Diabetes mellitus is characterized by elevated plasma glucose and increased rates of skin infections. Altered immune responses have been suggested to contribute to this prevalent complication, which involves microbial invasion. In this study we explored the effects of a high-glucose environment on the innate immunity of keratinocytes by focusing on β defensin-3 (BD3) using in vivo and in vitro models. Our results demonstrated that the perilesional skins of diabetic rats failed to show enhanced BD3 expression after wounding. In addition, high-glucose treatment reduced human BD3 (hBD3) expression of cultured human keratinocytes. This pathogenic process involved inhibition of p38MAPK signaling, an event that resulted from increased formation of advanced glycation end products. On the other hand, toll-like receptor-2 expression and function of cultured keratinocytes were not significantly affected by high-glucose treatment. In summary, high-glucose conditions inhibited the BD3 expression of epidermal keratinocytes, which in turn contributed to the frequent occurrences of infection associated with diabetic wounding.
Photodynamic therapy (PDT), a therapeutic approach employing a photosensitizer and a specific wavelength of light, is an emerging option for treating neoplastic and nonneoplastic diseases. Keloids are fibroproliferative dermal lesions characterized by the proliferation of fibroblasts. Recently, PDT has been demonstrated as a potential treatment for keloids.To investigate the effects of our newly synthesized photosensitizer 2-(4-aminophenyl)-7-methoxybenzothiazole (6d) plus ultraviolet (UV)A irradiation (6d-UVA) on proliferation and apoptosis in keloid fibroblasts (KFs).Fibroblasts cultured from normal skin and keloids were treated with 6d-UVA. Relevant assays including 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, 5-bromo-2'-deoxyuridine incorporation assay, immunofluorescence assay and flow cytometry analysis were performed.The combination of 6d (2.0 or 5.0 μmol/L) and UVA 0.5 J/cm(2) significantly decreased the viability and proliferation of KFs but not normal fibroblasts (NFs). Cell cycle analyses showed significant G0/G1 arrest and increased sub-G1 distribution in NFs induced by UVA-activated 6d at 5.0 μmol/L (hereafter referred to as 6d-UVA). This treatment also significantly induced generation of intracellular reactive oxygen species (ROS), loss of mitochondrial membrane potential (ΔΨm), and increased expression of active caspase-3. Pretreatment with N-acetyl-L-cysteine (aROS scavenger) reversed the increased active caspase-3 expression induced by 6d-UVA, indicating the involvement of ROS in 6d-UVA-induced apoptosis.This study indicates that 6d-UVA treatment exerts antiproliferative and pro-apoptotic effects in KFs. We propose that 6d-UVA could be a potentially usefull ancillary method for keloid treatment.
The title of the following article was incorrectly published: Cheng-Che E Lan, Ching-Shuang Wu, Shu-Mei Huang, Hsuan-Yu Kuo, I-Hui Wu, Chien-Hui Wen, Chee-Yin Chai, Ai-Hui Fang, and Gwo-Shing Chen. High-Glucose Environment Inhibits p38MAPK Signaling and Reduces Human β-3 Expression in Keratinocytes. Mol. Med. 2011;17(7–8):771–9.
Modulation of nuclear factor-kappa B (NF-κB) expression has important clinical implications including anti-inflammation. Recently, we have shown that direct regulation of NF-κB/p65 subunit may account for tacrolimus ointment's remarkable clinical efficacy on treating inflammatory dermatoses. However, NF-κB is a dimeric transcription factor formed by hetero- or homodimeration of the five Rel family proteins. The complete operational scheme of different NF-κB subunits remains obscure. It has been shown that homodimers consist of NF-κB/p50 may serve an inhibitory role in suppressing inflammation while dimers consisting of NF-κB/p65 activate inflammatory pathway. Our current study aimed to explore the effects of ultraviolet B (UVB) on epidermal keratinocytes in terms of specific NF-κB subunits NF-κB/p50 and NF-κB/p65. Additionally, the effects of tacrolimus on differential regulation of NF-κB subunits of UVB irradiated keratinocytes were also investigated. Our result showed that UVB sequentially regulated the activities of different subunits of NF-κB: the activity of NF-κB/p50 was downregulated in the early stage (6 hours), followed by upregulation of NF-κB/p65 in the later stage (12 hours). The results from immunofluorescence, immunocytochemical, and immunohistochemical analyses indicated that the nuclear expression of NF-κB/p50 could be seen constitutively while the nuclear expression of NF-κB/p65 could only be seen after UVB irradiation. Furthermore, treatment with tacrolimus didn't affect the nuclear activation and translocation of NF-κB/p50, while the UVB induced NF-κB/p65 nuclear expression was suppressed by tacrolimus. In summary, we have shown that UVB irradiation sequentially regulated different NF-κB subunits. The clinical efficacy of tacrolimus may be attributed to its specific regulatory effect on NF-κB/p65 but not NF-κB/p50 of the NF-κB pathway.
Wound healing is a dynamic and complicated process in which inflammation, re-epithelialization and angiogenesis play important roles. Intriguingly, all three processes have been found to be defective during diabetic wound healing conditions. One common denominator associated with regulation of these events is human β-defensin-2 (hBD2). It has been shown that skin wounding induces cutaneous hBD2 expression, and diabetic wounds have been associated with inadequate hBD expression.The current study was launched to explore the effects of a high-glucose environment on cultured human keratinocytes.Human keratinocytes were exposed to indicated culture conditions. The mRNA and protein levels of hBD2 were determined, and activation of relevant pathways was evaluated. The small interference RNA approach was used to validate the functional role of the proposed pathway on hBD2 expression.We showed that high-glucose cultivated keratinocytes expressed reduced levels of hBD2 and phosphorylated signal transducer and activator of transcription (pSTAT)-1 constitutively. In addition, pSTAT-1 signalling is critically involved in hBD2 expression. Formation of advanced glycation endproducts, a direct consequence of a high-glucose environment, involves constitutive downregulation of pSTAT-1 and hBD2. The addition of interleukin-1β, an important cytokine during the cutaneous wound healing process, enabled the upregulation of hBD2 expression of both normal- and high-glucose cultivated keratinocytes, but the absolute levels of hBD2 were still significantly lower in the high-glucose-treated group.As hBD2 plays multifaceted roles during the wound healing process, the inadequate expression of hBD2 during diabetic conditions contributes to impaired wound healing.
Journal Article Topical tacrolimus has a limited direct effect on ultraviolet B‐irradiated keratinocytes: implications for its photocarcinogenic potential Get access C.‐C. E. Lan, C.‐C. E. Lan Department of Dermatology, Kaohsiung Medical University Hospital and College of Medicine, Kaohsiung Medical University, Kaohsiung, TaiwanCenter of Excellence for Environmental Science, Kaohsiung Medical University, Kaohsiung, Taiwan Search for other works by this author on: Oxford Academic Google Scholar H.‐S. Yu, H.‐S. Yu Department of Dermatology, Kaohsiung Medical University Hospital and College of Medicine, Kaohsiung Medical University, Kaohsiung, TaiwanCenter of Excellence for Environmental Science, Kaohsiung Medical University, Kaohsiung, Taiwan Search for other works by this author on: Oxford Academic Google Scholar S.‐M. Huang, S.‐M. Huang Department of Dermatology, Kaohsiung Medical University Hospital and College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan Search for other works by this author on: Oxford Academic Google Scholar C.‐S. Wu, C.‐S. Wu Faculty of Biomedical Laboratory Science, Kaohsiung Medical University, Kaohsiung, Taiwan Search for other works by this author on: Oxford Academic Google Scholar H.‐Y. Kuo, H.‐Y. Kuo Department of Dermatology, Kaohsiung Medical University Hospital and College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan Search for other works by this author on: Oxford Academic Google Scholar C.‐H. Lee, C.‐H. Lee Department of Public Health, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, TaiwanDivision of Environmental Health and Occupational Medicine, National Health Research Institutes, Taiwan Search for other works by this author on: Oxford Academic Google Scholar C.‐S. Lin, C.‐S. Lin Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan Search for other works by this author on: Oxford Academic Google Scholar G.‐S. Chen G.‐S. Chen Department of Dermatology, Kaohsiung Medical University Hospital and College of Medicine, Kaohsiung Medical University, Kaohsiung, TaiwanCenter of Excellence for Environmental Science, Kaohsiung Medical University, Kaohsiung, Taiwan Dr Gwo‐Shing Chen, 100 Shih‐Chuan 1st Road, Department of Dermatology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan. E‐mail: d700086@kmu.edu.tw Search for other works by this author on: Oxford Academic Google Scholar Clinical and Experimental Dermatology, Volume 35, Issue 2, 1 March 2010, Pages 173–179, https://doi.org/10.1111/j.1365-2230.2009.03311.x Published: 01 March 2010
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