Skin barrier: new therapeutic targets for chronic kidney disease-associated pruritus - a narrative review.

The current incidence of chronic kidney disease-associated pruritus (CKD-aP) in patients with end-stage renal disease (ESRD) is approximately 70%, especially in those receiving dialysis, which negatively affects their work and private lives. The CKD-aP pathogenesis remains unclear, but uremic toxin accumulation, histamine release, and opioid imbalance have been suggested to lead to CKD-aP. Current therapeutic approaches, such as opioid receptor modulators, antihistamines, and ultraviolet B irradiation, are associated with some limitations and adverse effects. The skin barrier is the first defense in preventing external injury to the body. Patients with chronic kidney disease often experience itch due to the damaged skin barrier and reduced secretion of sweat and secretion from sebaceous glands. Surprisingly, skin barrier-repairing agents repair the skin barrier and inhibit the release of inflammatory cytokines, maintain skin immunity, and ameliorate the micro-inflammatory status of afferent nerve fibers. Here, we summarize the epidemiology, pathogenesis, and treatment status of CKD-aP and explore the possibility of skin barrier repair in CKD-aP treatment.

Cold atmospheric plasma for chronic kidney disease-related skin disorders.

BACKGROUND AND HYPOTHESIS: An estimated 80% of individuals with chronic kidney disease (CKD) experience concomitant skin disorders, yet experimental research that elucidates the pathological changes in CKD-affected skin is limited. Cold atmospheric plasma (CAP) has shown promise in regulating keratinocyte proliferation, skin barrier function, and anti-inflammatory activity. We hypothesize that CAP emerges as a promising therapeutic avenue for CKD-related skin diseases. METHODS: Male and female C57/BL6 mice were administered a 0.2% adenine diet to generate a CKD mouse model. Skin samples from dialysis patients were also collected. These models were used to investigate the pathological alterations in the renal glomeruli, tubules, and epidermis. Subsequently, the potential impact of CAP on the stratum corneum, keratinocytes, skin hydration, and inflammation in mice with CKD were examined. RESULTS: Renal biopsies revealed glomerular and tubular atrophy, epithelial degeneration and necrosis in uriniferous tubules, and significant renal interstitial fibrosis. Skin biopsies from patients with CKD and mice showed stratum corneum thickening, epidermis atrophy, skin hydration dysfunction, and excessive inflammation. CAP attenuated skin atrophy, hydration dysfunction, and inflammation in mice with CKD, as evidenced by the activated level of YAP1/ß-catenin and Nrf-2/OH-1, enhanced expression of K5 and Ki67, increased levels of AQP3, collagen I, and GLUT1, reduced infiltration of CD3+ T cells, and diminished levels of IL-6 and TNF-α. CONCLUSION: This study provides valuable insights into the pathological changes in skin associated with CKD in both patients and animal models. It also establishes that CAP has the potential to effectively mitigate skin atrophy, hydration dysfunction, and inflammation, suggesting a novel therapeutic avenue for the treatment of CKD-related skin disorders.

Cold Atmospheric Plasma: A Promising and Safe Therapeutic Strategy for Atopic Dermatitis.

Atopic dermatitis (AD) is a chronic inflammatory skin disease. Microbial infection, immune system dysfunction, and skin barrier defunctionalization have been regarded as the central events in AD pathogenesis. Cold atmospheric plasma (CAP) is an unbound system composed of many free electrons, ions, and neutral particles, with macroscopic time and spatial scales. Based on dielectric barrier discharge, glow discharge, corona discharge, or arch discharge, CAP is generated at normal atmospheric pressure. Its special physical properties maintain its temperature at 20°C-40°C, combining the advantages of high safety and strong ionic activity. CAP has been tentatively used in inflammatory or pruritic skin disorders such as psoriasis, pruritus, and ichthyosis. Increasing data suggest that CAP can attack the microbial structure due to its unique effects, such as heat, ultraviolet radiation, and free radicals, resulting in its inactivation. Meanwhile, CAP regulates reactive oxygen species and reactive nitrogen species in and out of the cells, thereby improving cell immunocompetence. In addition, CAP has a beneficial effect on the skin barrier function via changing the skin lipid contents and increasing the skin permeability to drugs. This review summarizes the potential effects of CAP on the major pathogenic causes of AD and discusses the safety of CAP application in dermatology in order to expand the clinical application value of CAP to AD.

Cold Atmospheric Plasma Ameliorates Skin Diseases Involving Reactive Oxygen/Nitrogen Species-Mediated Functions.

Skin diseases are mainly divided into infectious diseases, non-infectious inflammatory diseases, cancers, and wounds. The pathogenesis might include microbial infections, autoimmune responses, aberrant cellular proliferation or differentiation, and the overproduction of inflammatory factors. The traditional therapies for skin diseases, such as oral or topical drugs, have still been unsatisfactory, partly due to systematic side effects and reappearance. Cold atmospheric plasma (CAP), as an innovative and non-invasive therapeutic approach, has demonstrated its safe and effective functions in dermatology. With its generation of reactive oxygen species and reactive nitrogen species, CAP exhibits significant efficacies in inhibiting bacterial, viral, and fungal infections, facilitating wound healing, restraining the proliferation of cancers, and ameliorating psoriatic or vitiligous lesions. This review summarizes recent advances in CAP therapies for various skin diseases and implicates future strategies for increasing effectiveness or broadening clinical indications.

Successful Treatment of Vitiligo with Cold Atmospheric Plasma‒Activated Hydrogel.

Vitiligo shows insufficient response to current therapies largely owing to T-lymphocyte dysfunction, abnormal inflammatory activation, and excessive oxidative stress in lesions. Cold atmospheric plasma (CAP) possesses pleiotropic antioxidant and anti-inflammatory properties and may offer an improvement to current treatment options. In this study, the efficacy and safety of CAP were investigated in a mouse model of vitiligo and a randomized and controlled trial of patients with active focal vitiligo. Skin biopsies showed that topical treatment of vitiligo-like lesions on mouse dorsal skin by CAP restored the distribution of melanin. In addition, CAP treatment reduced the infiltration of CD11c+ dendritic cells, CD3+ T cells, and CD8+ T cells; inhibited the release of CXCL10 and cytokine IFN-γ; and enhanced cellular resistance to oxidative stress and excessive immune response by enhancing the expression of the transcription factor NRF2 and attenuating the activity of inducible nitric oxide synthase. In a randomized and controlled trial, CAP treatment achieved partial and complete repigmentation in 80% and 20% of vitiligo lesions, respectively, without hyperpigmentation in surrounding areas or other adverse events during the treatment period and its follow-up period. In conclusion, CAP offers a promising option for the management of vitiligo.

Inhibition of fibroblast growth factor-inducible 14 attenuates experimental tubulointerstitial fibrosis and profibrotic factor expression of proximal tubular epithelial cells.

BACKGROUND AND AIM: As a proinflammatory cytokine, tumor necrosis factor-like weak inducer of apoptosis (TWEAK) participates in the progression of renal fibrosis by binding to its receptor, fibroblast growth factor-inducible 14 (Fn14). However, the effect of Fn14 inhibition on tubular epithelial cell-mediated tubulointerstitial fibrosis remains unclear. This study aimed to elucidate the role of TWEAK/Fn14 interaction in the development of experimental tubulointerstitial fibrosis as well as the protective effect of Fn14 knockdown on proximal tubular epithelial cells. METHODS: A murine model of unilateral ureteral obstruction was constructed in both wild-type and Fn14-deficient BALB/c mice, followed by observation of the tubulointerstitial pathologies. RESULTS: Fn14 deficiency ameliorated the pathological changes, including inflammatory cell infiltration and cell proliferation, accompanied by reduced production of profibrotic factors and extracellular matrix deposition. In vitro experiments showed that TWEAK dose-dependently enhanced the expression of collagen I, fibronectin, and α-smooth muscle actin in proximal tubular epithelial cells. Interestingly, TWEAK also upregulated the expression levels of Notch1/Jagged1. Fn14 knockdown and Notch1/Jagged1 inhibition also mitigated the effect of TWEAK on these cells. CONCLUSIONS: In conclusion, TWEAK/Fn14 signals contributed to tubulointerstitial fibrosis by acting on proximal tubular epithelial cells. Fn14 inhibition might be a therapeutic strategy for protecting against renal interstitial fibrosis.

ALW peptide ameliorates lupus nephritis in MRL/lpr mice.

BACKGROUND: Lupus nephritis (LN) is a common and serious complication of systemic lupus erythematosus. Anti-double-stranded (ds) DNA immunoglobulin G (IgG) plays a pivotal role in the pathogenesis of LN. Currently, there are various therapies for patients with LN; however, most of them are associated with considerable side effects. We confirmed previously that ALW (ALWPPNLHAWVP), a 12-amino acid peptide, inhibited the binding of polyclonal anti-dsDNA antibodies to mesangial cells and isolated glomeruli in vitro. In this study, we further investigate whether the administration of ALW peptide decreases renal IgG deposition and relevant damage in MRL/lpr lupus-prone mice. METHODS: Forty female MRL/lpr mice were randomly divided into four groups. The mice were intravenously injected with D-form ALW peptide (ALW group), scrambled peptide (PLP group), and normal saline (NaCl group) or were not treated (blank group). The IgG deposition, the histopathologic changes, and the expressions of profibrotic factors were analyzed in the kidney of MRL/lpr mice. RESULTS: Compared with the other groups, glomerular deposition of IgG, IgG2a, IgG2b, and IgG3 was decreased in the ALW group. Moreover, ALW administration attenuated renal histopathologic changes in MRL/lpr mice, including mesangial proliferation and infiltration of inflammatory cells. Furthermore, the expressions of profibrotic cytokines, such as transforming growth factor-beta1 (TGF-ß1) and platelet-derived growth factor B (PDGF-B), decreased in the serum and kidney tissue of ALW-treated mice. CONCLUSIONS: Our study demonstrated that ALW peptide ameliorates the murine model of LN, possibly through inhibiting renal IgG deposition and relevant tissue inflammation and fibrosis.

TWEAK/Fn14 Interaction Confers Aggressive Properties to Cutaneous Squamous Cell Carcinoma.

Recent studies showed that TWEAK/Fn14 signaling participates in the progression of internal malignancies. However, its role in the biological properties of cutaneous squamous cell carcinoma (SCC) remains unclear. This study was designed to explore the effect of TWEAK/Fn14 activation on cutaneous SCC as well as the relevant mechanism. The expression of TWEAK and Fn14 was determined in tissue samples of patients with cutaneous SCC. Human primary keratinocytes and SCC cell lines were cultured in vitro, receiving stimulation of TWEAK. The xenografts of SCC were generated subcutaneously in BALB/c nude mice. The results showed that both TWEAK and Fn14 were highly expressed in human cutaneous SCC. Moreover, TWEAK/Fn14 activation promoted the proliferation, migration, and invasion of cultured SCC cells. Interestingly, TNFR2 was upregulated in cultured SCC cells, and the transfection of TNFR2 small interfering RNA abrogated the effect of TWEAK on these cells. Finally, the favorable effect of TWEAK/Fn14 signals was confirmed in BALB/c nude mice with SCC xenografts. In conclusion, TWEAK/Fn14 signals contribute to the progression of cutaneous SCC, possibly involving the TNF-α-independent TNFR2 signal transduction.