Search

Background: We previously identified that botulinum toxin A (BTX-A) suppressed pressure ulcer (PU) formation after cutaneous ischemia-reperfusion (I/R) injury; however, regulation of cutaneous I/R-induced oxidative and endoplasmic reticulum (ER) stress by BTX-B was not investigated. Additionally, the efficacy of BTX-B injection has never been examined., Objective: Objective was to assess the effects of BTX-B on the formation of PU by cutaneous I/R injury, and the regulation of oxidative and ER stress in I/R injury by BTX-B., Methods: BTX-B was subcutaneously injected into I/R area, and wound size, vascular damage, hypoxic area, and apoptotic cells in I/R area were analyzed. We evaluated the extent of oxidative and ER stress in I/R area by using OKD48 mice and ERAI mice, respectively, which enabled evaluating oxidative and ER stress through bioluminescence detection., Results: BTX-B injection significantly suppressed the formation of PU by cutaneous I/R injury. Cutaneous I/R-induced vascular damage, hypoxic area, and number of oxidative-damaged cells and apoptotic cells were suppressed by BTX-B injection. BTX-B administration significantly inhibited I/R-induced oxidative stress signal in OKD48 mice. BTX-B reduced the I/R-induced oxidative stress-associated factors. BTX-B significantly inhibited the oxidant-induced reactive oxygen species and apoptosis of endothelial cells and fibroblasts. BTX-B significantly inhibited I/R-induced ER stress signal in ERAI mice. Cutaneous I/R injury-induced ER stress-response factors and GRP78/BiP and CHOP-positive cells in I/R area were significantly decreased by BTX-B injection., Conclusion: BTX-B injection might have protective effects against PU formation after cutaneous I/R injury by reducing vascular damage, hypoxia-induced oxidative and ER stress, and apoptosis., (Copyright © 2018 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)

Cutaneous ischemia-reperfusion (I/R) injury is associated with the early pathogenesis of cutaneous pressure ulcers (PUs). The objective of this study was to investigate the effect of mesenchymal stem cells (MSCs) injection on the formation of PUs after I/R injury and determine the underlying mechanisms. We found that the subcutaneous injection of MSCs into areas of I/R injured skin significantly suppressed the formation of PUs. I/R-induced vascular damage, hypoxia, oxidative DNA damage, and apoptosis were decreased by MSCs injection. Oxidative stress signals detected after I/R in OKD48 (Keap1-dependent oxidative stress detector, No-48-luciferase) mice were decreased by the injection of MSCs. In cultured fibroblasts, MSCs-conditioned medium significantly inhibited oxidant-induced reactive oxygen species (ROS) generation and apoptosis. Furthermore, endoplasmic reticulum (ER) stress signals detected after I/R in ERAI (ER stress-activated indicator) mice were also decreased by the injection of MSCs. These results suggest that the injection of MSCs might protect against the development of PUs after cutaneous I/R injury by reducing vascular damage, oxidative cellular damage, oxidative stress, ER stress, and apoptosis.

Oxidative stress has been reported to play an important role in the pathogenesis of skin fibrosis in systemic sclerosis (SSc). We previously identified that botulinum toxin (BTX) injection suppresses pressure ulcer formation in a cutaneous ischemia–reperfusion injury mouse model by regulation of oxidative stress. However, the therapeutic possibility of BTX administration for preventing skin fibrosis in SSc is unclear. The objective of this study was to investigate the effect of BTX‐B on skin fibrosis in a murine model of SSc and determine the underlying mechanism. We found that BTX‐B injection significantly reduced dermal thickness and inflammatory cell infiltration in bleomycin‐induced skin fibrosis lesion in mice. We also identified that the oxidative stress signal detected through bioluminescence in OKD48 mice after bleomycin injection in the skin was significantly decreased by BTX‐B. Additionally, mRNA levels of oxidative stress associated factors (NOX2, HO‐1, Trx2) were significantly decreased by BTX‐B. Apoptotic cells in the lesional skin of bleomycin‐treated mice were significantly reduced by BTX‐B. Oxidant‐induced intracellular accumulation of reactive oxygen species in SSc fibroblasts was also inhibited by BTX‐B. In conclusion, BTX‐B might improve bleomycin‐induced skin fibrosis via the suppression of oxidative stress and inflammatory cells in the skin. BTX‐B injection may have a therapeutic effect on skin fibrosis in SSc. [ABSTRACT FROM AUTHOR]

Ischemia‐reperfusion (I/R) is associated with various pathogenic conditions, and there has been increasing evidence that cutaneous I/R injury is associated with the pathogenesis of pressure ulcers (PUs), especially at the early stage presenting as non‐blanchable erythema. Several studies demonstrated that oxidative stress is a key player in I/R injury, and the inhibition of oxidative stress may be capable of protecting tissue damage after I/R injury in various organs including skin. Dimethyl fumarate (DMF) approved by the Food and Drug Administration is Nrf2 activator, and recent studies revealed the antioxidative and anti‐inflammatory effects of DMF on I/R injury in animal models. Our objective was to assess the effects of oral administration of DMF on the development of PUs after cutaneous I/R injury in mice. We found that DMF administration significantly decreased the size of PUs after cutaneous I/R. Cutaneous I/R‐induced oxidative stress was also significantly inhibited by DMF in OKD48 mice, in which oxidative stress can be visually assessed. In addition, DMF treatment decreased hypoxic area, the numbers of apoptotic cells, and vascular loss in I/R area. DMF treatment suppressed the infiltration of MPO+ neutrophils and the production of proinflammatory cytokines in I/R site after cutaneous I/R injury. in vitro experiments, DMF treatment suppressed the production of reactive oxygen species in pericyte‐like cells. These results suggest that DMF treatment might prevent the formation of PUs induced by cutaneous I/R injury via suppressing oxidative stress and subsequent inflammation. DMF treatment during the early phase of decubitus ulcers might protect against further progression. [ABSTRACT FROM AUTHOR]

Ischaemia-reperfusion (I/R) is involved in the development of various organ diseases. There has been increasing evidence that cutaneous I/R injury is associated with the pathogenesis of pressure ulcers ( PUs), especially at the early stage presenting as non-blanchable erythema. However, there is no evidence-based treatment for early-stage PUs. Our objective was to assess the effects of topical steroid on the development of PUs after cutaneous I/R injury in mice. Cutaneous I/R was performed by trapping the dorsal skin between two magnetic plates for 12 h, followed by plate removal. Topical application of betamethasone butyrate propionate ( BBP) in I/R areas significantly increased the size of PUs after I/R. The number of thromboses was increased, and CD31+ vessels were decreased in the I/R area treated with topical BBP. The number of oxidative stress-associated DNA-damaged cells and apoptotic cells in the I/R area was increased by topical BBP treatment. In addition, the mRNA level of NADPH oxidase 4 (Nox4), the essential enzyme that produces reactive oxygen species, was significantly increased and that of NF-E2-related factor 2 (Nrf2), a transcription factor that regulates the expression of antioxidant proteins, was inhibited in the I/R area treated by BBP. The number of CD68+ macrophages and the level of transforming growth factor-beta in lesional skin were also decreased by BBP. These results suggest that a topical steroid might accelerate the formation of PUs induced by cutaneous I/R injury by aggravating oxidative stress-induced tissue damage. Topical steroids might not be recommended for the treatment of acute-phase decubitus ulcers. [ABSTRACT FROM AUTHOR]

Ischemia– reperfusion (I/R) injury-induced oxidative stress is a key factor in the pathogenesis of pressure ulcer formation. Ferroptosis is an iron-dependent programmed cell death that connects oxidative stress and inflammation in various diseases. Recent studies revealed the protective effect of inhibition of ferroptosis in I/R injury. However, the role of ferroptosis in cutaneous I/R injury remains elusive. To assess the role of ferroptosis in the progression of cutaneous I/R injury. Cutaneous I/R injury experiments and histopathological studies were performed in wild-type mice with or without exposure to volatile ferroptosis inhibitor, TEMPO (2,2,6,6-Tetramethylpiperidine-1-oxyl). The suppressive effects of TEMPO on ferroptosis inducing cell death and oxidative stress were examined in vitro. Inhibition of ferroptosis with TEMPO significantly reduced ulcer formation after cutaneous I/R injury. Fluctuated ferroptosis markers, such as GPX4, ACSL4, and 4-HNE expression in the I/R skin site, were reversed by TEMPO treatment. Inhibition of ferroptosis reduced apoptosis, CD3+ infiltrating lymphocytes, and improved vascularity in the I/R skin site. Inhibition of ferroptosis also suppressed the enhancement of Nrf2 activation. In vitro , ferroptosis and the activation of ferroptosis-related gene expression by RSL3 stimulation were markedly ameliorated by TEMPO treatment in mouse fibroblasts. Inhibiting ferroptosis also suppressed the elevation of the mRNA levels of NOX2 and HO-1 caused by ferroptosis. Cutaneous I/R injury-induced ferroptosis likely promotes cell death, vascular loss, infiltration of inflammatory cells, and oxidative stress. The inhibition of ferroptosis with TEMPO might have potential clinical application as novel therapeutic agent for cutaneous I/R injury. • Cutaneous I/R injury induced ferroptosis in wound area. • Inhibition of ferroptosis by TEMO suppressed PUs after cutaneous I/R injury. • Inhibition of ferroptosis reduced oxidative stress after cutaneous I/R injury. • Oxidative stress and cell death caused by ferroptosis was improved by TEMPO. [ABSTRACT FROM AUTHOR]

Atopic dermatitis is a common skin disease caused by genetic susceptibility, environmental factors, immune response, and skin barrier dysfunction. Kaempferol is a natural flavonoid widely found in tea, vegetables, and fruits and has been reported to have excellent anti-inflammation activity. However, the therapeutic effect of kaempferol on atopic dermatitis is unclear. This study aimed to elucidate the effect of kaempferol on skin inflammation in atopic dermatitis. The suppressive effect of kaempferol administration on skin inflammation was examined using MC903-induced atopic dermatitis-like skin inflammation mouse model. Quantification of skin dermatitis and transepidermal water loss was performed. A histopathological study was performed to examine thymic stromal lymphopoietin expression, cornified envelope proteins such as filaggrin, loricrin, and involucrin, and the numbers of infiltrating inflammatory cells, including lymphocytes, macrophages, and mast cells in the dermatitis area. The expressions of IL-4 and IL-13 were investigated by qPCR and flow cytometry analysis using skin tissues. The expression of HO-1 was investigated by western blot and qPCR. Kaempferol therapy significantly suppressed MC903-induced dermatitis, TEWL, TSLP, and HO-1 expression, and infiltration of inflammatory cells. Kaempferol therapy improved the decreased expressions of filaggrin, loricrin, and involucrin in MC903-induced dermatitis skin site. The expressions of IL-4, and IL-13 were partially decreased in kaempferol-treated mice. Kaempferol might improve MC903-induced dermatitis via suppression of type 2 inflammation and improvement of barrier dysfunction by inhibition of TSLP expression and oxidative stress. Kaempferol might have the potential to be a new treatment for atopic dermatitis. • Kaempferol improved AD-like dermatitis in mouse. • Kaempferol inhibited TSLP expression in AD mouse model. • Kaempferol inhibited oxidative stress in AD mouse model. • Kaempferol suppressed type 2 inflammation in AD mouse model. [ABSTRACT FROM AUTHOR]