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Non-viral gene therapy for hereditary skin diseases is an attractive prospect. However, research efforts dedicated to this area are rare. Taking advantage of the branched structural ...possibilities of polymeric vectors, we have developed a gene delivery platform for the treatment of an incurable monogenic skin disease – recessive dystrophic epidermolysis bullosa (RDEB) – based on highly branched poly(β-amino ester)s (HPAEs). The screening of HPAEs and optimization of therapeutic gene constructs, together with evaluation of the combined system for gene transfection, were comprehensively reviewed. The successful restoration of type VII collagen (C7) expression both in vitro and in vivo highlights HPAEs as a promising generation of polymeric vectors for RDEB gene therapy into the clinic. Considering that the treatment of patients with genetic cutaneous disorders, such as other subtypes of epidermolysis bullosa, pachyonychia congenita, ichthyosis and Netherton syndrome, remains challenging, the success of HPAEs in RDEB treatment indicates that the development of viable polymeric gene delivery vectors could potentially expedite the translation of gene therapy for these diseases from bench to bedside.
Purpose of Review
At the juncture of the COVID-19 pandemic, the world is currently in an early phase of collecting clinical data and reports of its skin manifestations, and its pathophysiology is ...still highly conjectural. We reviewed cutaneous manifestations associated with COVID-19 in the pediatric age group.
Recent Findings
Children infected by SARS-CoV-2 usually develop milder respiratory symptoms, but cutaneous manifestations seem a little more prevalent than in adults. These skin features of infection by the coronavirus can be similar to those produced by other common viruses, but there are also reports of cases with more heterogeneous clinical pictures, which have made their classification difficult. To date, the more frequently reported skin variants featured in pediatric cases are purpuric (pseudo-chilblain, necrotic-acral ischemia, hemorrhagic macules, and/or cutaneous necrosis), morbilliform/maculopapular, erythema multiforme, urticarial, vesicular, Kawasaki-like, and miscellaneous (highly variable in both frequency and severity). Their pathophysiological mechanism is still elusive and is likely to be the result of the complex involvement of one or more mechanisms, like direct virus-induced skin damage, vasculitis-like reactions, and/or indirect injury as a consequence of a systemic inflammatory reaction.
Summary
In this review, we presented and discussed clinical cases as examples of different cutaneous responses reported in some children with SARS-CoV-2 infection, differential diagnosis considerations, and a preliminary conceptual approach to some of their probable associated pathologic mechanisms.
TRP channels in the skin Toth, Balázs I; Olah, Attila; Szollsi, Attila Gábor ...
British journal of pharmacology,
20/May , Letnik:
171, Številka:
10
Journal Article
Recenzirano
Odprti dostop
Emerging evidence suggests that transient receptor potential (TRP) ion channels not only act as ‘polymodal cellular sensors’ on sensory neurons but are also functionally expressed by a multitude of ...non‐neuronal cell types. This is especially true in the skin, one of the largest organs of the body, where they appear to be critically involved in regulating various cutaneous functions both under physiological and pathophysiological conditions. In this review, we focus on introducing the roles of several cutaneous TRP channels in the regulation of the skin barrier, skin cell proliferation and differentiation, and immune functions. Moreover, we also describe the putative involvement of several TRP channels in the development of certain skin diseases and identify future TRP channel‐targeted therapeutic opportunities.
Linked Articles
This article is part of a themed section on the pharmacology of TRP channels. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue‐10
To characterize keratin intermediate filament assembly mechanisms at atomic resolution, we determined the crystal structure of wild‐type human keratin‐1/keratin‐10 helix 1B heterotetramer at 3.0 Å ...resolution. It revealed biochemical determinants for the A11 mode of axial alignment in keratin filaments. Four regions on a hydrophobic face of the K1/K10‐1B heterodimer dictated tetramer assembly: the N‐terminal hydrophobic pocket (defined by L227K1, Y230K1, F231K1, and F234K1), the K10 hydrophobic stripe, K1 interaction residues, and the C‐terminal anchoring knob (formed by F314K1 and L318K1). Mutation of both knob residues to alanine disrupted keratin 1B tetramer and full‐length filament assembly. Individual knob residue mutant F314AK1, but not L318AK1, abolished 1B tetramer formation. The K1‐1B knob/pocket mechanism is conserved across keratins and many non‐keratin intermediate filaments. To demonstrate how pathogenic mutations cause skin disease by altering filament assembly, we additionally determined the 2.39 Å structure of K1/10‐1B containing a S233LK1 mutation linked to epidermolytic palmoplantar keratoderma. Light scattering and circular dichroism measurements demonstrated enhanced aggregation of K1S233L/K10‐1B in solution without affecting secondary structure. The K1S233L/K10‐1B octamer structure revealed S233LK1 causes aberrant hydrophobic interactions between 1B tetramers.
Synopsis
Crystal structures of keratin 1/keratin 10 1B tetramers reveal a knob‐pocket interaction important for the assembly of mature intermediate filaments. An epidermolytic palmoplantar keratoderma‐related mutation is localized in the pocket region and causes aberrant filament formation.
Symmetrical knob‐pocket interactions in the 1B domain termini of type II keratins drive A11‐tetramer formation.
Mutation of 1B domain knob residues is detrimental to mature full‐length intermediate filament formation in K1/K10, K8/K18, and vimentin.
Keratin 1 mutation S233L, associated with epidermolytic palmoplantar keratoderma, causes aberrant hydrophobic interactions between K1/K10‐1B tetramers in an octameric crystal structure.
New crystal structures reveal modes of keratin assembly in health and keratinopathy.
Skin neurogenic inflammation Choi, Jae Eun; Di Nardo, Anna
Seminars in immunopathology,
05/2018, Letnik:
40, Številka:
3
Journal Article
Recenzirano
Odprti dostop
The epidermis closely interacts with nerve endings, and both epidermis and nerves produce substances for mutual sustenance. Neuropeptides, like substance P (SP) and calcitonin gene-related protein ...(CGRP), are produced by sensory nerves in the dermis; they induce mast cells to release vasoactive amines that facilitate infiltration of neutrophils and T cells. Some receptors are more important than others in the generation of itch. The Mas-related G protein-coupled receptors (Mrgpr) family as well as transient receptor potential ankyrin 1 (TRPA1) and protease activated receptor 2(Par2) have important roles in itch and inflammation. The activation of MrgprX1 degranulates mast cells to communicate with sensory nerve and cutaneous cells for developing neurogenic inflammation. Mrgprs and transient receptor potential vanilloid 4 (TRPV4) are crucial for the generation of skin diseases like rosacea, while SP, CGRP, somatostatin, β-endorphin, vasoactive intestinal peptide (VIP), and pituitary adenylate cyclase-activating polypeptide (PACAP) can modulate the immune system during psoriasis development. The increased level of SP, in atopic dermatitis, induces the release of interferon (IFN)-γ, interleukin (IL)-4, tumor necrosis factor (TNF)-α, and IL-10 from the peripheral blood mononuclear leukocytes. We are finally starting to understand the intricate connections between the skin neurons and resident skin cells and how their interaction can be key to controlling inflammation and from there the pathogenesis of diseases like atopic dermatitis, psoriasis, and rosacea.
We describe a series of Epstein Barr virus (EBV)-positive circumscribed, ulcerative lesions associated with various types of immunosuppression (IS). The study group (26 patients) comprised 10 males ...and 16 females, median age 77 years (range 42 to 101). IS in 9 cases included azathioprine (AZA), methotrexate (MTX) or cyclosporin-A (CyA). Seventeen patients had age-related immunosenescence. Patients presented with isolated sharply circumscribed ulcers involving oropharyngeal mucosa (16), skin (6), and gastrointestinal tract (4). Lesions were histologically characterized by a polymorphous infiltrate and atypical large B-cell blasts often with Hodgkin/Reed-Sternberg (HRS) cell-like morphology. The B cells showed strong CD30 and EBER positivity, some with reduced CD20 expression, in a background of abundant T cells. CD15 was positive in 43% of cases (10/23). The pathologic features were identical regardless of the anatomic site or cause of IS. Polymerase chain reaction revealed 39% (7/18) clonal Ig gene rearrangements with 38% (6/16) and 31% (5/16) clonal and restricted T-cell patterns, respectively. Twenty-five percent of patients (5/20) received standard chemotherapy and/or radiotherapy. Forty-five percent (9/20) regressed spontaneously with no treatment and 15% (3/20) were characterized by a relapsing and remitting course. All of the iatrogenic lesions (6/6) with available follow-up responded to reduction of IS. All patients achieved complete remission with no disease-associated deaths over a median follow-up period of 22 months (range 3 to 72). We propose EBV-positive mucocutaneous ulcer as a newly recognized clinicopathologic entity with Hodgkin-like features and a self-limited, indolent course, generally responding well to conservative management. Association with various forms of IS implies a common pathogenetic mechanism. The localized nature of the disease may be owing to a minimal and localized lapse in immunosurveillance over EBV.
Perianal lesions in children are common reasons for dermatology clinic visits and a well-defined approach to diagnosis and management is helpful to the practicing clinician. In this article, we ...review and update various etiologies of perianal lesions in the pediatric population, including infectious, papulosquamous, vascular, and neoplastic. We provide a standard initial approach to diagnosis and updates on current management. Infectious etiologies of perianal lesions discussed in this article include fungal, bacterial, parasitic, and viral. Perianal papulosquamous lesions often encountered in children, and discussed in this article, include acrodermatitis enteropathica, psoriasis, contact dermatitis, and many others. We also discuss the diagnosis and management of other entities including infantile hemangiomas, Langerhans cell histiocytosis, and fibrous hamartoma of infancy.
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