An alkaloid-rich phytopharmaceutical prepared from Qing Dai against IL-17A-induced psoriasis.

ETHNOPHARMACOLOGICAL RELEVANCE: Psoriasis is a chronic inflammatory disease due to immune dysregulation that cannot be cured. The skin conditions of psoriasis negatively impact patients' quality of life worldwide. Qing Dai (Indigo Naturalis), a traditional Chinese medicine (TCM) processed from Strobilanthes cusia is a clinical medicine used for psoriasis patient in Taiwan and the gene overexpression of interleukin (IL)-17A could be notably reduced in skin lesions after using Qing Dai ointment and its alkaloid ingredients. AIM OF THE STUDY: To develop a potential anti-psoriatic phytopharmaceutical, an alkaloid-rich fraction named INM-A was prepared from Qing Dai. The chemical profile and anti-psoriatic activity of INM-A were analyzed and evaluated to define its in vitro mechanism and in vivo efficacy for psoriasis therapy. MATERIALS AND METHODS: Dowex® 50WX4 hydrogen form resin was used for column chromatography to prepare INM-A. To track alkaloids, INM-A was conducted with Dragendorff's, Mayer's, and Wagner's reagents. HPLC and UV-Vis spectrophotometer were applied to analyze the chemical profile and relative total alkaloid content in INM-A. A psoriatic mouse model induced by imiquimod (IMQ) was performed to verify in vivo efficacy of INM-A. IL-17A-dominated cellular oxygen consumption rate, oxidative stress, and cytokines in keratinocytes were measured to clarify in vitro mechanism of INM-A. RESULTS: An alkaloid-rich fraction, INM-A, consisted of seven active alkaloid compounds 1-7 was obtained from Qing Dai. INM-A improved the skin condition severities in IMQ-induced psoriatic mice and decreased IL-17A in not only psoriatic mice but also polarized Th17 cells. In addition, INM-A targeted IL-17A to inhibit inflammation and OXPHOS-driven oxidative stress in human keratinocytes. CONCLUSION: Accordingly, INM-A manufactured from Qing Dai may be a promising lead phytopharmaceutical for further IL-17A-related inflammatory disease studies such as psoriasis.

Clinical Assessment, Diagnosis, and Management of Infraorbital Wrinkles and Pigmentation.

Lower eyelid skin is unique and different from that of other areas. In addition to being an area of high exposure to the sun and elements, there are anatomic considerations and specific histologic characteristics that can cause the skin in this area to be more sensitive. These attributes can readily cause under-eye wrinkling and pigmentation. This review aims to present an updated overview of the current knowledge regarding the clinical characteristics, diagnosis, and management of wrinkles and pigmentation in this area. These disorders are usually caused by different factors, such as genetics, aging, sun exposure, lack of sleep, and stress.

Vascular Lesions.

Vascular lesions impact up to 5% of children and range in clinical impact from minor cutaneous aberrations to large masses impacting both form and function. Vascular lesions may be characterized as tumors or malformations. Establishing a clear diagnosis is imperative to understanding the natural history of a vascular lesion and developing a treatment plan. Medical, surgical, intralesional, and laser therapy are all effective and indicated on a case-by-case basis. There are a number of important surgical considerations for operative management of these lesions.

Polygonum perfoliatum L. ethanol extract ameliorates 2,4-dinitrochlorobenzene-induced atopic dermatitis-like skin inflammation.

ETHNOPHARMACOLOGICAL RELEVANCE: Polygonum perfoliatum L. (PP) is classified as a heat-clearing and detoxifying agent in traditional Chinese medicine, and is believed to possess therapeutic properties for treating eczema, furuncles, and venomous snake bites. Previous studies have demonstrated that PP extract exhibits multiple bioactivities, including antibacterial, anti-inflammatory, antitumor, antioxidation, and antiviral properties. However, no existing studies have evaluated the effects of PP on animal models of atopic dermatitis (AD)-like skin symptoms, which are closely associated with traditional ethnic usage. AIM OF THE STUDY: In present study, therefore, we aimed to explore the potential anti-atopic effect of Polygonum perfoliatum L. ethanol extract (PPE) in 2,4-Dinitrochlorobenzene (DNCB)-induced dermatitis-like skin lesions. MATERIALS AND METHODS: For reaching this aim, DNCB-induced mice with AD-like skin inflammation were subjected to topical administration of PPE gels for a period of 21 days, and subsequently, the biological impacts of PPE were evaluated. RESULTS: PPE gels effectively mitigated AD-like skin symptoms induced by DNCB in mice, as demonstrated by a marked reduction in epidermal thickness and dermatitis severity. Moreover, PPE significantly decreased the production of various cytokines, including TNF-α, IL-6, IL-1ß, IL-4, IL-5, IL-13 and IgE, in addition to suppressed the production of key inflammation-related enzymes (iNOS and COX-2) and decreased the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-κB in AD-like skin samples. Furthermore, PPE treatment inhibited the abnormally elevated CD4+/CD8+ ratio in DNCB-induced AD mice. The results of the skin irritation test revealed that PPE exhibited no adverse toxicity in mice at dose of 10 mg/day. CONCLUSIONS: PPE exhibits potential as a safe therapeutic agent for atopic dermatitis by efficiently mitigating DNCB-induced atopic symptoms and diminishing inflammation, and does not carry the risk of over-immunosuppression or treatment-associated adverse effects.

Acute generalized exanthematous pustulosis caused by hydroxychloroquine in a patient with rheumatoid arthritis and CARD14 mutation: Case report.

RATIONALE: Acute generalized exanthematous pustulosis (AGEP) is a serious adverse skin reaction characterized by the rapid appearance of densely distributed, small, sterile pustules with erythema. However, its pathogenesis is not fully understood. Hydroxychloroquine is widely used for the treatment of autoimmune diseases. Some patients presenting with AGEP have IL36RN and CARD14 gene mutations. Our report describes a patient with rheumatoid arthritis and AGEP associated with hydroxychloroquine and a newly discovered CARD14 gene mutation. PATIENT CONCERNS: A 28-year-old woman with rheumatoid arthritis, treated with leflunomide therapy without marked relief of joint pain, developed multiple rashes with pruritis covering the body 5 days after switching to hydroxychloroquine treatment. DIAGNOSES: Based on the patient's history, symptoms, and histopathological findings, AGEP was diagnosed. INTERVENTIONS: Whole-exome sequencing and Sanger validation revealed no mutations in the IL36RN gene; however, a CARD14 gene mutation was present. The patient was treated using ketotifen fumarate tablets, dexamethasone sodium phosphate, calcium gluconate injection, methylprednisolone injection, vitamins C and B12, hydrocortisone butyrate cream, Reed acne cream, potassium chloride tablets, and pantoprazole enteric-coated capsules. OUTCOMES: The rash improved after 15 days. LESSONS SUBSECTIONS: There has been little basic research on AGEP-related genetics, and the CARD14 mutation may underlie several pustular rashes, including AGEP and generalized pustular psoriasis. Follow-up studies and further accumulation of patient data are required.

Leishmanicidal and healing effects of 3ß,6ß,16ß-trihydroxy lup-20 (29)-ene isolated from Combretum leprosum on Leishmania braziliensis infection in vitro and in vivo.

Treatment of cutaneous leishmaniasis depends on drugs that potentially cause serious side effects and resistance. Thus, topical therapies are attractive alternatives to the drugs currently used. 3ß, 6ß, 16ß-trihydroxylup-20 (29)-ene is a lupane triterpene isolated from Combretum leprosum Mart. leaves (CLF-1), with reports of in vitro antileishmanial effect against L. amazonensis and to promote lesion healing in animal model. Herein, we evaluated the in vitro and in vivo antileishmanial and healing effects of CLF-1 against L. braziliensis. CLF-1 treatment showed low toxicity in macrophages and significantly reduced parasite load in vitro. CLF-1 induced higher IL-12 and TNF-α production and more discrete IL-4 and IL-10 production. For in vivo evaluation, a CLF-1 cream formulation was prepared to treat hamsters infected with L. braziliensis. CLF-1 treatment was able to reduce parasite load of the infected skin and lymph node more efficiently than the conventional treatment. Histopathological analysis indicated a strong inflammatory response accompanied by an important healing response. Data from this study indicate that topical CLF-1 treatment was effective and non-toxic in L. braziliensis infected hamsters suggesting its potential for further development as a future therapeutic intervention.

Combination of Fractional Microneedling Radiofrequency and Ablative Fractional Laser versus Ablative Fractional Laser Alone for Acne and Acne Scars.

PURPOSE: Fractional microneedle radiofrequency (FMR) systems are used to treat inflammatory acne and scarring. Nonetheless, few controlled studies have combined this treatment with the traditional ablative fractional laser (AFL). We aimed to assess the safety and efficacy of the combination of FMR and AFL versus AFL alone in treating acne and acne scars. MATERIALS AND METHODS: In this 20-week, randomized, split-face study, 23 Korean patients with facial acne and acne scars underwent FMR and AFL treatments. One half of each patient's face was randomly assigned to receive FMR+AFL, whereas the other half received AFL alone. Treatments were administered in three consecutive sessions at 4-week intervals. This study investigated the severity of inflammatory acne, acne scars, individual lesion counts, depressed scar volumes, as well as patient and physician satisfaction. In addition, five patients underwent skin biopsy, and sebum output was measured. RESULTS: The FMR+AFL treatment demonstrated superior efficacy compared to AFL alone in terms of inflammatory acne and acne scar grading, lesion counts, and subjective satisfaction. The side effects were minimal and well-tolerated in both groups. Immunohistochemical findings from skin biopsy samples revealed that the application of FMR+AFL could induce an inhibitory effect on sebum secretion at the molecular level. CONCLUSION: FMR combined with AFL is a well-tolerated and effective treatment modality for inflammatory acne and acne scarring.

Effects of Magnoliae Flos on Atopic Dermatitis-Like Inflammation Evaluated via Extracellular Signal-regulated Kinase or Signal Transducers and Activators of Transcription 1/3 Signalling Pathways.

Atopic dermatitis is a chronic inflammatory skin  disease. Skin is the largest organ and plays a pivotal role in protecting the body. Not only does the skin act as a physical barrier against the external environment, but it also has its own immune system. Atopic dermatitis is caused by prolonged excessive inflammatory responses that worsen under imbalanced cutaneous immune system skin conditions. Although the prevalence and burden of atopic dermatitis is increasing, the standard therapeutic agents remain unclear due to  the complicated pathophysiology of the condition. The objective of this study is to examine the use of Magnoliae flos, the dried flower bud of Magnolia biondii or  related plants. The effects and underlying mechanism of  action of aqueous extract of the buds of Magnoliae flos (MF) were evaluated. Immortalized human keratinocytes (HaCaT) stimulated with tumour necrosis factor-α and interferon-γ mixture and NC/Nga mice stimulated with 2,4-dinitrochlorobenzene were used as atopic dermatitis models, in vitro and in vivo, respectively. The effects of MF were determined by measuring the suppression of pro-inflammatory signalling pathways, such as extracellular signal-regulated kinase or signal transducers and activators of transcription 1/3 and restoring skin barrier molecules. In conclusion, MF is a potential therapeutic alternative for the treatment of atopic dermatitis through repressing inflammatory pathways.

Extensive fatal Pyoderma gangrenosum in a dog after drug exposure.

A 4-year-old, spayed female mixed breed dog was presented with large crater-like, well-demarcated, erosive and ulcerative necrotic lesions of the skin, elevated body temperature and lethargy, that began 14 days after vaccination and treatment with fluralaner and milbemycin/praziquantel. Cytology revealed severe pyogranulomatous inflammation with moderate numbers of extracellular microorganisms. Histopathologic examination showed severe multifocal pyogranulomatous dermatitis and panniculitis with severe dermal edema and severe neutrophilic exocytosis with band-like infiltration of the lower portion of the epidermis consistent with pyoderma gangrenosum. Despite intensive immunosuppressive and antimicrobial therapy and intensive inpatient care, the dog was euthanized 16 days after admission due to complications with clinical signs of sepsis, acute dyspnea and thoracic effusion.

The roles of T cells in psoriasis.

Psoriasis is a recurring inflammatory skin condition characterized by scaly, red patches on the skin. It affects approximately 3% of the US population and is associated with histological changes such as epidermal hyperplasia, increased blood vessel proliferation, and infiltration of leukocytes into the skin's dermis. T cells, which are classified into various subtypes, have been found to play significant roles in immune-mediated diseases, particularly psoriasis. This paper provides a review of the different T lymphocyte subtypes and their functions in psoriasis, as well as an overview of targeted therapies for treating psoriasis.

Brown adipose tissue transplantation improves skin fibrosis in localized scleroderma.

Adipose tissue transplantation shows great therapeutic potential in reversing localized scleroderma-associated skin fibrosis. Brown adipose tissue (BAT) can specifically secrete various cytokines against fibrosis, but its therapeutic potential in improving skin fibrosis has not yet been demonstrated. In this study, we have demonstrated the superior therapeutic efficacy of BAT transplantation for sclerotic skin by transplanting two distinct types of adipose tissue. In comparison to the white adipose tissue (WAT) group, mice treated with BAT transplantation exhibited a significant reduction in dermal thickness. BAT transplantation effectively reverses skin sclerosis through mechanisms involving inflammation reduction, promotion of angiogenesis, inhibition of myofibroblast accumulation, and collagen deposition. This therapeutic effect can be attributed to its unique paracrine effects. Furthermore, transcriptome sequencing (RNA-Seq) revealed upregulation of pathways associated with lipogenesis and fatty acid metabolism in BAT while downregulating pathways are related to transforming growth factor ß(TGF-ß), epithelial-mesenchymal transition (EMT), and inflammatory response. These findings suggest that BAT transplantation holds great promise as a novel approach for localized scleroderma treatment.

Effects of photobiomodulation with blue Light Emitting Diode (LED) on the healing of skin burns.

The management of skin burns is still challenging. Among the therapeutic methods used, there are topical treatments with pharmacological and herbal agents, low-intensity therapeutic ultrasound, use of biomaterials, reconstructive techniques and photobiomodulation therapy. The aim of this study was to evaluate the effects of photobiomodulation with blue Light Emitting Diode (LED) on burn healing. Fifty Wistar rats were divided into control (CTRL) (n = 25) and blue LED (LED) (n = 25), with subgroups (n = 5) for each time of euthanasia (7, 14, 21, 28 and 32 days). Treated animals were daily irradiated (470 nm, 1W, 0.44 W/cm2, 50 J/cm2). Clinical evaluations were performed and the Wound Retraction Index (WRI) was determined. Histological sections were submitted to hematoxylin-eosin, toluidine blue and the immunohistochemical technique, with anti-α-SMA and anti-TGF-ß1 antibodies. All data were directly collected by previously calibrated evaluators in a blind manner. The values were included in a statistical program. For all statistical tests used, 5% significance level (p < 0.05) was considered. No statistically significant differences in WRI between groups were observed (p > 0.05). Re-epithelialization was higher using LED at 7 and 14 days (p < 0.05) and greater amount of inflammatory cells was observed at 7 days (p = 0.01). With LED at 21 and 32 days, greater number of mast cells were observed (p < 0.05), as well as smaller number of myofibroblasts at 14, 21, 28 and 32 days (p < 0.05) and lower percentage of TGF-ß1 positive cells in the conjunctiva at 7, 14 and 21 days (p < 0.05). Negative correlations were observed in LED between the percentage of TGF-ß1 in the epithelium and the mean number of inflammatory cells and number of myofibroblasts (p < 0.05). The results suggest that, depending on the period, blue LED can modulate the healing processes of third-degree skin burns, such as re-epithelialization, inflammatory response, mast cell concentration, myofibroblast differentiation and TGF-ß1 immunoexpression. Despite these effects, this therapy does not seem to have significant influence on the retraction of these wounds. Future studies, using different protocols, should be carried out to expand the knowledge about the photobiomodulatory mechanisms of this type of light in the healing process.

Progesterone hypersensitivity: a cyclical history.

Hypersensitivity reaction to progesterone is rare, with less than 200 cases reported. It occurs mainly in women in their third decade of life and can have a heterogeneous presentation (cutaneous and/or systemic), with temporal relation to serum levels of progesterone. Diagnosis is based on history and physical examination, supported by skin tests. We describe the case of a woman in her late 20s with pruritic erythema on the chest that manifested in the luteal phase of the menstrual cycle, with spontaneous resolution in less than 5 days, without secondary scarring. The histological diagnosis was non-specific, with evidence of interface dermatitis, but positive skin tests supported the diagnosis of autoimmune progesterone dermatitis. It is intended to alert to the manifestations of a pathology that is rare and difficult to diagnose but with a great impact on daily life.

Canine Models of Inflammatory Skin Diseases and Their Application in Pharmacological Research.

The purpose of this article is to provide an overview of existing pharmacological models of canine dermatitis. Canine models of dermatitis have contributed significantly to our current understanding of the pathology of dermatitis and to the development of corresponding pharmacological interventions. Specifically, canine atopic dermatitis (AD) is reviewed here, as it is one of the most common inflammatory skin diseases in dogs. Canine AD also shares clinicopathological features with human AD, making the dog a natural and optimal model for human disease. Thus, pharmacological models of canine AD may be uniquely applicable to human pharmacological research. In this article, particular attention is dedicated to relevant in vivo, in vitro, and ex vivo models of canine AD, skin barrier defect models, pruritus models, and skin immunology models. Additionally, models of superficial pyoderma and food allergy are also discussed. With understanding of findings from canine models, researchers can select the most salient features for future pharmacological drug development. © 2023 Wiley Periodicals LLC.

A Chitosan-Based Biomaterial Combined with Mesenchymal Stem Cell-Conditioned Medium for Wound Healing and Skin Regeneration.

The aim of this study was to provide a beneficial treatment effect of novel chitosan bio-polymeric material enriched with mesenchymal stem cell products derived from the canine adipose tissue (AT-MSC) on the artificial skin defect in a rabbit model. For the objectivity of the regeneration evaluation, we used histological analysis and a scoring system created by us, taking into account all the attributes of regeneration, such as inflammatory reaction, necrosis, granulation, formation of individual skin layers and hair follicles. We observed an acceleration and improvement in the healing of an artificially created skin defect after eight and ten weeks in comparison with negative control (spontaneous healing without biomaterial). Moreover, we were able to described hair follicles and epidermis layer in histological skin samples treated with a chitosan-based biomaterial on the eighth week after grafting.

Approach to the so-called "Invisible Dermatosis": When Subtle Histopathological Findings Guide Diagnosis.

ABSTRACT: Invisible dermatosis is a concept that can be applied either to clinical or histopathological findings. We will focus on the dermatopathological aspect of this invisible dermatosis that can be seen as dermatosis with subtle histopathological findings that are mandatory to known to stablish the diagnosis. With a proper approach facing in depth the different skin layers from stratum corneum to subcutaneous tissue combined with some especial stains, special investigations and mostly a proper clinicopathological correlation, the problem of missing out a diagnosis can be decreased. We will review the general aspects for diagnosis and the peculiar findings of an in-depth review of them because it is important to note that minor changes on a skin biopsy do not mean it is disease free. We will review classic clues, we will add some new useful ones, and we will also provide a guide on the special stains helpful, such as periodic acid-Schiff when facing fungi, orcein-Giemsa and van Gieson when altered elastic fibers are suspected, or Pearl and Masson Fontana when an altered skin pigmentation is suspected.

Scars.

Wound healing occurs as a response to disruption of the epidermis and dermis. It is an intricate and well-orchestrated response with the goal to restore skin integrity and function. However, in hundreds of millions of patients, skin wound healing results in abnormal scarring, including keloid lesions or hypertrophic scarring. Although the underlying mechanisms of hypertrophic scars and keloid lesions are not well defined, evidence suggests that the changes in the extracellular matrix are perpetuated by ongoing inflammation in susceptible individuals, resulting in a fibrotic phenotype. The lesions then become established, with ongoing deposition of excess disordered collagen. Not only can abnormal scarring be debilitating and painful, it can also cause functional impairment and profound changes in appearance, thereby substantially affecting patients' lives. Despite the vast demand on patient health and the medical society, very little progress has been made in the care of patients with abnormal scarring. To improve the outcome of pathological scarring, standardized and innovative approaches are required.

Crosstalk: keratinocytes and immune cells in psoriasis.

In the past, psoriasis was considered a skin disease caused only by keratinocyte disorders. However, the efficacy of immunosuppressive drugs and biologics used to treat psoriasis proves that psoriasis is an immune-mediated disease. Indeed, a variety of immune cells are involved in the pathogenesis of psoriasis, including dendritic cells, Th17 cells, and resident memory T cells. Furthermore, keratinocytes play a role in the development of psoriasis as immune cells by secreting antibacterial peptides, chemokines, tumor necrosis factor-α, interleukin (IL)-36, and IL-23. These immune cells and skin cells interact and drive the aberrant differentiation and proliferation of keratinocytes. This crosstalk between keratinocytes and immune cells critical in the pathogenesis of psoriasis forms an inflammatory loop, resulting in the persistence or exacerbation of psoriasis plaques.

In the skin lesions of patients with mycosis fungoides, the number of MRGPRX2-expressing cells is increased and correlates with mast cell numbers.

Background: Mycosis fungoides (MF) is an indolent T-cell lymphoma that mainly affects the skin and presents with itch in more than half of the patients. Recently, the expression of Mas-related G protein-coupled receptor X2 (MRGPRX2), a receptor of mast cell (MC) responsible for the IgE-independent non-histaminergic itch, has been shown in lesional skin of patients with pruritic skin diseases, including chronic urticaria, prurigo, and mastocytosis. As of yet, limited knowledge exists regarding the MRGPRX2 expression in the skin of patients with MF. Objectives: To investigate the number of MRGPRX2-expressing (MRGPRX2+) cells in the skin of patients with MF and its correlation with clinical and laboratory characteristics of the disease. Methods: MRGPRX2 was analyzed in lesional and non-lesional skin of MF patients and healthy skin tissues by immunohistochemistry. Co-localization of MRGPRX2 with the MC marker tryptase was assessed by immunofluorescence. Public single-cell RNAseq data was reanalyzed to identify the MRGPRX2 expression on the distinct cell types. Results: In lesional skin of MF patients, MRGPRX2+ cell number was higher than in non-lesional skin and healthy control skin (mean:15.12 vs. 6.84 vs. 5.51 cells/mm2, p=0.04), and correlated with MC numbers (r=0.73, p=0.02). MC was the primary cell type expressing MRGPRX2 in MF patients. The ratio of MRGPRX2+ MCs to MRGPRX2+ cells in lesional and non-lesional skin correlated with the severity of disease (r=0.71, p=0.02 and r=0.67, p=0.03, respectively). Conclusions: Our findings point to the role of MRGPRX2 and MC in the pathogenesis of MF that should be investigated in further studies.