Exploring the potential of intradermal platelet-rich plasma in treating acquired bilateral nevus of Ota-like macule (Hori's nevus): A pilot study.

BACKGROUND: Hori's nevus is a common and challenging dermatological condition, often complicated by post-inflammatory hyperpigmentation following treatment. Platelet-rich plasma (PRP) has demonstrated efficacy in the treatment of hyperpigmentation disorders such as melasma and periorbital darkening. Given the benefits and minimally invasive nature of PRP treatments, exploring its application in managing Hori's nevus through further investigation is worthwhile. AIMS: To evaluate the safety and effectiveness of intradermal PRP therapy for the treatment of Hori's nevus. METHODS: Ten female patients received bilateral intradermal PRP injections every 2 weeks for a total of four treatments. The modified dermal pigmentation and severity index (mDPASI), mean melanin index (MI), brightening score, patient self-assessment, and clinical photographs were evaluated at 2, 4, 8, and 12 weeks post-treatment. Adverse events were also recorded to determine treatment safety. RESULTS: At 12 weeks post-treatment, mDPASI decreased 38.86%, from 0.929 ± 0.617 to 0.568 ± 0.415 (p < 0.05). The mean melanin index decreased 12.75%, from 208.650 ± 26.319 to 182.052 ± 17.028 (p < 0.05). In addition, the mean brightness score evaluated by two experts was 1.4, indicating 25-50% improvement. At the end of the study, 50% of the patients reported 50-75% improvement. Side effects included pain, mild edema, and bruising, which resolved spontaneously within 3 days. No serious side effects were found. CONCLUSION: Our results suggest that intradermal PRP therapy may be a safe and effective alternative for the treatment of Hori's nevus and can complement conventional interventions. However, further research with a larger sample size, control groups, and longer follow-up is needed to confirm these findings.

Role of antimicrobial peptides in atopic dermatitis.

Host defense peptides (HDPs) or antimicrobial peptides (AMPs) are short cationic amphipathic peptides of divergent sequences, which are part of the innate immune system and produced by various types of cells and tissues. The predominant role of HDPs is to respond to and protect humans against infection and inflammation. Common human HDPs include defensins, cathelicidin, psoriasin, dermcidin, and ribonucleases, but these peptides may be dysregulated in the skin of patients with atopic dermatitis (AD). Current evidence suggests that the antimicrobial properties and immunomodulatory effects of HDPs are involved in AD pathogenesis, making HDPs research a promising area for predicting disease severity and developing novel treatments for AD. In this review, we describe a potential role for human HDPs in the development, exacerbation, and progression of AD and propose their potential therapeutic benefits.

Opposing Roles of Antimicrobial Peptides in Skin Cancers.

Antimicrobial peptides (AMPs), also known as host defense peptides, are ubiquitous naturally occurring molecules secreted by various cell types of the body. In the skin, AMPs serve as a first-line innate immune defense against exogenous microorganisms, and they orchestrate adaptive immune responses to exert several immunomodulatory functions. Emerging evidence indicates that AMPs not only contribute to certain inflammatory skin diseases but also play a role in skin tumor carcinogenesis. Available data support the hypothesis that AMPs possess both pro-tumor and anti-neoplastic properties. Although inconsistent observations reported by multiple studies make it challenging to summarize the precise roles of AMPs in cancer, the differential expression of AMPs in skin cancers, such as the increased expression of human beta-defensins in squamous cell carcinoma and the ability of cathelicidin LL-37 to induce malignant melanoma cell invasion, implies they have procancer activities. On the other hand, the observation that certain AMPs show cytotoxic activity against cancer cells of the colon and kidney suggests their inherent antitumor properties. In this review, we describe the roles and mechanisms of AMPs in skin cancer development. We believe that further research is needed to elucidate the impact of these AMPs in skin cancer biology and to explore their potential roles as diagnostic/prognostic biomarkers and as novel therapeutic targets.

Intractable Itch in Atopic Dermatitis: Causes and Treatments.

Itch or pruritus is the hallmark of atopic dermatitis and is defined as an unpleasant sensation that evokes the desire to scratch. It is also believed that itch is a signal of danger from various environmental factors or physiological abnormalities. Because histamine is a well-known substance inducing itch, H1-antihistamines are the most frequently used drugs to treat pruritus. However, H1-antihistamines are not fully effective against intractable itch in patients with atopic dermatitis. Given that intractable itch is a clinical problem that markedly decreases quality of life, its treatment in atopic dermatitis is of high importance. Histamine-independent itch may be elicited by various pruritogens, including proteases, cytokines, neuropeptides, lipids, and opioids, and their cognate receptors, such as protease-activated receptors, cytokine receptors, Mas-related G protein-coupled receptors, opioid receptors, and transient receptor potential channels. In addition, cutaneous hyperinnervation is partly involved in itch sensitization in the periphery. It is believed that dry skin is a key feature of intractable itch in atopic dermatitis. Treatment of the underlying conditions that cause itch is necessary to improve the quality of life of patients with atopic dermatitis. This review describes current insights into the pathophysiology of itch and its treatment in atopic dermatitis.

Exogenous factors in the pathogenesis of atopic dermatitis: Irritants and cutaneous infections.

Atopic dermatitis (AD) is a chronic relapsing inflammatory cutaneous disease that is often associated with other atopic symptoms, such as food allergy, allergic rhinitis and asthma, leading to significant morbidity and healthcare costs. The pathogenesis of AD is complicated and multifactorial. Although the aetiology of AD remains incompletely understood, recent studies have provided further insight into AD pathophysiology, demonstrating that the interaction among genetic predisposition, immune dysfunction and environmental provocation factors contributes to its development. However, the increasing prevalence of AD suggests that environmental factors such as irritation and cutaneous infection play a crucial role in triggering and/or aggravating the disease. Of note, AD skin is susceptible to bacterial, fungal and viral infections, and microorganisms may colonize the skin and aggravate AD symptoms. Overall, understanding the mechanisms by which these risk factors affect the cutaneous immunity of patients with AD is of great importance for developing a precision medicine approach for treatment. This review summarizes recent developments in exogenous factors involved in the pathogenesis of AD, with special emphasis on irritants and microbial infections.

The Inhibitory Effect of Human Beta-defensin-3 on Candida Glabrata Isolated from Patients with Candidiasis.

Candida glabrata is a common non-albicans Candida species found in patients with candidiasis and it sometimes develops antifungal resistance. Human beta-defensin-3 (hBD-3) is an antimicrobial peptide of immune system active against various types of microbes including Candida spp. This study investigated antifungal activity of hBD-3 and its synergistic effect with a first-line antifungal agent on C. glabrata clinical isolates. Candida spp. were characterised in patients with candidiasis. The antifungal activities of hBD-3 and fluconazole against C. glabrata were evaluated using Broth microdilution assay. The synergistic activity of these two agents was determined by checkerboard microdilution and time-killing assays. The cytotoxicity of hBD-3 was evaluated using LDH-cytotoxicity colorimetric assay. Of 307 episodes from 254 patients diagnosed with candidiasis, C. glabrata was found in 21 clinical isolates. Antifungal susceptibility tests of C. glabrata were performed, fluconazole demonstrated an inhibitory effect at concentrations of 0.25-8 µg/ml, but one antifungal resistant strain was identified (>64 µg/ml). hBD-3 showed an inhibitory effect against all selected strains at concentrations of 50-75 µg/ml and exhibited a synergistic effect with fluconazole at the fractional inhibitory concentration index (FICI) of 0.25-0.50. A concentration of 25 µg/ml of hBD-3 alone showed no cytotoxicity but synergistic activity was seen with fluconazole. In conclusion, hBD-3 has antifungal activity against C. glabrata and synergistic effects with fluconazole at concentrations that alone, have no cytotoxicity. hBD-3 could be used as an adjunctive therapy with first-line antifungal agents for patients with C. glabrata infection particularly those infected with fluconazole-resistant strains.

Role of Antimicrobial Peptides in Skin Barrier Repair in Individuals with Atopic Dermatitis.

Atopic dermatitis (AD) is a common chronic inflammatory skin disease that exhibits a complex interplay of skin barrier disruption and immune dysregulation. Patients with AD are susceptible to cutaneous infections that may progress to complications, including staphylococcal septicemia. Although most studies have focused on filaggrin mutations, the physical barrier and antimicrobial barrier also play critical roles in the pathogenesis of AD. Within the physical barrier, the stratum corneum and tight junctions play the most important roles. The tight junction barrier is involved in the pathogenesis of AD, as structural and functional defects in tight junctions not only disrupt the physical barrier but also contribute to immunological impairments. Furthermore, antimicrobial peptides, such as LL-37, human b-defensins, and S100A7, improve tight junction barrier function. Recent studies elucidating the pathogenesis of AD have led to the development of barrier repair therapy for skin barrier defects in patients with this disease. This review analyzes the association between skin barrier disruption in patients with AD and antimicrobial peptides to determine the effect of these peptides on skin barrier repair and to consider employing antimicrobial peptides in barrier repair strategies as an additional approach for AD management.

The clinical significance of fungi in atopic dermatitis.

Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases and is caused by multiple factors including genetic factors, skin barrier defects, host immune responses, allergen sensitivity, environmental effects, and infections. Commonly, bacterial and viral infections are present in the eczematous lesions of AD patients and clearly aggravate the symptoms. However, studies of fungal infections in AD are limited in spite of the fact that there are reports showing that Malassezia, Candida, and some dermatophytes can affect the symptoms of AD. Moreover, certain fungal infections are sometimes overlooked and need to be considered particularly in AD patients with treatment failure as clinical features of those fungal infections could mimic eczematous lesions in AD. Here, we review the epidemiology, pathogenesis, clinical manifestations, and overlooked features of fungal infections associated with the symptoms of AD including the diagnosis and effectiveness of fungal treatments in AD patients.

The Role of Host Defense Peptide Human ß-defensins in the Maintenance of Skin Barriers.

The epidermis functions as a first-line defense barrier that protects the body from the external environment. As a chemical hindrance, the epidermis possesses acidic pH, highly organized lipids and various host defense peptides, also known as antimicrobial peptides. Human ß-defensins (hBDs), one of the most important host defense peptide families found in our skin, are well-known for their broad-spectrum microbicidal activities. However, there is a growing body of evidence indicating that hBDs also orchestrate several immunomodulatory functions and are the cornerstone that bridges the innate and adaptive immune responses during skin inflammation and infection. Moreover, recent work identified the potential role of hBDs in the regulation and maintenance of the skin barrier function. In this review, we describe the current knowledge concerning the role of hBDs in skin barriers and discuss the potential clinical implications of these peptides in cutaneous biology. Understanding the roles of hBDs in the regulation and maintenance of skin barriers may aid in the development of novel therapeutic strategies for skin conditions where the skin barrier is impaired, such as atopic dermatitis and psoriasis.

Unilateral Linear Punctate Palmoplantar Keratoderma: A Case Report.

Punctate palmoplantar keratoderma (PPPK) is a rare entity with an estimated prevalence rate of 1.17/100,000. PPPK usually presents with bilateral asymptomatic, tiny, hyperkeratotic punctate papules and plaques on the palmoplantar surface. Among the PPPK varieties, the linear presentation is much rarer, and so far there have been only 3 case reports. Here, we report the case of a 27-year-old female Thai patient who presented to our outpatient clinic with unilateral asymptomatic linear thickening lesions on her right sole since childhood. There were no similar lesions on other parts of the body. A histopathologic examination revealed epidermal hyperplasia and hyperkeratosis without columns of parakeratosis or cornoid lamella. The other examinations were normal. The clinical and histological contexts were consistent with a diagnosis of unilateral linear PPPK. The patient was treated with topical 10% urea cream and 10% salicylic acid cream twice daily. To the best of our knowledge, this is the first reported case of unilateral linear PPPK in Thailand, and the fourth reported case worldwide.

The antimicrobial peptide derived from insulin-like growth factor-binding protein 5, AMP-IBP5, regulates keratinocyte functions through Mas-related gene X receptors.

BACKGROUND: In addition to their microbicidal properties, host defense peptides (HDPs) display various immunomodulatory functions, including keratinocyte production of cytokines/chemokines, proliferation, migration and wound healing. Recently, a novel HDP named AMP-IBP5 (antimicrobial peptide derived from insulin-like growth factor-binding protein 5) was shown to exhibit antimicrobial activity against numerous pathogens, even at concentrations comparable to those of human ß-defensins and LL-37. However, the immunomodulatory role of AMP-IBP5 in cutaneous tissue remains unknown. OBJECTIVES: To investigate whether AMP-IBP5 triggers keratinocyte activation and to clarify its mechanism. METHODS: Production of cytokines/chemokines and growth factors was determined by appropriate ELISA kits. Cell migration was assessed by in vitro wound closure assay, whereas cell proliferation was analyzed using BrdU incorporation assay complimented with XTT assay. MAPK and NF-κB activation was determined by Western blotting. Intracellular cAMP levels were assessed using cAMP enzyme immunoassay kit. RESULTS: Among various cytokines/chemokines and growth factors tested, AMP-IBP5 selectively increased the production of IL-8 and VEGF. Moreover, AMP-IBP5 markedly enhanced keratinocyte migration and proliferation. AMP-IBP5-induced keratinocyte activation was mediated by Mrg X1-X4 receptors with MAPK and NF-κB pathways working downstream, as evidenced by the inhibitory effects of MrgX1-X4 siRNAs and ERK-, JNK-, p38- and NF-κB-specific inhibitors. We confirmed that AMP-IBP5 indeed induced MAPK and NF-κB activation. Furthermore, AMP-IBP5-induced VEGF but not IL-8 production correlated with an increase in intracellular cAMP. CONCLUSIONS: Our findings suggest that in addition to its antimicrobial function, AMP-IBP5 might contribute to wound healing process through activation of keratinocytes.

Friends or Foes? Host defense (antimicrobial) peptides and proteins in human skin diseases.

Host defense peptides/proteins (HDPs), also known as antimicrobial peptides/proteins (AMPs), are key molecules in the cutaneous innate immune system. AMPs/HDPs historically exhibit broad-spectrum killing activity against bacteria, enveloped viruses, fungi and several parasites. Recently, AMPs/HDPs were shown to have important biological functions, including inducing cell proliferation, migration and differentiation; regulating inflammatory responses; controlling the production of various cytokines/chemokines; promoting wound healing; and improving skin barrier function. Despite the fact that AMPs/HDPs protect our body, several studies have hypothesized that these molecules actively contribute to the pathogenesis of various skin diseases. For example, AMPs/HDPs play crucial roles in the pathological processes of psoriasis, atopic dermatitis, rosacea, acne vulgaris, systemic lupus erythematosus and systemic sclerosis. Thus, AMPs/HDPs may be a double-edged sword, promoting cutaneous immunity while simultaneously initiating the pathogenesis of some skin disorders. This review will describe the most common skin-derived AMPs/HDPs (defensins, cathelicidins, S100 proteins, ribonucleases and dermcidin) and discuss the biology and both the positive and negative aspects of these AMPs/HDPs in skin inflammatory/infectious diseases. Understanding the regulation, functions and mechanisms of AMPs/HDPs may offer new therapeutic opportunities in the treatment of various skin disorders.

Angiogenic peptide (AG)-30/5C activates human keratinocytes to produce cytokines/chemokines and to migrate and proliferate via MrgX receptors.

BACKGROUND: In addition to their antimicrobial activities, antimicrobial peptides, also known as host defense peptides (HDPs) activate keratinocytes; promote wound healing; and improve the skin barrier. AG-30/5C is a novel angiogenic HDP that activates various functions of fibroblasts and endothelial cells, including cytokine/chemokine production and wound healing. OBJECTIVES: To investigate whether AG-30/5C activates human keratinocytes and to examine the underlying mechanisms. METHODS: Production of cytokines/chemokines was assessed by ELISA. Expression of Mas-related G-protein coupled receptors X (MrgXs) in keratinocytes was determined by real-time PCR and Western blot. MAPK and NF-κB activation was analysed by Western blot. Cell migration was assessed by chemotaxis microchamber and in vitro wound closure assay, whereas cell proliferation was analysed using an XTT assay. RESULTS: We found that AG-30/5C was more efficient than its parent peptide AG-30 in increasing the production of various cytokines/chemokines and promoting keratinocyte migration and proliferation. Furthermore, MrgX3 and MrgX4 receptors were constitutively expressed in keratinocytes at higher levels than MrgX1 and MrgX2, and were up-regulated upon stimulation with TLR ligands. Because MrgX3 and MrgX4 siRNAs suppressed AG-30/5C-mediated cytokine/chemokine production, keratinocyte migration and proliferation, we propose that AG-30/5C utilizes these MrgXs to stimulate keratinocytes. In addition, AG-30/5C-induced activation of keratinocytes was controlled by MAPK and NF-κB pathways, as evidenced by the inhibitory effects of ERK-, JNK-, p38- and NF-κB-specific inhibitors. Indeed, we confirmed that AG-30/5C enhanced phosphorylation of MAPKs and IκB. CONCLUSIONS: Our findings provide novel evidence that AG-30/5C may be a useful therapeutic agent for wound healing by activating human keratinocytes.

Human ß-defensin-3 increases the expression of interleukin-37 through CCR6 in human keratinocytes.

BACKGROUND: Interleukin (IL)-37, a new member of the IL-1 family, is characterized as a fundamental inhibitor of innate immunity: it dampens the production of proinflammatory cytokines, protects against inflammatory and autoimmune diseases, and plays a potent immunosuppressive role in the pathogenesis of psoriasis. IL-37 is highly expressed in psoriatic skin, in which human ß-defensins (hBDs) have been detected. Although hBDs enhance the production of cytokines, including IL-1 cytokines, whether they stimulate the production of IL-37 remains unclear. OBJECTIVES: To assess the ability of hBDs to stimulate IL-37 expression/production by human keratinocytes and to determine the mechanism involved. METHODS: Real-time PCR and Western blotting were used to evaluate IL-37 expression. Caspase activities were assessed using colorimetric assay kits. A CCR6 antibody, siRNA, and caspase, Smad3, MAPK and NF-κB inhibitors were used to investigate the signaling mechanism of hBDs. RESULTS: Among the four hBDs used, only hBD-3 up-regulated the mRNA and protein expression of IL-37. The combination of TNF-α, EGF and poly (I:C) with hBD-3 synergistically enhanced the mRNA but not the protein expression of IL-37. Furthermore, hBD-3 increased the release of IL-37 into the culture supernatants. Evaluation of the signaling mechanism of hBD-3 suggested that caspases 1 and 4, Smad3, CCR6, MAPKs and NF-κB were required for hBD-3-mediated IL-37 expression. CONCLUSIONS: The finding that hBD-3 stimulates IL-37 expression, a novel target for the pathogenesis and therapy of cutaneous inflammatory diseases, provides evidence that hBDs contribute to the suppression of inflammatory and innate immune responses through the regulation of IL-37 expression.

The human cathelicidin LL-37 host defense peptide upregulates tight junction-related proteins and increases human epidermal keratinocyte barrier function.

Both psoriasis and atopic dermatitis (AD) are not only associated with an impaired stratum corneum barrier, but also with abnormal expression of the tight junction (TJ) proteins. Because host defense peptides, including LL-37, are overexpressed in lesional psoriatic skin but are downregulated in lesional AD skin, we hypothesized that LL-37 might regulate the TJ function in keratinocytes. We demonstrated that LL-37 selectively increased the expression of several claudins and occludin, and enhanced their membrane distribution. Furthermore, LL-37 elevated the transepithelial electrical resistance while reducing the paracellular permeability of keratinocyte layers, and this activity was weakened by the claudin inhibitor ochratoxin A. A characterization of the molecular mechanism underlying the regulation of the TJ barrier by LL-37 revealed that LL-37 induced the activation of the Rac1, atypical PKC, glycogen synthase kinase-3 and PI3K pathways, and the specific inhibition of these pathways reversed the LL-37-mediated regulation of TJ function. In addition, LL-37 enhanced the expression of differentiation markers under the control of ochratoxin A, suggesting an association between LL-37-induced TJ function and keratinocyte differentiation. These data provide novel evidence that, in addition to its antimicrobial and other immunoregulatory functions, LL-37 contributes to cutaneous immunity by strengthening the skin's barrier function.

Host defense (Antimicrobial) peptide, human ß-defensin-3, improves the function of the epithelial tight-junction barrier in human keratinocytes.

Human ß-defensins (hBDs) are host defense peptides that not only exhibit microbicidal properties but also stimulate various cellular activities, including keratinocyte proliferation, migration, and wound healing. hBDs are overexpressed in the skin in cases of psoriasis but are downregulated in atopic dermatitis skin, although both diseases are associated with stratum corneum barrier defects. Because the tight-junction (TJ) barrier is also dysfunctional in both atopic dermatitis and psoriasis patients, we hypothesized that hBDs may regulate the TJ barrier function in keratinocytes. We observed that, among the hBDs tested, only hBD-3 increased the expression of several claudins and their localization along the cell-cell borders. In addition, hBD-3 elevated the transepithelial electrical resistance and reduced the paracellular permeability of keratinocyte layers, and this effect was reversed by the claudin inhibitor ochratoxin A, CCR6 antibody, and CCR6 small interfering RNA. Moreover, hBD-3 enhanced the activation of Rac1, atypical protein kinase C, glycogen synthase kinase-3, and phosphatidylinositol 3 kinase, which are required for the hBD-3-mediated regulation of the TJ barrier function, as evidenced by the effects of their respective inhibitors. Collectively, our findings provide evidence regarding the contribution of host defense peptides to the innate immunity of skin by regulating TJ barrier function, in addition to their antimicrobial and other immunomodulatory activities.