Skin Aging and the Upcoming Role of Ferroptosis in Geroscience.

The skin is considered the most important organ system in mammals, and as the population ages, it is important to consider skin aging and anti-aging therapeutic strategies. Exposure of the skin to various insults induces significant changes throughout our lives, differentiating the skin of a young adult from that of an older adult. These changes are caused by a combination of intrinsic and extrinsic aging. We report the interactions between skin aging and its metabolism, showing that the network is due to several factors. For example, iron is an important nutrient for humans, but its level increases with aging, inducing deleterious effects on cellular functions. Recently, it was discovered that ferroptosis, or iron-dependent cell death, is linked to aging and skin diseases. The pursuit of new molecular targets for ferroptosis has recently attracted attention. Prevention of ferroptosis is an effective therapeutic strategy for the treatment of diseases, especially in old age. However, the pathological and biological mechanisms underlying ferroptosis are still not fully understood, especially in skin diseases such as melanoma and autoimmune diseases. Only a few basic studies on regulated cell death exist, and the challenge is to turn the studies into clinical applications.

Advances in the human skin microbiota and its roles in cutaneous diseases.

Skin is the largest organ in the human body, and the interplay between the environment factors and human skin leads to some skin diseases, such as acne, psoriasis, and atopic dermatitis. As the first line of human immune defense, skin plays significant roles in human health via preventing the invasion of pathogens that is heavily influenced by the skin microbiota. Despite being a challenging niche for microbes, human skin is colonized by diverse commensal microorganisms that shape the skin environment. The skin microbiota can affect human health, and its imbalance and dysbiosis contribute to the skin diseases. This review focuses on the advances in our understanding of skin microbiota and its interaction with human skin. Moreover, the potential roles of microbiota in skin health and diseases are described, and some key species are highlighted. The prevention, diagnosis and treatment strategies for microbe-related skin diseases, such as healthy diets, lifestyles, probiotics and prebiotics, are discussed. Strategies for modulation of skin microbiota using synthetic biology are discussed as an interesting venue for optimization of the skin-microbiota interactions. In summary, this review provides insights into human skin microbiota recovery, the interactions between human skin microbiota and diseases, and the strategies for engineering/rebuilding human skin microbiota.

Recent advances on topical antimicrobials for skin and soft tissue infections and their safety concerns.

Antimicrobial resistance of disease-related microorganisms is considered a worldwide prevalent and serious issue which increases the failure of treatment outcomes and leads to high mortality. Considering that the increased resistance to systemic antimicrobial therapy often needs of the use of more toxic agents, topical antimicrobial therapy emerges as an attractive route for the treatment of infectious diseases. The topical antimicrobial therapy is based on the absorption of high drug doses in a readily accessible skin surface, resulting in a reduction of microbial proliferation at infected skin sites. Topical antimicrobials retain the following features: (a) they are able to escape the enzymatic degradation and rapid clearance in the gastrointestinal tract or the first-pass metabolism during oral administration; (b) alleviate the physical discomfort related to intravenous injection; (c) reduce possible adverse effects and drug interactions of systemic administrations; (d) increase patient compliance and convenience; and (e) reduce the treatment costs. Novel antimicrobials for topical application have been widely exploited to control the emergence of drug-resistant microorganisms. This review provides a description of antimicrobial resistance, common microorganisms causing skin and soft tissue infections, topical delivery route of antimicrobials, safety concerns of topical antimicrobials, recent advances, challenges and future prospective in topical antimicrobial development.

Lobomycosis-like disease in common bottlenose dolphins Tursiops truncatus from Belize and Mexico: bridging the gap between the Americas.

Lobomycosis and lobomycosis-like diseases (LLD) (also: paracoccidioidomycosis) are chronic cutaneous infections that affect Delphinidae in tropical and subtropical regions worldwide. In the Americas, these diseases have been relatively well-described, but gaps still exist in our understanding of their distribution across the continent. Here we report on LLD affecting inshore bottlenose dolphins Tursiops truncatus from the Caribbean waters of Belize and from the eastern tropical Pacific Ocean off the southwestern coast of Mexico. Photo-identification and catalog data gathered between 1992 and 2017 for 371 and 41 individuals, respectively from Belize and Mexico, were examined for the presence of LLD. In Belize, 5 free-ranging and 1 stranded dolphin were found positive in at least 3 communities with the highest prevalence in the south. In Guerrero, Mexico, 4 inshore bottlenose dolphins sighted in 2014-2017 were affected by LLD. These data highlight the need for histological and molecular studies to confirm the etiological agent. Additionally, we document a single case of LLD in an adult Atlantic spotted dolphin Stenella frontalis in southern Belize, the first report in this species. The role of environmental and anthropogenic factors in the occurrence, severity, and epidemiology of LLD in South and Central America requires further investigation.

Cutaneous histiocytoid Sweet syndrome and its relationship to hematological diseases.

Sweet syndrome (SS) was described over 50 years ago as a distinctive form of neutrophilic dermatosis. It may be idiopathic, drug-induced or paraneoplastic, and in the last of those subtypes, myeloproliferative diseases are prominently represented. A peculiar variant of SS is termed 'histiocytoid' SS (HSS), and early accounts of that condition asserted that it showed no linkage to hematological disorders. We herein report two additional cases of HSS--both of which were associated with myeloid dyscrasias--together with a review of the pertinent literature. Along with our observations, the latter process appears to contradict the contention that HSS has no relationship to hematopoietic diseases; between 35 and 55% of reported cases have indeed shown such an association, usually with myelogenous leukemia or myelodysplastic syndromes.

Inflammatory Cutaneous Diseases in Renal Transplant Recipients.

Kidney transplant recipients frequently suffer from skin infections and malignancies, possibly due to the effects of long-term immunosuppressive therapy. While the relationships between immunosuppression and these pathological conditions have been widely investigated, little is known about the relative incidence and characteristics of inflammatory skin diseases in this type of patient. In this study, we analyze the incidence of a number of inflammatory cutaneous diseases in a cohort of patients who underwent kidney transplantation. Although our study shows a relatively low incidence of these pathologies in transplanted patients-in agreement with the general action of immunosuppressant therapies in reducing inflammation-we scored a different efficacy of the various immunosuppressive regimens on inflammatory and autoimmune skin diseases. This information can be key for designing immunosuppressive regimens and devising accurate follow-up protocols.

Phototherapy in dermatology: A call for action.

Of the wide range of treatment modalities available to dermatologists, few possess the history, efficacy, and safety of phototherapy. It should be emphasized that dermatologists are the only group of physicians optimally trained and qualified to understand the medical indications of phototherapy. Phototherapy, recognized for its cost-effectiveness, should remain a consideration in patient treatment. Continued training and education in residency and thereafter is needed to maintain the proficiency of physicians. In addition, payors need continued education to ensure that insurance coverage of phototherapy is not a barrier for patients to access this therapy. To further improve and optimize the outcome, phototherapy research needs to be supported.

Clinicopathologic correlation of dermatologic diseases in patients with darker pigmentation.

OBJECTIVES: Cutaneous diseases that disproportionately affect patients with darker pigmentation and their histologic features are historically understudied and undertreated. This review article aims to highlight the key clinical features, histopathology, and diagnostic pearls of several cutaneous diseases that commonly present in patients with darker pigmentation. METHODS: A literature search was conducted, and a list of cutaneous diseases that frequently affect patients with darker pigmentation was compiled. A group of experts expounded upon those that were most common or misdiagnosed according to scientific evidence and clinical practice. RESULTS: The diseases were divided into hypopigmented disorders, hyperpigmented disorders, scarring disorders, and alopecic disorders. Within each category, the etiology, clinical features, histopathology, and key histologic differential diagnoses are described and discussed. CONCLUSIONS: As many clinicians are taught that there are no effective treatment options or that these diseases are considered "cosmetic" in nature, patients often do not get a thorough medical workup or skin biopsy. This article aims to decrease the knowledge gap and serve as a resource for anyone involved in the care of patients with these cutaneous conditions.

Development of a Clioquinol Nanocarrier as a New, Promising Option for the Treatment of Dermatomycosis.

Dermatomycosis is a common fungal infection, and its treatment is limited by few antifungal agents. Clioquinol (CQ) is an antiparasitic agent that has been studied for new uses, such as antifungal and antiviral applications. CQ was incorporated into a lipid-based nanocarrier as a new, promising option for dermatomycosis. This study aimed to develop a CQ-loaded lipid-based nanocarrier for cutaneous application and to evaluate its antifungal activity. CQ-loaded nanoformulation (LBN-CQ) was developed using the ultrasonication method, and the particle size, polydispersity index (PDI), pH, zeta potential, and drug content were monitored for 45 days. To evaluate antifungal activity, broth microdilution and a time-kill assay were performed. LBN-CQ presented a particle size of 91 ± 3 nm and PDI of 0.102 ± 0.009. The zeta potential and pH values were -9.7 ± 2.0 mV and 6.0 ± 0.1, respectively. The drug content was 96.4 ± 2.3%, and the encapsulation efficiency was 98.4%. LBN-CQ was able to reduce the minimum inhibitory concentration (MIC) in a 2-fold or 4-fold manner in most of the tested strains. Additionally, LBN-CQ presented stable fungistatic action that was not concentration- or time-dependent. In conclusion, the developed CQ-loaded nanocarrier is a promising treatment for skin fungal infections and a promising candidate for future randomized clinical trials.

A Wall Fragment of Cutibacterium acnes Preserves Junctional Integrity Altered by Staphylococcus aureus in an Ex Vivo Porcine Skin Model.

(1) Background alteration of the skin microbiota, dysbiosis, causes skin barrier impairment resulting in disease development. Staphylococcus aureus, the main pathogen associated with dysbiosis, secretes several virulence factors, including α-toxin that damages tight junctions and compromises the integrity of the skin barrier. The use of members of the resident microbiota to restore the skin barrier, bacteriotherapy, represents a safe treatment for skin conditions among innovative options. The aim of this study is the evaluation of a wall fragment derived from a patented strain of Cutibacterium acnes DSM28251 (c40) alone and conjugated to a mucopolysaccharide carrier (HAc40) in counteracting S. aureus pathogenic action on two tight junction proteins (Claudin-1 and ZO-1) in an ex vivo porcine skin infection model. Methods: skin biopsies were infected with live S. aureus strains ATCC29213 and DSM20491. Tissue was pre-incubated or co-incubated with c40 and HAc40. (3) Results: c40 and HAc40 prevent and counteract Claudin-1 and Zo-1 damage (4) Conclusions: c40 and the functional ingredient HAc40 represent a potential non-pharmacological treatment of skin diseases associated with cutaneous dysbiosis of S. aureus. These findings offer numerous avenues for new research.

Mucocutaneous Manifestations in Kidney Transplant Patients: Risk Factors.

Introduction Mucocutaneous complications in kidney transplant patients are due to drug toxicity or immunosuppression. The main objective of our study was to determine the risk factors associated with their occurrence. Methods We conducted a prospective analytical study (January 2020- June 2021) including kidney transplant patients seen at the Nephrology Department. We described the characteristics of the patients who presented mucocutaneous complications and then compared them to those who didn't to deduce the risk factors. Statistical analysis was performed using SPSS 20.0 (p<0.05). Results Of the 86 patients recruited, thirty patients had mucocutaneous complications. The mean age was 42.73, with a male predominance (73%). Ten kidney transplants were performed from a living-related donor. All the patients received corticosteroids, Mycophenolate Mofetil, and the Calcineurin Inhibitor: Tacrolimus (76.7%) or Ciclosporin (23.3%). Induction was performed with Thymoglobulin (n=20) or Basiliximab (n=10). Mucocutaneous complications were dominated by infectious manifestations (53.4%): eight cases of fungal infections; six cases of viral infections: warts (n=3), herpes labialis (n=2), intercostal herpes zoster (n=1), and two cases of bacterial infections: atypical mycobacteria and boils. Inflammatory complications (36.6%) included acne (n=4), urticaria (n=3), rosacea (n=1), simple maculopapular exanthema (n=1), aphthous lesion (n=1), and black hairy tongue (n=1). Actinic keratosis, skin xerosis, and bruises were found in one patient respectively. The evolution with a symptomatic treatment was good in all the patients. After statistical analysis, the factors significantly associated with the occurrence of mucocutaneous complications were advanced age, male gender, anemia, HLA non-identical donor, as well as the use of Tacrolimus or Thymoglobulin. Conclusion Infectious mucocutaneous complications are the most common dermatological manifestations among renal transplant recipients. Their occurrence is related to advanced age, male gender, anemia, HLA non-identical donor, and the use of Tacrolimus or Thymoglobulin.

The Role of VD/VDR Signaling Pathway in Autoimmune Skin Diseases.

BACKGROUND: Immune-related cutaneous diseases are a series of disorders, such as alopecia areata, psoriasis, atopic dermatitis, systemic lupus erythematosus and autoimmune bullous dermatoses. Vitamin D is a fat-soluble vitamin, which is known for its classical pleiotropic effect. Recent studies have found that vitamin D, after catalyzed into its biologically active form [1,25(OH) 2D], correlated with its receptor, vitamin D receptor, plays a vital role in multiple pathophysiological processes, including immune-related dermatoses. This review mainly summarizes evidence on the role of vitamin D/vitamin D receptor in immune-related cutaneous diseases and the potential therapeutic targets for skin disorders. METHODS: We have carried out a comprehensive literature search in PubMed and Google Scholar databases using keywords like "vitamin D", "vitamin D receptor", "immune", "psoriasis", "atopic dermatitis", "skin", "systemic lupus erythematosus", "alopecia areata" and "autoimmune bullous dermatoses". Only articles related to the topic were included in this review. Conference, patent, graduation thesis and articles without available full text were excluded. RESULTS: Vitamin D/vitamin D receptor is critical for skin in regulating the proliferation and differentiation of keratinocytes, keeping the integrity of the skin barrier as well as maintaining the homeostasis of the "skin's immune system". Vitamin D deficiency/vitamin D receptor mutations are potential risk factors for some immune-related cutaneous diseases. CONCLUSION: Vitamin D is a pleiotropic hormone, which is important in the homeostasis of human body. Many studies have revealed vitamin D deficiency in several skin diseases. Thus, vitamin D supplementation may be a useful therapeutic option for immune-related skin diseases.

Remembering Karl Gustav Theodor Simon (1810-1857).

Karl Gustav Theodor Simon is considered as the founder of dermatopathology, because for the first time in modern times he beds the bases of the microscopical examination of the cutaneous diseases. He worked in Berlin as a private physician, general practitioner, especially for the poor patients, continuing his research in pathology and focusing on the cutaneous diseases, in which the use of the microscope had a central role. During his medical career, he achieved to be acknowledged as one of the most important figures in the treatment of cutaneous diseases and to be included among the best dermatologists and venerologists at the time worldwide.

Dermatological Opportunistic Infections in HIV Seropositive Patients: An Observational Study.

Background and objective In developing countries, the dermatological manifestation of the human immunodeficiency virus (HIV) has a high prevalence. Apart from the systemic infection that ensues HIV, skin manifestations form a major part of the disease burden. They can present with atypical forms, and necessary tools for diagnosis may not be available in rural and remote parts of the country. Hence, they can stay misdiagnosed or undiagnosed, contributing to the morbidity of the patients. We attempted to enumerate the dermatologic opportunistic infections (OIs) in Rajkot city, Gujarat, India, in order to disseminate knowledge regarding the same.  Material and methods It is a retrospective observational study. A total of 253 patients under treatment for HIV/acquired immunodeficiency syndrome (AIDS) at the ART Center (anti-retroviral therapy center) from 2011 to 2019 were included. The data recorded in the registry during the above-mentioned period were utilized in the study. The diagnoses of OIs were made clinically by multiple health care providers experienced in the field. Result Two hundred twenty-seven (227) of 253 (89.72%) of the patients had some form of dermatologic OI during the course of their treatment. Overall, fungal infections (33.03%) were most common, followed by bacterial infections (28.18%) and viral (14.55%) infections. Among the non-infectious causes, cheilitis/angular stomatitis topped the list. Among the STDs, herpes was the most common skin manifestation seen with a 10.57% prevalence. The CD4+ cell count for fungal infection ranged from 353-467 and was seen in stage 2 of the disease course. Bacterial infections were seen mainly during the early and middle stages of the disease while viral infections were most prevalent in stage 2 of the disease. Conclusion Skin manifestations can be useful clinical predictors of the disease stage, especially in resource-limited settings and in developing countries. They can present with unusual and atypical forms. Hence, knowledge about the prevalence of these OIs in a particular geographical area can be very useful for physicians in treating them and decreasing the disease burden.

Male Sexual Health and Reproduction in Cutaneous Immune-Mediated Diseases: A Systematic Review.

INTRODUCTION: Information about the possible effects of cutaneous immune-mediated diseases (cIMDs) on male sexual function and reproduction is scarce. Factors known to impair sexual health and reproduction, such as inflammation, medication use, and hypogonadism, can be present in a significant proportion of male patients with cIMD. OBJECTIVES: To systematically review the literature for the influence of paternal cIMD on many aspects of male sexual and reproductive health, such as sexual function, reproductive hormones, fertility, and pregnancy and offspring outcomes. METHODS: A systematic literature search was performed. The searches combined keywords regarding male sexual function and fertility, pregnancy outcomes, and offspring's health with a list of cIMDs. RESULTS: The majority of the identified studies included patients with psoriasis (22 of 27), and sexual function was the most common outcome of interest (20 of 27). For patients diagnosed with psoriasis, the prevalence of male sexual dysfunction reported in these studies ranged from 34 to 81%. Hypogonadism in patients with psoriasis was reported in 2 of 3 studies. Sperm analysis abnormalities in patients with psoriasis were reported in 3 of 4 studies. No information about the effect of paternal disease on pregnancy and offspring outcomes was identified. CONCLUSIONS: Disease activity in psoriasis might play an important role in the development of sexual dysfunction, hypogonadism, and abnormal sperm quality. For the other cIMD included in this review, there is insufficient information regarding male sexual and reproductive health to draw firm conclusions. More research is needed to understand the association between cIMD and impaired male sexual and reproductive health. Perez-Garcia LF, Dolhain R, te Winkel B, et al. Male Sexual Health and Reproduction in Cutaneous Immune-Mediated Diseases: A Systematic Review. Sex Med Rev 2021;9:423-433.

Tuberous sclerosis with negative genetic testing and multiple cerebral cavernomas: A new association (Case report).

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder with multisystemic involvement usually resulting from mutations in the tuberous sclerosis 1 (TSC1) or TSC2 genes. However, 10 to 25% of patients do not exhibit these mutations. Cerebral cavernous malformations (CCMs) are capillary-venous malformations that can be asymptomatic or cause variable neurological manifestations, including seizures. Familial CCMs are recognized. In both conditions, specific dermatological lesions are associated. We present the case of a 31-year-old female with TSC diagnosed at the age of 18 years who presented with negative genetic testing. She was admitted to our department in 2019 for a sudden increased frequency of focal seizures. Patient examination revealed multiple facial and intraoral angiofibroma, diplopia, right hemihypoesthesia, brisk deep tendon reflexes, and distal leg paresthesia. VideoEEG indicated a frontal paramedian epileptogenic focus. Cerebral magnetic resonance imaging (MRI) and angioMRI identified multiple fronto-parietal cortical tubers, as well as multiple CCMs, with evidence of bleeding in one. Under antiepileptic drug (AED) and mTOR inhibitor treatment, the seizure frequency significantly improved in a short period of time. This is the first reported case of tuberous sclerosis with negative genetic testing associated with multiple cerebral cavernoma. Such complex patients require multidisciplinary management and detailed genetic testing for increasing knowledge on neuro-cutaneous disorders.

Skin microbiota in health and disease: From sequencing to biology.

Microbiota live in a closely regulated interaction with their environment, and vice versa. The presence and absence of microbial entities is greatly influenced by features of the niche in which they thrive. Characteristic of this phenomenon is that different human skin sites harbor niche-specific communities of microbes. Microbial diversity is considerable, and the current challenge lies in determining which microbes and (corresponding) functionality are of importance to a given ecological niche. Furthermore, as there is increasing evidence of microbial involvement in health and disease, the need arises to fundamentally understand microbiome processes for application in health care, nutrition and personal care products (e.g. diet, cosmetics, probiotics). This review provides a current overview of state-of-the-art sequencing-based techniques and corresponding data analysis methodology for profiling of complex microbial communities. Furthermore, we also summarize the existing knowledge regarding cutaneous microbiota and their human host for a wide range of skin diseases.

Non-animal models in dermatological research.

Despite widely used for basic and preclinical studies in dermatology, available animal models only partly recapitulate human skin features often leading to disappointing outputs when preclinical results are translated to the clinic. Therefore, the need to develop alternative, non-animal models is widely recognized to more closely recapitulate human skin pathophysiology and to address the pressing ethical demand of reducing the number of animals used for research purposes, following the globally accepted 3Rs principle (Replacement, Reduction and Refinement). Skin is the outermost organ of the body, and, as such, easily accessible. Different skin cell types can be propagated in vitro and skin can be reconstructed for therapeutic transplantation as well as for in vitro modeling of physiopathological conditions. Bioengineered skin substitutes have been developed and evolved from elementary to complex systems, more and more closely resembling complete skin architecture and biological responses. In silico analyses take advantage from the huge amount of data already available from human studies for identifying and modeling molecular pathways involved in skin pathophysiology without further animal testing. The present review recapitulates the available non-animal models for dermatological research and sheds lights on their prospective technological evolution.

The contribution of interleukin-2 to effective wound healing.

Ineffective skin wound healing is a significant source of morbidity and mortality. Roughly 6.5 million Americans experience chronically open wounds and the cost of treating these wounds numbers in the billions of dollars annually. In contrast, robust wound healing can lead to the development of either hypertrophic scarring or keloidosis, both of which can cause discomfort and can be cosmetically undesirable. Appropriate wound healing requires the interplay of a variety of factors, including the skin, the local microenvironment, the immune system, and the external environment. When these interactions are perturbed, wounds can be a nidus for infection, which can cause them to remain open an extended period of time, or can scar excessively. Interleukin-2, a cytokine that directs T-cell expansion and phenotypic development, appears to play an important role in wound healing. The best-studied role for Interleukin-2 is in influencing T-cell development. However, other cell types, including fibroblasts, the skin cells responsible for closing wounds, express the Interleukin-2 receptor, and therefore may respond to Interleukin-2. Studies have shown that treatment with Interleukin-2 can improve the strength of healed skin, which implicates Interleukin-2 in the wound healing process. Furthermore, diseases that involve impaired wound healing, such as diabetes and systemic lupus erythematosus, have been linked to deficiencies in Interleukin-2 or defects Interleukin-2-receptor signaling. The focus of this review is to summarize the current understanding of the role of Interleukin-2 in wound healing, to highlight diseases in which Interleukin-2 and its receptor may contribute to impaired wound healing, and to assess Interleukin-2-modulating approaches as potential therapies to improve wound healing.