assuntos
Doença Crônica/terapia , Peptídeos e Proteínas de Sinalização Intercelular/uso terapêutico , Reepitelização/efeitos dos fármacos , Dermatopatias/tratamento farmacológico , Cicatrização/efeitos dos fármacos , Ferimentos e Lesões/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
8.
J Invest Dermatol ; 140(2): 455-464.e8, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31344385

RESUMO

Re-epithelialization is a complex process during skin wound healing, and cell migration is an integral part of this phenomenon. Here we identified a role for LRG1 as a key regulator of epidermal keratinocyte migration where LRG1 acts via enhancement of HIF-1α stability. We showed that LRG1 is upregulated at murine skin wound edges and that addition of recombinant human LRG1 accelerates keratinocyte migration and skin wound healing. Furthermore, we identified transcription factor ELK3 as a downstream effector of LRG1. We confirmed that elevated ELK3 levels manipulated by LRG1 can promote cell migration through upregulation of HIF-1α stability. Because hyperglycemia complicatedly affects HIF-1α stability and activation, our findings provide insights into the molecular controls of wound-associated cell migration and identify potential therapeutic targets for the treatment of chronic diabetic wounds. In conclusion, we demonstrated that LRG1 promotes wound repair through keratinocyte migration and is important for normalization of an abnormal process of diabetic wound healing where HIF-1α stability is insufficient.


Assuntos
Glicoproteínas/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Queratinócitos/fisiologia , Reepitelização/fisiologia , Animais , Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Pé Diabético/sangue , Pé Diabético/tratamento farmacológico , Pé Diabético/patologia , Modelos Animais de Doenças , Feminino , Glicoproteínas/administração & dosagem , Humanos , Hiperglicemia/complicações , Queratinócitos/efeitos dos fármacos , Masculino , Camundongos , Estabilidade Proteica , Proteínas Proto-Oncogênicas c-ets/metabolismo , RNA-Seq , Reepitelização/efeitos dos fármacos , Proteínas Recombinantes/administração & dosagem , Pele/efeitos dos fármacos , Pele/patologia , Ferida Cirúrgica/tratamento farmacológico , Ferida Cirúrgica/patologia , Regulação para Cima
9.
J Invest Surg ; 33(1): 49-58, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29856665

RESUMO

Aim: The aim of this study was to evaluate the effect of Hypericum perforatum (HP) oil on wound-healing process in rabbit palatal mucosa. Materials and Methods: Thirty-six New Zealand albino rabbits were randomly allocated to following groups; (1) HP oil (test, n = 18) and (2) olive oil (control, n = 18). Palatinal excisional wounds were created and the oils were topically applied (0.1 ml, 30 s, twice a day). Gingival biopsies were excised, and analyzed for re-epithelialization (RE) and granulation tissue maturation (GTM) on days 3, 7, and 14 after surgery. Levels of vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF-2) were assessed using the immunohistochemical method. Apoptotic cells (ACs) were evaluated using TUNEL staining. Enzyme-linked immunosorbent assay was used to assess tissue catalase (CAT) and malondialdehyde (MDA) levels. Results: RE and GTM were completed earlier in the HP oil group than in the control group. The number of positively stained cells/vessels was higher in olive oil than in the test group on day 3 for FGF-2 and on days 3 and 7 for VEGF (p < 0.05). In contrast, on day 14, a higher number of vessels was observed in the HP oil group than in the control group. HP oil treatment reduced the number of ACs compared to olive oil (p < 0.05), but the difference during the healing period did not reach significance. Tissue CAT and MDA levels between groups were not different, and also the results were the same when the levels were analyzed by the evaluated time periods (p > 0.05). Conclusions: The results of this study demonstrated that topical HP oil treatment did not provide an additional benefit to its base, olive oil, in the early phase of secondary wound healing.


Assuntos
Hypericum/química , Mucosa Bucal/efeitos dos fármacos , Óleos Vegetais/administração & dosagem , Reepitelização/efeitos dos fármacos , Ferida Cirúrgica/tratamento farmacológico , Administração Tópica , Animais , Biópsia , Modelos Animais de Doenças , Gengiva/efeitos dos fármacos , Gengiva/patologia , Gengiva/cirurgia , Humanos , Masculino , Mucosa Bucal/cirurgia , Palato/efeitos dos fármacos , Palato/patologia , Palato/cirurgia , Coelhos
10.
J Ethnopharmacol ; 248: 112307, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-31629026

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Sorocea guilleminina Gaudich. is a tree or shrub endemic to Brazil. Its leaves are used in Brazilian folk medicine for the healing of wounds, stomach problems, inflammation and as diuretic. The present study evaluates the activity and action mechanisms of the healing properties of the aqueous extract of S. guilleminiana leaves (AESg), in experimental models in vivo and in vitro, as well as performs a phytochemical analysis of the extract. MATERIALS AND METHODS: The AESg was prepared by infusion: Ten g of dry leaves powder in 1 L hot water, soaked for 15 min, filtered, lyophilized, and stored at -30 °C. Phytochemical analyses were realized by colorimetry and HPLC/ESI/MS. Its' in vitro cytotoxicity was evaluated on fibroblastic N3T3 cells. The potential of the wound healing activity in vivo was evaluated using excision and incision wound rat models, by histopathology of the injured skin along with the determination of nitric oxide, cytokines (IL-1ß, IL-10, and TNF-α), and antioxidant parameters (GSH, MPO and CAT). In vitro wound healing activity was also demonstrated in scratched N3T3 cells, by measuring the proliferation/migration rate. RESULTS: The phytochemical analysis of the AESg revealed a strong presence of polar compounds, especially flavonoids (4 majoritarian), as well as terpenes and/or sterols (2 majoritarian). The AESg showed no toxicity in the N3T3 cell line (IC50 > 800 µg/mL). Topical treatment with the AESg showed an increase (p < 0.05) in wound contraction with 2 mg/g cream on days 5 and 9 (43.56% and 6.70% increase, respectively), and with 50 mg/g on days 7 and 9 (10.88% and 7.91%, respectively), compared to the vehicle (non-ionic neutral cream). Topical application of AESg (2 or 50 mg/g non-ionic cream) in incised wounds caused an increase in the force necessary for the rupture of the wound when compared to the vehicle group. No changes in cytokines (IL-1ß, IL-10, or TNF-α) or NO accumulation was found with up to 50 mg/g AESg treatment. For antioxidant activity on the incision wound, an increase in GSH levels was denoted with the AESg use, at the lowest and highest dose (2 and 50 mg/g) by 75.86% and 61.20% respectively, when compared to the vehicle. Also, the CAT activity was accentuated by AESg at the highest dose (50 mg/g) by 85.87%. Finally, the AESg at all doses attenuated MPO activity significantly in the incision wound by 71.35%, 73.21%, 78.08%, respectively. In the scratch test on N3T3 cells, the treatment with AESg resulted also in an increase in fibroblast proliferation/migration rate, compared to the vehicle. CONCLUSION: AESg is not cytotoxic. The results confirm the popular use of the leaf infusion of S. guilleminiana for the treatment of cutaneous wounds, possibly by stimulating the proliferation of fibroblasts with a consequent deposition of collagen, fastening rearrangement of collagen fibers, and greater transformation into myofibroblasts, essential in the healing process. Preliminary chemical analyzes of AESg revealed the presence mainly of phenolic compounds, being salicylic acid, gallic acid, pinocembrin and isoquercitrin the majoritarian ones.


Assuntos
Moraceae , Extratos Vegetais/farmacologia , Folhas de Planta , Pele/efeitos dos fármacos , Cicatrização/efeitos dos fármacos , Ferimentos Penetrantes/tratamento farmacológico , Animais , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Camundongos , Moraceae/química , Células NIH 3T3 , Óxido Nítrico/metabolismo , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/toxicidade , Folhas de Planta/química , Ratos Wistar , Reepitelização/efeitos dos fármacos , Pele/lesões , Pele/metabolismo , Pele/patologia , Ferimentos Penetrantes/metabolismo , Ferimentos Penetrantes/patologia
11.
Ther Deliv ; 10(11): 719-735, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31789109

RESUMO

Regarded as a silent epidemic, chronic wounds are a global public health issue. Wound healing is a complex, synchronized cascade of physiological processes restoring the anatomic and functional integrity of the skin; however, chronic wounds fail to proceed through the wound healing cascade. Wound pH oscillates during wound healing, usually traversing from a neutral pH to an acidic pH, while chronic wounds perpetuate in an elevated alkaline milieu. Although a neglected clinical parameter, pH has implications for relatively all pathologies of wound healing affecting oxygen release, angiogenesis, protease activity, bacterial toxicity and antimicrobial activity. Despite the array of wound healing products currently marketed, understanding the implications of pH on arresting wound healing can stimulate innovation within this vast market.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Concentração de Íons de Hidrogênio , Reepitelização/fisiologia , Pele/química , Ferimentos e Lesões/patologia , Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Bandagens , Doença Crônica , Desbridamento , Humanos , Tratamento de Ferimentos com Pressão Negativa , Oxigênio/administração & dosagem , Oxigênio/farmacocinética , Permeabilidade , Reepitelização/efeitos dos fármacos , Pele/efeitos dos fármacos , Pele/metabolismo , Pele/patologia , Envelhecimento da Pele/fisiologia , Transplante de Pele , Ferimentos e Lesões/terapia
12.
BJS Open ; 3(6): 840-851, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31832591

RESUMO

Background: Topical administration of tranexamic acid (TXA) reduces bleeding from surgical wounds similarly to intravenous use, but with negligible risk of adverse systemic events. Topical use is expanding, but is off-label. Surgeons lack guidelines regarding safe topical dosages and modes of administration. The effects of topical TXA on skin cells and wound healing are unknown. This study investigated whether topical TXA might be cytotoxic or affect wound re-epithelialization. Methods: Human keratinocytes and fibroblast cell cultures and an ex vivo human skin wound model were subjected to both short (limited) and long (chronic) exposure to various clinically relevant concentrations of TXA to mimic different modalities of topical administration. Cytotoxicity and effects on wound re-epithelialization were evaluated. Results: In cell culture, toxicity from chronic exposure was associated with increasing concentration and exposure time. Limited exposure to TXA did not cause significant cytotoxicity even at high concentrations. Re-epithelialization was completely absent in wounds chronically exposed to TXA concentrations of 25 mg/ml or above, and 50-100 mg/ml induced epidermolysis of normal epithelium, possibly by a non-toxic mechanism. Wound re-epithelialization was slightly delayed, but not impaired, by limited exposure to 100 mg/ml or chronic exposure to 6·25 mg/ml. Conclusion: Although short exposure to even high concentrations of topical TXA seems well tolerated in vitro, prolonged exposure can be cytotoxic and may affect wound re-epithelialization. Surgeons should adjust the TXA concentration to the planned mode of topical administration in clinical practice.


Assuntos
Antifibrinolíticos/toxicidade , Hemostasia Cirúrgica/efeitos adversos , Técnicas Hemostáticas/efeitos adversos , Reepitelização/efeitos dos fármacos , Ferida Cirúrgica/complicações , Ácido Tranexâmico/toxicidade , Administração Tópica , Antifibrinolíticos/administração & dosagem , Perda Sanguínea Cirúrgica/prevenção & controle , Técnicas de Cultura de Células , Linhagem Celular , Relação Dose-Resposta a Droga , Fibroblastos , Humanos , Queratinócitos , Pele/efeitos dos fármacos , Ferida Cirúrgica/patologia , Fatores de Tempo , Testes de Toxicidade Aguda , Testes de Toxicidade Crônica , Ácido Tranexâmico/administração & dosagem
13.
Bull Exp Biol Med ; 168(2): 242-246, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31776954

RESUMO

We studied the effect of bovine brain gangliosides, individual ganglioside GM1, and melatonin on the rate of wound closure under in vitro conditions and the effect of melatonin on the rate of wound healing under in vivo conditions. It was shown that bovine brain gangliosides and melatonin reliably increased cell migration in the experimental wound model. This effect was detected when the cell cultures were treated with the test preparations after wound infliction and when the cultures of human keratinocytes were pretreated before wounding. Analysis of the effect of melatonin on the rate of wound healing in vivo showed that melatonin accelerated this process, especially at the middle stages corresponding to the proliferation phase (days 3-6 after surgery). Histological analysis revealed intensification of epidermal cell proliferation at the edges of the wound starting from day 4 after surgery.


Assuntos
Gangliosídeo G(M1)/farmacologia , Queratinócitos/efeitos dos fármacos , Melatonina/farmacologia , Reepitelização/efeitos dos fármacos , Cicatrização/efeitos dos fármacos , Animais , Bovinos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pele/crescimento & desenvolvimento
14.
Biomolecules ; 9(12)2019 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-31766379

RESUMO

A growing body of evidence supports the use of probiotics in the treatment of several skin conditions, including wounds. Even if in vitro and in vivo studies have highlighted the pro-healing effects of some probiotic bacteria, the underlying mechanisms are still not fully defined. The current investigation aimed to determine the re-epithelialization potential of the soluble fraction from lysate of seven different probiotic strains belonging to different genera (i.e., Streptococcus, Lactobacillus, and Bifidobacterium) on in vitro physically wounded HaCaT monolayer model. The results suggested that the soluble fraction of S. thermophilus, L. plantarum, and L. acidophilus promoted the re-epithelialization of scratched HaCaT monolayers, whereas those from B. longum, B. infantis, and B. breve significantly inhibited the process. On the other hand, L. bulgaricus showed no significant effect on in vitro wound repair. The mechanisms underlying the pro- or anti-healing properties of selected bacterial strains strictly and positively correlated with their ability to modulate nitric oxide synthase 2 (NOS2) expression and activity. Accordingly, the pre-treatment with aminoguanidine (AG), a specific inhibitor of NOS2 activity, abrogated the pro-healing effects of S. thermophilus, L. plantarum, and L. acidophilus.


Assuntos
Queratinócitos/enzimologia , Óxido Nítrico Sintase Tipo II/metabolismo , Probióticos/farmacologia , Reepitelização/efeitos dos fármacos , Bactérias/metabolismo , Inibidores Enzimáticos/farmacologia , Guanidinas/farmacologia , Humanos , Queratinócitos/efeitos dos fármacos , Nitritos/metabolismo , Solubilidade
15.
Sci Rep ; 9(1): 17316, 2019 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-31754254

RESUMO

Vascular progenitors such as endothelial progenitor cells (EPCs) and smooth muscle-like progenitor cells (SMPCs) may play different roles in vascular repair. Ginkgo biloba extract (GBE) is an exogenous activator of heme oxygenase (HO)-1, which has been suggested to improve vascular repair; however, the detailed mechanisms have yet to be elucidated. This study aimed to investigate whether GBE can modulate different vascular progenitor cells by activating HO-1 for vascular repair. A bone marrow transplantation mouse model was used to evaluate the in vivo effects of GBE treatment on wire-injury induced neointimal hyperplasia, which is representative of impaired vascular repair. On day 14 of GBE treatment, the mice were subjected to wire injury of the femoral artery to identify vascular reendothelialization. Compared to the mice without treatment, neointimal hyperplasia was reduced in the mice that received GBE treatment for 28 days in a dose-dependent manner. Furthermore, GBE treatment increased bone marrow-derived EPCs, accelerated endothelial recovery, and reduced the number of SMPCs attached to vascular injury sites. The effects of GBE treatment on neointimal hyperplasia could be abolished by co-treatment with zinc protoporphyrin IX, an HO-1 inhibitor, suggesting the in vivo role of HO-1. In this in vitro study, treatment with GBE activated human early and late EPCs and suppressed SMPC migration. These effects were abolished by HO-1 siRNA and an HO-1 inhibitor. Furthermore, GBE induced the expression of HO-1 by activating PI3K/Akt/eNOS signaling in human late EPCs and via p38 pathways in SMPCs, suggesting that GBE can induce HO-1 in vitro through different molecular mechanisms in different vascular progenitor cells. Accordingly, GBE could activate early and late EPCs, suppress the migration of SMPCs, and improve in vivo vascular repair after mechanical injury by activating HO-1, suggesting the potential role of pharmacological HO-1 activators, such as GBE, for vascular protection in atherosclerotic diseases.


Assuntos
Células Endoteliais/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Neointima/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Células-Tronco/efeitos dos fármacos , Lesões do Sistema Vascular/tratamento farmacológico , Animais , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Células Endoteliais/fisiologia , Endotélio Vascular/citologia , Voluntários Saudáveis , Humanos , Camundongos , Camundongos Transgênicos , Músculo Liso/citologia , Neointima/etiologia , Neointima/patologia , Cultura Primária de Células , Protoporfirinas/administração & dosagem , Reepitelização/efeitos dos fármacos , Células-Tronco/fisiologia , Lesões do Sistema Vascular/complicações , Lesões do Sistema Vascular/patologia
16.
Sci Transl Med ; 11(516)2019 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-31666403

RESUMO

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most important causes of peptic ulcer disease in high-income countries. Proton pump inhibitors are the current standard treatment; however, safety and long-term adverse effects of using these drugs are attracting more and more concerns in recent years. Using a porcine model of NSAID-related gastric ulcer, we herein show that adipose-derived mesenchymal stem cells (ADMSCs) delivered by endoscopic submucosal injection promoted ulcer healing with less inflammatory infiltration and enhanced reepithelization and neovascularization at day 7 and day 21 when compared with the controls (saline injection). However, only few engrafted ADMSCs showed myofibroblast and epithelial cell phenotype in vivo, suggesting the ulcer healing process might be much less dependent on the stem cell transdifferentiation. Further experiment with submucosal injection of MSC-derived secretome revealed a therapeutic efficacy comparable to that of stem cell transplantation. Profiling analysis showed up-regulation of genes associated with inflammation, granulation formation, and extracellular matrix remodeling at day 7 after injection of MSC-derived secretome. In addition, the extracellular signal-regulated kinase/mitogen-activated protein kinase and the phosphoinositide-3-kinase/protein kinase B pathways were activated after injection of ADMSCs or MSC-derived secretome. Both signaling pathways were involved in mediating the major events critical to gastric ulcer healing, including cell survival, migration, and angiogenesis. Our data suggest that endoscopic submucosal injection of ADMSCs serves as a promising approach to promote healing of NSAID-related peptic ulcer, and the paracrine effectors released from stem cells play a crucial role in this process.


Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Comunicação Parácrina , Úlcera Péptica/induzido quimicamente , Úlcera Péptica/terapia , Cicatrização , Animais , Proliferação de Células/efeitos dos fármacos , Transdiferenciação Celular/efeitos dos fármacos , Meios de Cultivo Condicionados/farmacologia , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Modelos Animais de Doenças , Endoscopia , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/patologia , Humanos , Indometacina/efeitos adversos , Inflamação/patologia , Inflamação/terapia , Células-Tronco Mesenquimais/efeitos dos fármacos , Neovascularização Fisiológica/efeitos dos fármacos , Estresse Oxidativo , Comunicação Parácrina/efeitos dos fármacos , Úlcera Péptica/patologia , Inibidores da Bomba de Prótons/farmacologia , Inibidores da Bomba de Prótons/uso terapêutico , Reepitelização/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/patologia , Úlcera Gástrica/terapia , Suínos , Resultado do Tratamento , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética , Cicatrização/efeitos dos fármacos
17.
Pharm Biol ; 57(1): 799-806, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31760838

RESUMO

Context: Cinnamomum verum J. Presl. (Lauraceae) has a high number of polyphenols with insulin-like activity, increases glucose utilization in animal muscle, and might be beneficial for diabetic patients.Objective: This study evaluated the effectiveness of an ointment prepared from Cinnamomum verum hydroethanolic extract on wound healing in diabetic mice.Materials and methods: A total of 54 male BALB/c mice were divided into three groups: (1) diabetic non-treated group mice that were treated with soft yellow paraffin, (2 and 3) mice that were treated with 5 and 10% C. verum. Two circular full-thickness excisional wounds were created in each mouse, and the trial lasted for 16 d following induction of the wound. Further evaluation was made on the wound contraction ratio, histopathology parameters and mRNA levels of cyclin D1, insulin-like growth factor 1 (IGF-1), glucose transporter-1 (GLUT-1), total antioxidant capacity, and malondialdehyde of granulation tissue contents. HPLC apparatus was utilized to identify the compounds.Results: The HPLC data for cinnamon hydroethanolic extract identified cinnamaldehyde (11.26%) and 2-hydroxyl cinnamaldehyde (6.7%) as the major components. A significant increase was observed in wound contraction ratio, fibroblast proliferation, collagen deposition, re-epithelialization and keratin biosynthesis in the C. verum-treated groups in comparison to the diabetic non-treated group (p < 0.05). The expression level of cyclin D1, IGF1, GLUT 1 and antioxidant capacity increased in the C. verum-treated groups in comparison to the diabetic non-treated group (p < 0.05).Conclusions: Topical administration of C. verum accelerated wound healing and can possibly be employed in treating the wounds of diabetic patients.


Assuntos
Cinnamomum/química , Queratinas/efeitos dos fármacos , Extratos Vegetais/farmacologia , Reepitelização/efeitos dos fármacos , Cicatrização/efeitos dos fármacos , Administração Tópica , Animais , Antioxidantes/efeitos adversos , Diabetes Mellitus Experimental/induzido quimicamente , Fator de Crescimento Insulin-Like I/metabolismo , Queratinas/biossíntese , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pomadas , Polifenóis , Pele/efeitos dos fármacos , Estreptozocina/farmacologia
18.
Int J Pharm ; 571: 118707, 2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31593807

RESUMO

The wound healing effects of pharmaceutic preparations of Periplaneta americana, Kangfuxin liquid, have been widely utilized in clinics. However, its wound repair efficacy is limited due to short retention capability on cutaneous wound location. Herein, Periplaneta americana extract (PAE), which showed pro-fibrogenic and pro-angiogeneic effects, was embedded into hydrogel film (PAE/Film) by solution cast method by blending polyvinyl alcohol, hydroxypropyl chitosan and carbomer at the weight ratio of 78/6/3, with glycerol as plasticizer. PAE/Film exhibited smooth, flexible, and excellent swelling ability (WVTR of 2464 ±â€¯31.5 g/m2/day), characterized by scanning electron microscopy, Fourier transform infrared spectroscopy, and differential scanning calorimetry, meting the condition of ideal wound dressing. The superior wound healing capacity of PAE/Film was demonstrated that it significantly accelerated wound healing process in vivo in both full-thickness skin defect and scald wounded models. Compared to saline, blank vehicle (drug-free) and free PAE group, PAE/Film could accelerate wound healed, promote re-epithelialization and collagen deposition by means of TGF-ß/Smad signal pathway activation. Taken together, this novel hydrogel film-loading PAE would be a useful pharmaceutic candidate for acute cutaneous wound health care.


Assuntos
Portadores de Fármacos/química , Composição de Medicamentos/métodos , Materia Medica/administração & dosagem , Periplaneta/química , Reepitelização/efeitos dos fármacos , Pele/lesões , Resinas Acrílicas/química , Animais , Curativos Hidrocoloides , Materiais Biocompatíveis/química , Quitosana/química , Modelos Animais de Doenças , Liberação Controlada de Fármacos , Glicerol/química , Humanos , Hidrogéis/química , Masculino , Materia Medica/farmacocinética , Metilgalactosídeos/química , Camundongos , Álcool de Polivinil/química , Pele/efeitos dos fármacos , Pele/patologia
19.
Oxid Med Cell Longev ; 2019: 1857086, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31641422

RESUMO

Our previous research revealed that trehalose, a nonreducing disaccharide of glucose and an important stress responsive factor, proved to have anti-inflammatory, antiapoptotic, and particularly antioxidant properties in UVB-irradiated corneas. Trehalose reduced oxidative stress in corneas induced by UVB irradiation, by means of a decrease in the antioxidant/prooxidant imbalance in the corneal epithelium. In this study, we demonstrate that trehalose of 3% or 6% concentration in eye drops directly decreases oxidative stress in UVB-irradiated corneas, by removing the excessive amount of reactive oxygen species (ROS). Trehalose drops applied on corneas during UVB irradiation once daily for four days resulted in a reduction or even absence of the oxidative stress, DNA damage, and peroxynitrite formation (detected by nitrotyrosine residues), seen in buffer-treated corneas. Furthermore, trehalose treatment applied curatively after repeated irradiation for the subsequent fourteen days led to the renewal of corneal transparency and significant suppression or even absence of neovascularization. This was in contrast to buffer-treated irradiated corneas, where the intracorneal inflammation was developed and the untransparent corneas were vascularized. In conclusion, the treatment of UVB-irradiated corneas with trehalose eye drops removed the excessive amount of ROS in the corneal epithelium, leading to the suppression of oxidative stress and favorable corneal healing. The 6% trehalose showed a higher intensive antioxidant effect.


Assuntos
Córnea/patologia , Córnea/efeitos da radiação , Lesões da Córnea/tratamento farmacológico , Estresse Oxidativo , Trealose/uso terapêutico , Raios Ultravioleta , Cicatrização/efeitos dos fármacos , Animais , Córnea/efeitos dos fármacos , Dano ao DNA , Feminino , Interleucina-1beta/metabolismo , Queratinas/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/efeitos da radiação , Coelhos , Reepitelização/efeitos dos fármacos , Reepitelização/efeitos da radiação , Espécies Reativas de Oxigênio/metabolismo , Trealose/farmacologia , Tirosina/análogos & derivados , Tirosina/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Cicatrização/efeitos da radiação
20.
Int J Nanomedicine ; 14: 3345-3360, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31190796

RESUMO

Background: Designing a wound dressing that effectively prevents multi-drug-resistant bacterial infection and promotes angiogenesis and re-epithelialization is of great significance for wound management. Methods and results: In this study, a biocompatible composite membrane comprising biomimetic polydopamine-modified eggshell membrane nano/microfibres coated with KR-12 antimicrobial peptide and hyaluronic acid (HA) was developed in an eco-friendly manner. The physicochemical properties of the composite membrane were thoroughly characterized, and the results showed that the surface hydrophilicity and water absorption ability of the composite membrane were improved after the successive conjugation of the HA and the KR-12 peptide. Furthermore, the in vitrobiological results revealed that the composite membrane had excellent antibacterial activity against Gram-positive Staphylococcus aureus, methicillin-resistant Staphylococcus aureus (MRSA) and Gram-negative Escherichia coli, and it could prevent MRSA biofilm formation on its surface. Additionally, it promoted the proliferation of keratinocytes and human umbilical vein endothelial cells and increased the secretion of VEGF. Finally, an in vivo animal study indicated that the composite membrane could promote wound healing via accelerating angiogenesis and re-epithelialization, which were demonstrated by the enhanced expression of angiogenetic markers (CD31 and VEGF) and keratinocyte proliferation marker (PCNA), respectively. Conclusion: These results indicated that the composite membrane is a potential candidate of wound dressings.


Assuntos
Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Casca de Ovo/química , Ácido Hialurônico/farmacologia , Neovascularização Fisiológica/efeitos dos fármacos , Peptídeos/farmacologia , Reepitelização/efeitos dos fármacos , Animais , Antibacterianos/farmacologia , Galinhas , Escherichia coli/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Queratinócitos/citologia , Queratinócitos/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Camundongos , Testes de Sensibilidade Microbiana , Peptídeos/química , Porosidade , Staphylococcus aureus/efeitos dos fármacos
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