Skin Cleansing without or with Compromise: Soaps and Syndets.

Products designed to cleanse the skin commonly do so through surfactant action, which leads to the lowering of the surface tension of the skin to facilitate the removal of dirt from its surface. Skin cleansers generally come in one of two types: soap-based and synthetic detergents, or syndets. While the latter can effectively maintain the native skin structure, function and integrity, the former tends to negatively affect the skin by causing barrier disruption, lipid dissolution and pH alteration. Despite this, soap is still often preferred, possibly due to the negative connotations around anything that is not perceived as 'natural'. It is, therefore, important that the science behind cleansers, especially those designed for the maintenance of healthy skin and the management of common skin conditions such as eczema, be understood by both formulators and end-users. Here, we carefully weigh the advantages and disadvantages of the different types of surfactant-the key ingredient(s) in skin cleansers-and provide insight into surfactants' physicochemical properties, biological activity and potential effects. Fine-tuning of the complex characteristics of surfactants can successfully lead to an 'optimal' skin cleanser that can simultaneously be milder in nature, highly effective and beneficial, and offer minimal skin interference and environmental impact.

A daily regimen of a ceramide-dominant moisturizing cream and cleanser restores the skin permeability barrier in adults with moderate eczema: A randomized trial.

The dysfunctional skin barrier in eczema patients may be attributed to decreased levels of ceramides in the stratum corneum. The aim of this study was to determine whether a two-part system consisting of a ceramide-dominant physiological lipid-based moisturizing cream and cleanser could ameliorate the signs and symptoms of moderate eczema in adults over 28 days compared to placebo. Assessments were conducted at baseline and every 7 days thereafter. Eczema area severity index score decreased significantly across all time points in both groups compared to baseline (P < .0001), however, this decrease was not significant between groups at day 28 (P = .7804). In contrast, transepidermal water loss and skin hydration significantly improved over time in the active group, while it either stayed the same or worsened in the placebo group (P = .0342 and P < .0001, respectively). There was no difference in the use of mometasone furoate as rescue medication over time between groups (P = .1579). Dermatology life quality index scores improved significantly in both groups (P < .0001), with no difference between groups (P = .5256). However, patient satisfaction was greater in the active compared to the placebo group for several parameters including relief of itch, dry skin, skin softness and smoothness (all P < .05). No patients withdrew from the study due to adverse events (AEs) and there were no serious AEs. The ceramide-dominant moisturizing cream and cleanser safely restores skin permeability and improves the signs and symptoms of eczema in adults.

Recruitment of adults with moderate eczema for a randomised trial: Comparison of traditional versus modern methods.

BACKGROUND: Clinical trial recruitment is challenging for investigators who often overestimate the pool of qualified, willing subjects. Moreover, there is a paucity of literature, particularly in dermatology, regarding recruitment and the comparative success of advertising strategies. METHODS: Both 'traditional' (physician referral, newspaper and radio advertisements, letterbox drops, posters/flyers, word-of-mouth) and 'modern' (patient recruitment services, social media, Google advertisements, websites, email) recruitment methods were used to enrol 100 patients (>18 years) diagnosed with moderate eczema for a randomised, double-blind, placebo-controlled trial investigating the efficacy and safety of a topical eczema treatment over 4 weeks. The relationships between recruitment method and patient age, sex, race, study completion and costs were analysed. RESULTS: The majority of patients recruited were young, with millennials and Gen Z comprising 77% of the study population. Both traditional and modern recruitment methods were equally successful in recruiting younger patients, with older patients predominately recruited by traditional methods. Eighty per cent more men were recruited by traditional compared to modern methods, whilst 67% more women than men were recruited by modern methods. Recruitment method neither appeared to be influenced by race, nor did it effect whether patients completed the study. Costs per enrolment were similar for both methods. CONCLUSIONS: This study shows that despite the high proportion of young patients and the rising popularity of social media and increased internet use, a combination of both traditional and modern recruitment methods was required to successfully meet the trial enrolment target of 100 adult patients with moderate eczema.

Understanding the biology of reactive oxygen species and their link to cancer: NADPH oxidases as novel pharmacological targets.

Reactive oxygen species (ROS), the cellular products of myriad physiological processes, have long been understood to lead to cellular damage if produced in excess and to be a causative factor in cancer through the oxidation and nitration of various macromolecules. Reactive oxygen species influence various hallmarks of cancer, such as cellular proliferation and angiogenesis, through the promotion of cell signalling pathways intrinsic to these processes and can also regulate the function of key immune cells, such as macrophages and regulatory T cells, which promote angiogenesis in the tumour environment. Herein we emphasize the family of NADPH oxidase enzymes as the most likely source of ROS, which promote angiogenesis and tumourigenesis through signalling pathways within endothelial, immune and tumour cells. In this review we focus on the pharmacological inhibitors of NADPH oxidases and suggest that, compared with traditional anti-oxidants, they are likely to offer better alternatives for suppression of tumour angiogenesis. Despite the emerging enthusiasm towards the use of NADPH oxidase inhibitors for cancer therapy, this field is still in its infancy; in particular, there is a glaring lack of knowledge of the roles of NADPH oxidases in in vivo animal models and in human cancers. Certainly a clearer understanding of the relevant signalling pathways influenced by NADPH oxidases during angiogenesis in cancer is likely to yield novel therapeutic approaches.

The heterogeneity and complexity of skin surface lipids in human skin health and disease.

The outermost epidermal layer of the skin, the stratum corneum, is not simply a barrier that safeguards skin integrity from external insults and invaders, it is also a delicately integrated interface composed of firm, essentially dead corneocytes and a distinctive lipid matrix. Together, the stratum corneum lipid matrix and sebum lipids derived from sebaceous glands give rise to a remarkably complex but quite unique blend of skin surface lipids that demonstrates tremendous heterogeneity and provides the skin with its indispensable protective coating. The stratum corneum lipid matrix is composed primarily of three major lipid classes: ceramides, non-esterified fatty acids and cholesterol, whereas sebum is a waxy mixture predominantly composed of acylglycerols, wax esters, non-esterified fatty acids, squalene, cholesterol and cholesterol esters. The balance of these skin surface lipids in terms of their relative abundance, composition, molecular organisation and dynamics, and their intricate interactions play a crucial role in the maintenance of healthy skin. For that reason, even minuscule alterations in skin surface lipid properties or overall lipid profile have been implicated in the aetiology of many common skin diseases including atopic dermatitis, psoriasis, xerosis, ichthyosis and acne. Novel lipid-based interventions aimed at correcting the skin surface lipid abnormalities have the potential to repair skin barrier integrity and the symptoms associated with such skin diseases, even though the exact mechanisms of lipid restoration remain elusive.

Autophagy is the key to making chronic wounds acute in skin wound healing.

As a highly regulated and dynamically balanced intracellular degradation mechanism, macroautophagy/autophagy plays an essential housekeeping role in different successive stages of skin wound healing; from the homeostasis and inflammatory stages to the proliferative and remodeling stages. Under both progressive and defective skin wound healing conditions, autophagy operates at different levels with a precise extent of activity, at the interface of inflammation, stress signaling and cell metabolism through a complex spatiotemporal cascade of molecular and cellular events. Depending on the wound healing conditions autophagic activity is fine-tuned and differentially modulated at each stage of skin wound healing in order to cope with stage-specific requirements. Here, we postulate that under favorable conditions autophagy may act as the key modulator of skin wound healing by making chronic wounds acute. Enhancing autophagy through the topical application of pro-autophagy biologics in an appropriate hydrating vehicle/moisturizing base such as hydrogels, onto a chronic skin wound may provide moisture and immune modulation, thus contributing to rapid and efficient skin wound healing. A moist environment is more conducive to skin wound healing as it helps to not only accelerate cell proliferation and migration, and extracellular matrix reorganization, but also promotes autophagy and reduces the incidence of inflammation.Abbreviation: AKT: AKT serine/threonine protein kinase; ECM: extracellular matrix; FN1: fibronectin 1; LAM: laminin; MMPs: matrix metallopeptidases; MMP2: matrix metallopeptidase 2; MRSA: methicillin-resistant Staphylococcus aureus; MTOR: mechanistic target of rapamycin kinase; PI3K: phosphoinositide 3-kinase; TNF/TNF-α: tumor necrosis factor.

Development of Novel High-Affinity Antagonists for the Relaxin Family Peptide Receptor 1.

H2 relaxin is a peptide hormone that exerts its biological actions through the G protein-coupled receptor, RXFP1. The numerous important biological functions of H2 relaxin, including potent renal, vasodilatory, cardioprotective, and anti-fibrotic actions, have resulted in considerable interest in its use as a therapeutic for various cardiovascular diseases and other fibrotic indications. Interestingly though, H2 relaxin and RXFP1 have been shown to be overexpressed in prostate cancer, allowing for the downregulation or blocking of relaxin/RXFP1 to decrease prostate tumor growth. These findings suggest the application of an RXFP1 antagonist for the treatment of prostate cancer. However, these therapeutically relevant actions are still poorly understood and have been hindered by the lack of a high-affinity antagonist. In this study, we chemically synthesized three novel H2 relaxin analogues that have complex insulin-like structures with two chains (A and B) and three disulfide bridges. We report here the structure-activity relationship studies on H2 relaxin that resulted in the development of a novel high-affinity RXFP1 antagonist, H2 B-R13HR (∼40 nM), that has only one extra methylene group in the side chain of arginine 13 in the B-chain (ArgB13) of H2 relaxin. Most notably, the synthetic peptide was shown to be active in a mouse model of prostate tumor growth in vivo where it inhibited relaxin-mediated tumor growth. Our compound H2 B-R13HR will be an important research tool to understand relaxin actions through RXFP1 and may be a potential lead compound for the treatment of prostate cancer.

Emerging Trends in the Use of Topical Antifungal-Corticosteroid Combinations.

A broad range of topical antifungal formulations containing miconazole or terbinafine as actives are commonly used as efficacious choices for combating fungal skin infections. Their many benefits, owing to their specific mechanism of action, include their ability to target the site of infection, enhance treatment efficacy and reduce the risk of systemic side effects. Their proven efficacy, and positioning in the treatment of fungal skin infections, is enhanced by high patient compliance, especially when appropriate vehicles such as creams, ointments and gels are used. However, inflammation as a result of fungal infection can often impede treatment, especially when combined with pruritus (itch), an unpleasant sensation that elicits an urge to scratch. The scratching that occurs in response to pruritus frequently accelerates skin damage, ultimately aggravating and spreading the fungal infection. To help overcome this issue, a topical antifungal-corticosteroid combination consisting of miconazole or terbinafine and corticosteroids of varying potencies should be used. Due to their inherent benefits, these topical antifungal-corticosteroid combinations can concomitantly and competently attenuate inflammation, relieve pruritus and treat fungal infection.

Vehicles for Drug Delivery and Cosmetic Moisturizers: Review and Comparison.

Many dermatological conditions, such as eczema and psoriasis, are treated with topical therapeutic products. Instead of applying the active drug directly onto the skin, it is combined with a vehicle to aid in its delivery across the stratum corneum (SC) and into deeper regions of the skin, namely the epidermis and dermis. Absorption into the systemic circulation is minimized. Topical vehicles are also used as cosmetic moisturizers (often termed emollient therapy) to ameliorate dry skin, which is a cornerstone of the management of various dermatological conditions, including xerosis, eczema, psoriasis, and aging. The most common topical vehicles include ointments, creams, gels, and lotions, among others. It is crucial that topical vehicles are chosen based upon the size and properties (wet/dry, mucous/non-mucous, healthy/diseased) of the skin to be treated in order to optimize application and contact of the product with the skin, as this can have profound impacts on potency, efficacy, and patient compliance. This review examines common topical vehicles used for drug delivery and cosmetic moisturizers, including their formulation, advantages and disadvantages, and effects on the skin. The unique rules imposed by governing regulatory bodies in Australia and around the world, in terms of topical product claims, are also briefly examined.

Breaking the Itch-Scratch Cycle: Topical Options for the Management of Chronic Cutaneous Itch in Atopic Dermatitis.

Chronic itch is an unpleasant sensation that triggers a desire to scratch that lasts for six weeks or more. It is a major diagnostic symptom of myriad diseases, including atopic dermatitis for which it is the most prominent feature. Chronic itch can be hugely debilitating for the sufferer, damaging in terms of both the monetary cost of treatment and its socioeconomic effects, and few treatment options exist that can adequately control it. Corticosteroids remain the first line treatment strategy for atopic dermatitis, but due to the risks associated with long-term use of corticosteroids, and the drawbacks of other topical options such as topical calcineurin inhibitors and capsaicin, topical options for itch management that are efficacious and can be used indefinitely are needed. In this review, we detail the pathophysiology of chronic pruritus, its key features, and the disease most commonly associated with it. We also assess the role of the skin and its components in maintaining a healthy barrier function, thus reducing dryness and the itch sensation. Lastly, we briefly detail examples of topical options for the management of chronic pruritus that can be used indefinitely, overcoming the risk associated with long-term use of corticosteroids.

Hydrogels for Atopic Dermatitis and Wound Management: A Superior Drug Delivery Vehicle.

Wound management, in addition to presenting a significant burden to patients and their families, also contributes significantly to a country’s healthcare costs. Treatment strategies are numerous, but in most cases not ideal. Hydrogels, three-dimensional polymeric materials that can withstand a great degree of swelling without losing structural integrity, are drawing great attention for their use as topical wound management solutions in the form of films and as vehicles for drug delivery, due to their unique properties of high water content, biocompatibility, and flexibility. Hydrogels, both naturally and synthetically derived, can be tuned to respond to specific stimuli such as pH, temperature and light and they are ideally suited as drug delivery vehicles. Here we provide a brief overview of the history and characteristics of hydrogels, assess their uses in wound management and drug delivery, and compare them with other types of common drug delivery vehicle.

NOX2 oxidase expressed in endosomes promotes cell proliferation and prostate tumour development.

Reactive oxygen species (ROS) promote growth factor signalling including for VEGF-A and have potent angiogenic and tumourigenic properties. However, the precise enzymatic source of ROS generation, the subcellular localization of ROS production and cellular targets in vivo that influence tumour-promoting processes, are largely undefined. Here, using mRNA microarrays, we show increased gene expression for NOX2, the catalytic subunit of the ROS-generating NADPH oxidase enzyme, in human primary prostate cancer compared to non-malignant tissue. In addition, NOX4 gene expression was markedly elevated in human metastatic prostate cancers, but not in primary prostate tumours. Using a syngeneic, orthotopic mouse model of prostate cancer the genetic deletion of NOX2 (i.e. NOX2 -/y mouse) resulted in reduced angiogenesis and an almost complete failure in tumour development. Furthermore, pharmacological inhibition of NOX2 oxidase suppressed established prostate tumours in mice. In isolated endothelial cells, and in human normal and prostate cancer cells, NOX2 co-located to varying degrees with early endosome markers including EEA1, Appl1 and Rab5A and the late endosome marker Rab7A, and this correlated with significant VEGF-A-dependent ROS production within acidified endosomal compartments and endothelial cell proliferation that was NOX2 oxidase- and hydrogen peroxide dependent. We concluded that NOX2 oxidase expression and endosomal ROS production were important for prostate cancer growth and that this was required to positively regulate the VEGF pathway. The research provides a paradigm for limiting tumour growth through a better understanding of NOX2 oxidase's effect on VEGF signalling and how controlling the development of tumour vasculature can limit prostate tumour development and metastasis.

A single-chain derivative of the relaxin hormone is a functionally selective agonist of the G protein-coupled receptor, RXFP1.

Human gene-2 relaxin (H2 relaxin) is a pleiotropic hormone with powerful vasodilatory and anti-fibrotic properties which has led to its clinical evaluation and provisional FDA approval as a treatment for acute heart failure. The diverse effects of H2 relaxin are mediated via its cognate G protein coupled-receptor (GPCR), Relaxin Family Peptide Receptor (RXFP1), leading to stimulation of a combination of cell signalling pathways that includes cyclic adenosine monophosphate (cAMP) and extracellular-signal-regulated kinases (ERK)1/2. However, its complex two-chain (A and B), disulfide-rich insulin-like structure is a limitation to its facile preparation, availability and affordability. Furthermore, its strong activation of cAMP signaling is likely responsible for reported detrimental tumor-promoting actions that may preclude long-term use of this drug for treating human disease. Here we report the design and synthesis of a H2 relaxin B-chain-only analogue, B7-33, which was shown to bind to RXFP1 and preferentially activate the pERK pathway over cAMP in cells that endogenously expressed RXFP1. Thus, B7-33 represents the first functionally selective agonist of the complex GPCR, RXFP1. Importantly, this small peptide agonist prevented or reversed organ fibrosis and dysfunction in three pre-clinical rodent models of heart or lung disease with similar potency to H2 relaxin. The molecular mechanism behind the strong anti-fibrotic actions of B7-33 involved its activation of RXFP1-angiotensin II type 2 receptor heterodimers that induced selective downstream signaling of pERK1/2 and the collagen-degrading enzyme, matrix metalloproteinase (MMP)-2. Furthermore, in contrast to H2 relaxin, B7-33 did not promote prostate tumor growth in vivo. Our results represent the first known example of the minimisation of a two-chain cyclic insulin-like peptide to a single-chain linear peptide that retains potent beneficial agonistic effects.