Journal Of Investigative Dermatology

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616 Synergistic effect between cigarette smoke and sunlight on human keratinocytes

Wed, 2020-07-01 00:00
Several environmental factors influence the skin aging process, including exposure to sun and cigarette smoke. Studied separately, these factors are known to accelerate skin aging. However, effects of a potential synergy between these two factors have been poorly characterized. It is well known that some cigarette smoke components can accumulate in the skin by contact or by systemic effect after inhalation and that solar rays can penetrate the epidermis and dermis. The aim of this study is to assess the harmful effects of this synergy on skin and more precisely on skin aging.

615 Inverse docking assisted identification of flavonols as c-Kit, CDK2 and mTOR inhibitors for melanoma and non-melanoma skin cancer management

Wed, 2020-07-01 00:00
Melanoma and non-melanoma skin cancers (NMSCs) are two major forms of skin cancers. Melanoma is the most aggressive form of skin cancer related deaths while basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are most prevalent forms of NMSCs with over 5.3million yearly cases in the US. Due to huddles including resistance, bioavailability and adverse effects with available treatments, there is the need for effective strategies against skin cancer progression. The cyclin dependent kinase-2(CDK2), c-kit and mammalian target of rapamycin (mTOR), are attractive targets for new anticancer drug development.

614 A novel treatment for skin repair using a combination of a MR antagonist + Vitamin D3

Wed, 2020-07-01 00:00
Exposure of the skin to toxic chemotherapy agents such as nitrogen mustard (NM) triggers activation of inflammatory dermal macrophages (Macs) with high expression of iNOS and TNFa resulting in delayed wounds. We have shown that Intervention with vitamin D3 (VD) mitigates Mac-mediated inflammation resulting in skin repair. Data from our in vitro drug screen using RAW 264.7-NFkB reporter cell line shows that VD with spironolactone (SP) has additive inhibition of NFkB activity. SP is a mineralocorticoid receptor antagonist known to be protective in chronic heart failure and other clinical conditions due to its abilitiesto delay progression of tissue injury and inhibit inflammation.

610 AHR agonist RLV102 suppresses inflammation in mouse models of eczema and psoriasis

Wed, 2020-07-01 00:00
Aryl hydrocarbon receptor (AHR) signal transduction pathway is involved in barrier formation and regulation of inflammation of the skin and the digestive system. Recently tapinarof, an AHR agonist, has shown effect for treatment of psoriasis in mouse models and in early phase clinical trials, revealing therapeutic potential by modulating AHR activities. Here we describe development of RLV102, a potent next generation AHR agonist and report its effect on psoriasis and atopic dermatitis in animal models.

609 The topical tanning agent dihydroxyacetone induces stress response gene expression and signaling in human reconstructed epidermis and SKH1 hairless mouse skin

Wed, 2020-07-01 00:00
Chemical tanning is widely regarded as a safe alternative to solar UV-induced skin tanning, but the cutaneous biology impacted by chemical tanning remains largely unexplored. Chemical tanning is based on the formation of melanin-mimetic cutaneous pigments (‘melanoidins’) from spontaneous glycation reactions between epidermal amino acid/protein components and reactive sugars including the glycolytic ketose dihydroxyacetone (DHA). Here, we have examined cutaneous effects of acute DHA exposure on cultured human keratinocytes, epidermal reconstructs, and mouse skin employing gene epression array analysis and immunodetection.

608 Targeting CtBP-mediated proinflammatory gene transcription to treat skin inflammation

Wed, 2020-07-01 00:00
Inflammatory skin diseases (ISDs) such as psoriasis and allergic contact dermatitis affects millions of people and poses a major public health burden. Aberrant cytokine production is a prominent characteristic of ISDs, although the molecular mechanisms underlying the imbalance between pro- and anti-inflammatory gene expression remain underexplored. C-terminal-binding protein (CtBP) 1 and 2 are transcriptional coregulators that repress diverse cellular processes. Our recently studies have uncovered a previously unrecognized proinflammatory role of CtBP in skin inflammation.

607 Targeting 14-3-3e-CDC25A interactions to trigger apoptotic cell death in skin cancer

Wed, 2020-07-01 00:00
Non-melanoma skin cancer is the most common form of cancer worldwide. We previously documented an anti-apoptotic role for CDC25A in cutaneous squamous cell carcinoma (SCC), an activity dependent on its association with 14-3-3 proteins. We hypothesized that targeting CDC25A-14-3-3ε interactions may be an effective strategy for inducing skin cancer cell apoptosis. Co-immunoprecipitation revealed that CDC25A associated with 14-3-3ε, 14-3-3γ and 14-3-3ζ in SCC cells but not normal keratinocytes. Additionally, in SCC cells, overexpression of CDC25A induced Akt/BAD/Survivin pro-survival signaling while knockdown of 14-3-3ε inhibited pro-survival signaling, suggesting that 14-3-3ε and CDC25A similarly activate pro-surivval signaling pathways to suppress cell death.

606 Small molecule blockade of T-type calcium channels by DX416 inhibits itch and reduces corresponding inflammation in acute and chronic itch mouse models

Wed, 2020-07-01 00:00
The processing of itch signals is regulated by many different ion channels. Among those are T-type calcium channels which are important regulators that contribute to the firing behavior of pruriceptors, or itch sensing neurons. The human genome encodes three different T-type channels: Cav3.1, Cav3.2, Cav3.3. It has been shown recently that pharmacological blockade of T-type calcium channels inhibits acute itch and that immune cells can express Cav 3 channels with roles in effector function. Thus, we hypothesized that local administration of the novel small molecule T-Type calcium channel inhibitor, DX416, would decrease cutaneous itch both through reducing pruriceptors signals triggering itch and decreasing local inflammatory immune responses potentiating itch.

605 Long-term management of moderate-to-severe plaque psoriasis: Maintenance of treatment success following cessation of halobetasol propionate 0.01%/tazarotene 0.045% lotion

Wed, 2020-07-01 00:00
Psoriasis is an immune-mediated disease that may have frequent remissions/exacerbations. Treating psoriasis by combining tazarotene (TAZ) with a topical corticosteroid, such as halobetasol propionate (HP), may enhance efficacy while reducing side effects of HP, which limit long-term use. TAZ also sustains response posttreatment and may play a role in maintenance therapy. This 1-year, open-label study assessed a fixed-combination, once-daily HP 0.01%/TAZ 0.045% lotion in participants with moderate-to-severe psoriasis.

603 Treatment of moderate-to-severe acne with once-daily tazarotene 0.045% lotion in pediatric patients: Pooled analysis of two phase 3 studies

Wed, 2020-07-01 00:00
Acne, common in adolescence, can be treated with topical retinoids, such as tazarotene (TAZ). TAZ is an anti-inflammatory and comedolytic prodrug whose active form, tazarotenic acid, selectively binds retinoic acid receptors β and γ. A lower-dose 0.045% TAZ lotion was developed using polymeric emulsion technology, as gel or cream 0.1% TAZ formulations can cause irritation and limit use. In two phase 3, double-blind, vehicle-controlled 12-week studies (N=1,614), patients with moderate-to-severe acne were randomized (1:1) to receive TAZ 0.045% lotion or vehicle once-daily.

602 Discovery of new olfactory receptors in human keratinocytes: A potential role on skin stress response

Wed, 2020-07-01 00:00
Olfactory receptors (ORs) are mainly expressed in the nasal olfactory epithelium but can also be found in different cell types throughout the body to regulate physiological cell functions beyond olfaction. Recently, ORs have been detected to be functionally expressed in the skin when activated with odorants. Olfaction is known to be disturbed under stress condition and is widely used in aromachology to afford relaxing effect. Therefore, we questioned the role of skin olfactory receptors in response to this environmental factor.

600 Treatment of facial flushing and erythema by carvedilol in rosacea patients with anxiety, a prospective randomized controlled clinical study

Wed, 2020-07-01 00:00
Introduction: Treatment of erythematotelangiectatic rosacea (ETR) is extremely challenging, because of the severe facial flushing and anxiety, which form a vicious cycle of reciprocal causation in the pathogenesis. There are no known specific treatments available, some cases have reported that beta-blokers play a role in the treatment of rosacea, but there are not yet any randomized controlled prospective, with larger seriers, clinical studies to evaluate the effects of systemic betabloker therapy in treating ETR.

598 Identification of a human skin commensal bacterium that selectively kills cutibacterium acnes

Wed, 2020-07-01 00:00
Cutibacterium acnes (C. acnes) is one of the most common bacterial species on human skin and can promote acne vulgaris. Most current therapeutics for acne are antibiotics that fail to discriminate C. acnes from the other skin resident microflora, many of which have important roles in health. Such approaches have significant drawbacks due to poor antimicrobial activity on the skin surface and emergence of antibiotic resistance. The microbiome represents a vast resource for drug discovery as its members engage in constant conflict to outcompete one another by deploying diverse strategies for survival.

597 An Aquaphilus dolomiae extract modulates cutaneous sensitivity on in vitro models of neuro-inflammation

Wed, 2020-07-01 00:00
Substance P is one of the neurotransmitters mainly involved in neurogenic inflammation on cutaneous level, a key point in the pathogenesis of inflammatory skin disorders such atopic dermatitis (AD), associated pruritus, and sensitive skin. In vitro models evaluated the effect of the original biological extract of Aquaphilus dolomiae E0 (Ad-E0) on cutaneous neurogenic inflammation. Ad-E0 significantly inhibited SP-stimulated release of IL-1β and TNF-α from normal human epidermal keratinocytes; significantly and dose-dependently inhibited SP-stimulated activation of human mast cells; significantly inhibited veratridine-stimulated release of SP from human sensory neurons; modulated expression of genes involved in lipid synthesis, innate immunity, corneocyte scaffolding and epidermal differentiation in a histamine-sensitized reconstructed human epidermis model; and, when applied topically to ex vivo human explants, inhibited IL-8 and histamine release.

596 Complementary sun protection of two antioxidants (OTZ and DTG) in a sunscreen emulsion based on skin release

Wed, 2020-07-01 00:00
Sunscreens have been shown to be extremely effective in preventing DNA lesions due to ultraviolet (UV) radiation. Indeed, recent studies indicate that the number of UV-induced lesions decreased up to 95% depending on sunfilter combination and sun protection factor (SPF). Thus, sunblockers protect the skin from the harmful effects of UV, but they do not provide 100% protection. As a result, sunscreens are now being developed with antioxidants to provide additional protection against oxidative stress-mediated cell damage especially reactive oxygen species (ROS).

595 Differential ligand binding distinguishes therapeutic from pathologic Aryl Hydrocarbon Receptor (AhR) modulating agents: Implications for inflammatory skin disease

Wed, 2020-07-01 00:00
The aryl hydrocarbon receptor (AhR) is a transcription factor highly expressed in epithelial cells and immune cells and is emerging as a therapeutic target for inflammatory skin disease. AhR activity can be influenced by several naturally occurring and manmade agonists and antagonists. Despite the discovery of 2,3,7,8-Tetrachlorodibenzodioxin (TCDD) as an AhR agonist, many compounds exert their effects via the AhR pathway, resulting in different physiological responses and clinical manifestations.

594 Dynamic cytokine profiles combined with ELISPOT assay are useful in immunologically confirming the dapsone hypersensitivity syndrome

Wed, 2020-07-01 00:00
Background: Dapsone hypersensitivity syndrome (DHS) is induced by drug-specific T cells. The specific dynamic cytokine profiles of DHS are unknown and the diagnosis of DHS in clinical practice remains a challenge. Objective: To investigate the DHS specific dynamic cytokine profiles, and explore specific enzyme-linked immunospot (ELISPOT) assay in the diagnosis of DHS. Methods: 14 types of cytokine levels (IFN-γ, Fas Ligand, Granzyme B, IL-4, IL-5, IL-6, IL-10, IL-13, IL-15, IL-17A, IL-21, IL-22, IL-23, and TNF-α) in DHS patients and dapsone tolerant patients carrying HLA-B*13:01 were analyzed using Luminex Bioplex assay.

591 Pan-caspase inhibition is a novel immunotherapeutic against MRSA skin infections in mice

Wed, 2020-07-01 00:00
Staphylococcus aureus causes the majority of skin infections, and the emergence of methicillin-resistant S. aureus (MRSA) strains has created a public health threat. There is an unmet clinical need for non-antibiotic immunotherapies to combat MRSA. Herein, the pan-caspase inhibitor Quinoline-Val-Asp-Difluorophenoxymethyl ketone (Q-VD-OPH) was investigated for efficacy against an MRSA skin infection in mice. A single intraperitoneal injection of Q-VD-OPH 4 hour’s post-infection substantially decreased skin lesion sizes and rapidly reduced bacterial burden compared with vehicle or untreated wildtype (wt) mice.

590 Increased psoriasis severity with obesity is associated with insufficient adiponectin-mediated regulatory T cell response

Wed, 2020-07-01 00:00
Psoriasis is a chronic inflammatory skin disease characterized by Th17 cell skewing. Obesity, the most common psoriasis co-morbidity, is associated with greater disease severity. We showed earlier onset and greater disease severity, as well as reduced adiponectin expression, in high fat diet (HFD)-fed obese mice compared to regular diet (RD)-fed controls when psoriasis-like disease is induced by topically-applied imiquimod (IMQ). Obesity is associated with a reduced Treg response, but its role in psoriasis is unknown.

589 Effects of CCR4 antagonists in cutaneous T-cell lymphoma cells

Wed, 2020-07-01 00:00
CC chemokine receptor 4 (CCR4) is responsible for T-cell skin homing. It is overexpressed in type 2 helper T-cells (Th2) as well as cutaneous T-cell lymphoma (CTCL) cells. Mycosis fungoides (MF) and Sézary syndrome (SS) are two most common types of CTCL. Currently, Mogamulizumab, a humanized anti-CCR4 antibody, has been FDA-approved to treat MF and SS. However, the clinical response rates for SS patients was 30% and for MF patients was 22% and severe drug eruptions following treatment were reported.

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