The role of enhancers in psoriasis and atopic dermatitis.

Regulatory elements, particularly enhancers, play a crucial role in disease susceptibility and progression. Enhancers are DNA sequences that activate gene expression and can be affected by epigenetic modifications, interactions with transcription factors (TFs) or changes to the enhancer DNA sequence itself. Altered enhancer activity impacts gene expression and contributes to disease. In this review, we define enhancers and the experimental techniques used to identify and characterize them. We also discuss recent studies that examine how enhancers contribute to atopic dermatitis (AD) and psoriasis. Articles in the PubMed database were identified (from 1 January 2010 to 28 February 2023) that were relevant to enhancer variants, enhancer-associated TFs and enhancer histone modifications in psoriasis or AD. Most enhancers associated with these conditions regulate genes affecting epidermal homeostasis or immune function. These discoveries present potential therapeutic targets to complement existing treatment options for AD and psoriasis.

Prevalence of allergic contact dermatitis in children with and without atopic dermatitis: A multicenter retrospective case-control study.

BACKGROUND: As both allergic contact dermatitis and atopic dermatitis (AD) have similar clinical presentations and are characterized by spongiotic dermatitis on skin biopsy, many children with AD are not referred for patch testing and allergic contact dermatitis is underdiagnosed. OBJECTIVE: To provide updated prevalence data of common contact allergens in children with and without AD. METHODS: This is a retrospective case-control study using the Pediatric Allergic Contact Dermatitis Registry from 2018 to 2022. RESULTS: A total of 912 children were included (615 with AD and 297 without AD). Children with AD were more likely to have a longer history of dermatitis (4.1 vs 1.6 years, P < .0001), have seen more providers (2.3 vs 2.1, P = .003), have greater than 1 positive patch test (PPT) result (P = .005), have a greater number of PPT results overall (2.3 vs 1.9, P = .012), and have a more generalized distribution of dermatitis (P = .001). PPT to bacitracin (P = .030), carba mix (P = .025), and cocamidopropyl betaine (P = .0007) were significantly increased in children with AD compared to those without AD. LIMITATIONS: Technical variation between providers and potential for misclassification, selection, and recall biases. CONCLUSION: Children with AD are significantly more likely to have PPT reactions and should be referred for evaluation of allergic contact dermatitis and obtain patch testing.

Type VII Collagen Deficiency in the Oncogenesis of Cutaneous Squamous Cell Carcinoma in Dystrophic Epidermolysis Bullosa.

Dystrophic epidermolysis bullosa is a rare genetic skin disorder caused by COL7A1 sequence variations that result in type VII collagen deficits and cutaneous and extracutaneous manifestations. One serious complication of dystrophic epidermolysis bullosa is cutaneous squamous cell carcinoma, a leading driver of morbidity and mortality, especially among patients with recessive dystrophic epidermolysis bullosa. Type VII collagen deficits alter TGFß signaling and evoke multiple other cutaneous squamous cell carcinoma progression-promoting activities within epidermal microenvironments. This review examines cutaneous squamous cell carcinoma pathophysiology in dystrophic epidermolysis bullosa with a focus on known oncogenesis pathways at play and explores the idea that therapeutic type VII collagen replacement may reduce cutaneous squamous cell carcinoma risk.

Serum zinc levels and efficacy of zinc treatment in acne vulgaris: A systematic review and meta-analysis.

Oral and topical zinc have been used for the treatment of acne, but there is a lack of definitive evidence for their efficacy. (a) To determine if mean serum zinc levels differ between acne patients and controls and (b) to determine the efficacy of zinc preparations in the treatment of acne. A systematic review and meta-analysis was performed according to recommended PRISMA [Preferred Reporting Items for Systematic Reviews and Meta-Analyses] guidelines. Subjects with acne had significantly lower serum zinc levels compared to controls. Patients who were treated with zinc had a significant improvement in mean inflammatory papule count compared to those who were not treated with zinc. There was no significant difference in the incidence of side effects in zinc supplementation vs comparators. Acne patients have decreased serum zinc levels. Zinc is effective for the treatment of acne, particularly at decreasing the number of inflammatory papules, when used as monotherapy or as an adjunctive treatment.

Cardiomyocyte Homeodomain-Interacting Protein Kinase 2 Maintains Basal Cardiac Function via Extracellular Signal-Regulated Kinase Signaling.

BACKGROUND: Cardiac kinases play a critical role in the development of heart failure, and represent potential tractable therapeutic targets. However, only a very small fraction of the cardiac kinome has been investigated. To identify novel cardiac kinases involved in heart failure, we used an integrated transcriptomics and bioinformatics analysis and identified Homeodomain-Interacting Protein Kinase 2 (HIPK2) as a novel candidate kinase. The role of HIPK2 in cardiac biology is unknown. METHODS: We used the Expression2Kinase algorithm for the screening of kinase targets. To determine the role of HIPK2 in the heart, we generated cardiomyocyte (CM)-specific HIPK2 knockout and heterozygous mice. Heart function was examined by echocardiography, and related cellular and molecular mechanisms were examined. Adeno-associated virus serotype 9 carrying cardiac-specific constitutively active MEK1 (TnT-MEK1-CA) was administrated to rescue cardiac dysfunction in CM-HIPK2 knockout mice. RESULTS: To our knowledge, this is the first study to define the role of HIPK2 in cardiac biology. Using multiple HIPK2 loss-of-function mouse models, we demonstrated that reduction of HIPK2 in CMs leads to cardiac dysfunction, suggesting a causal role in heart failure. It is important to note that cardiac dysfunction in HIPK2 knockout mice developed with advancing age, but not during development. In addition, CM-HIPK2 knockout mice and CM-HIPK2 heterozygous mice exhibited a gene dose-response relationship of CM-HIPK2 on heart function. HIPK2 expression in the heart was significantly reduced in human end-stage ischemic cardiomyopathy in comparison to nonfailing myocardium, suggesting a clinical relevance of HIPK2 in cardiac biology. In vitro studies with neonatal rat ventricular CMscorroborated the in vivo findings. Specifically, adenovirus-mediated overexpression of HIPK2 suppressed the expression of heart failure markers, NPPA and NPPB, at basal condition and abolished phenylephrine-induced pathological gene expression. An array of mechanistic studies revealed impaired extracellular signal-regulated kinase 1/2 signaling in HIPK2-deficient hearts. An in vivo rescue experiment with adeno-associated virus serotype 9 TnT-MEK1-CA nearly abolished the detrimental phenotype of knockout mice, suggesting that impaired extracellular signal-regulated kinase signaling mediated apoptosis as the key factor driving the detrimental phenotype in CM-HIPK2 knockout mice hearts. CONCLUSIONS: Taken together, these findings suggest that CM-HIPK2 is required to maintain normal cardiac function via extracellular signal-regulated kinase signaling.

Cardiomyocyte-specific deletion of GSK-3ß leads to cardiac dysfunction in a diet induced obesity model.

BACKGROUND AND RATIONALE: Obesity, an independent risk factor for the development of myocardial diseases is a growing healthcare problem worldwide. It's well established that GSK-3ß is critical to cardiac pathophysiology. However, the role cardiomyocyte (CM) GSK-3ß in diet-induced cardiac dysfunction is unknown. METHODS: CM-specific GSK-3ß knockout (CM-GSK-3ß-KO) and littermate controls (WT) mice were fed either a control diet (CD) or high-fat diet (HFD) for 55weeks. Cardiac function was assessed by transthoracic echocardiography. RESULTS: At baseline, body weights and cardiac function were comparable between the WT and CM-GSK-3ß-KOs. However, HFD-fed CM-GSK-3ß-KO mice developed severe cardiac dysfunction. Consistently, both heart weight/tibia length and lung weight/tibia length were significantly elevated in the HFD-fed CM-GSK-3ß-KO mice. The impaired cardiac function and adverse ventricular remodeling in the CM-GSK-3ß-KOs were independent of body weight or the lean/fat mass composition as HFD-fed CM-GSK-3ß-KO and controls demonstrated comparable body weight and body masses. At the molecular level, on a CD, CM-GSK-3α compensated for the loss of CM-GSK-3ß, as evident by significantly reduced GSK-3αs21 phosphorylation (activation) resulting in a preserved canonical ß-catenin ubiquitination pathway and cardiac function. However, this protective compensatory mechanism is lost with HFD, leading to excessive accumulation of ß-catenin in HFD-fed CM-GSK-3ß-KO hearts, resulting in adverse ventricular remodeling and cardiac dysfunction. CONCLUSION: In summary, these results suggest that cardiac GSK-3ß is crucial to protect against obesity-induced adverse ventricular remodeling and cardiac dysfunction.

Entanglement of GSK-3ß, ß-catenin and TGF-ß1 signaling network to regulate myocardial fibrosis.

Nearly every form of the heart disease is associated with myocardial fibrosis, which is characterized by the accumulation of activated cardiac fibroblasts (CFs) and excess deposition of extracellular matrix (ECM). Although, CFs are the primary mediators of myocardial fibrosis in a diseased heart, in the traditional view, activated CFs (myofibroblasts) and resulting fibrosis were simply considered the secondary consequence of the disease, not the cause. Recent studies from our lab and others have challenged this concept by demonstrating that fibroblast activation and fibrosis are not simply the secondary consequence of a diseased heart, but are crucial for mediating various myocardial disease processes. In regards to the mechanism, the vast majority of literature is focused on the direct role of canonical SMAD-2/3-mediated TGF-ß signaling to govern the fibrogenic process. Herein, we will discuss the emerging role of the GSK-3ß, ß-catenin and TGF-ß1-SMAD-3 signaling network as a critical regulator of myocardial fibrosis in the diseased heart. The underlying molecular interactions and cross-talk among signaling pathways will be discussed. We will primarily focus on recent in vivo reports demonstrating that CF-specific genetic manipulation can lead to aberrant myocardial fibrosis and sturdy cardiac phenotype. This will allow for a better understanding of the driving role of CFs in the myocardial disease process. We will also review the specificity and limitations of the currently available genetic tools used to study myocardial fibrosis and its associated mechanisms. A better understanding of the GSK-3ß, ß-catenin and SMAD-3 signaling network may provide a novel therapeutic target for the management of myocardial fibrosis in the diseased heart.