Voriconazole enhances UV-induced DNA damage by inhibiting catalase and promoting oxidative stress.

Cutaneous squamous cell carcinoma (cSCC) is the second most common form of skin cancer and is associated with cumulative UV exposure. Studies have shown that prolonged voriconazole use promotes cSCC formation; however, the biological mechanisms responsible for the increased incidence remain unclear. Here, we show that voriconazole directly increases oxidative stress in human keratinocytes and promotes UV-induced DNA damage as determined by comet assay, 8-oxoguanine immunofluorescence and mass spectrometry.

Therapeutic Elimination of the Type 1 Interferon Receptor for Treating Psoriatic Skin Inflammation.

Phototherapy with UV light is a standard treatment for psoriasis, yet the mechanisms underlying the therapeutic effects are not well understood. Studies in human and mouse keratinocytes and in the skin tissues from human patients and mice showed that UV treatment triggers ubiquitination and downregulation of the type I IFN receptor chain IFNAR1, leading to suppression of IFN signaling and an ensuing decrease in the expression of inflammatory cytokines and chemokines. The severity of imiquimod-induced psoriasiform inflammation was greatly exacerbated in skin of mice deficient in IFNAR1 ubiquitination (Ifnar1(SA)).

Reconstructing skin cancers using animal models.

The American Cancer Society estimates that skin cancer is the most prevalent of all cancers with over 2 million cases of nonmelanoma skin cancer each year and 75,000 melanoma cases in 2012. Representative animal cancer models are important for understanding the underlying molecular pathogenesis of these cancers and the development of novel targeted anticancer therapeutics. In this review, we will discuss some of the important animal models that have been useful to identify important pathways involved in basal cell carcinoma, squamous cell carcinoma, and melanoma.

From keratinocyte to cancer: the pathogenesis and modeling of cutaneous squamous cell carcinoma.

Cutaneous squamous cell carcinoma (cSCC) is the second most common human cancer with over 250,000 new cases annually in the US and is second in incidence only to basal cell carcinoma. cSCC typically manifests as a spectrum of progressively advanced malignancies, ranging from a precursor actinic keratosis (AK) to squamous cell carcinoma (SCC) in situ (SCCIS), invasive cSCC, and finally metastatic SCC. In this Review we discuss clinical and molecular parameters used to define this range of cutaneous neoplasia and integrate these with the multiple experimental approaches used to study this disease.

Allergic contact dermatitis.

Allergic contact dermatitis is a classic example of a cell mediated hypersensitivity reaction in the skin. This occurs as a result of xenobiotic chemicals penetrating into the skin, chemically reacting with self proteins, eventually resulting in a hapten-specific immune response. It is precisely because of this localized immune response that allergic signs and symptoms occur (redness, edema, warmth and pruritus).

Human natural killer T cells infiltrate into the skin at elicitation sites of allergic contact dermatitis.

The purpose of this study is to identify invariant natural killer T cells (NKT cells) in cellular infiltrate of human allergic contact dermatitis (ACD) skin challenge sites. Skin biopsy specimens were taken from positive patch test reactions from 10 different patients (9 different allergens) and studied by immunochemistry, real-time PCR, nested PCR, and in situ hybridization to identify NKT cells and the cytokines associated with this cell type. Invariant NKT cells were identified in all the 10 skin biopsy specimens studied, ranging from 1.

The Herpes simplex virus gene Pol expressed in herpes-associated erythema multiforme lesions upregulates/activates SP1 and inflammatory cytokines.

Background/aims: Herpes-simplex-virus-associated erythema multiforme (HAEM) is characterized by lesional skin expression of the viral protein Pol and localized inflammation. The objective of this study is to examine the mechanism whereby Pol induces localized inflammation.

Methods: A431 cells transfected with Pol or an empty vector and lesional skin from HAEM or drug-induced erythema multiforme patients were examined for expression of the transcription factor SP1 and SP1-regulated genes by immunoblotting, immunohistochemistry and immunofluorescence.

Novel homozygous frameshift mutation of EVER1 gene in an epidermodysplasia verruciformis patient.

Epidermodysplasia verruciformis (EV) is a rare genetic skin disease with an autosomal recessive trait, and the patients have susceptibility to a specific group of human papillomavirus genotypes. Recently germline mutations in EVER1/2 genes have been detected in EV patients with different ethnic origins. In this study, we have applied PCR, single-stranded conformational polymorphism analysis, and sequencing as well as restriction fragment length polymorphism analysis for identifying potential mutation(s) of EVER genes in an EV patient and in the parents of Pakistani origin.

The growth compromised HSV-2 mutant DeltaRR prevents kainic acid-induced apoptosis and loss of function in organotypic hippocampal cultures.

We have previously shown that the HSV-2 anti-apoptotic protein ICP10PK is delivered by the replication incompetent virus mutant DeltaRR and prevents kainic acid (KA)-induced epileptiform seizures and neuronal cell loss in the mouse and rat models of temporal lobe epilepsy. The present studies used DeltaRR and the ICP10PK deleted virus mutant DeltaPK to examine the mechanism of neuroprotection. DeltaRR-infected neuronal cells expressed a chimeric protein in which ICP10PK is fused in frame to LacZ (p175) while retaining ICP10PK kinase activity.

Intranasal administration of the growth-compromised HSV-2 vector DeltaRR prevents kainate-induced seizures and neuronal loss in rats and mice.

Identification of targets and delivery platforms for gene therapy of neurodegenerative disorders is a clinical challenge. We describe a novel paradigm in which the neuroprotective gene is the herpes simplex virus type 2 (HSV-2) antiapoptotic gene ICP10PK and the vector is the growth-compromised HSV-2 mutant DeltaRR. DeltaRR is delivered intranasally.

Stress up-regulates neuronal expression of the herpes simplex virus type 2 large subunit of ribonucleotide reductase (R1; ICP10) by activating activator protein 1.

Herpes simplex virus type 2 (HSV-2) genes expressed in neuronal cells in response to stress stimuli that trigger latency reactivation are largely unknown. Using a chloramphenicol acetyltransferase (CAT) reporter assay we found that stress caused a significant (P < .001) increase in ICP10 expression in neuronal cells.

Herpes simplex virus type 2 encodes a heat shock protein homologue with apoptosis regulatory functions.

The decision to undergo apoptosis lies in the balance between pro- and anti-apoptotic proteins. Since virus replication relies on the cellular machinery, viruses have evolved various strategies to alter this balance. They target the Bcl-2 and signaling protein kinase (PK) apoptosis modulatory families by encoding homologues or altering the expression of the cellular proteins.

Forced expression of the H11 heat shock protein can be regulated by DNA methylation and trigger apoptosis in human cells.

H11, the eukaryotic homologue of a herpes simplex virus protein, has the crystallin motif of heat shock proteins (Hsp), but it differs from canonical family members in that mRNA and protein levels were reduced in various tumor tissues and cell lines (viz. melanoma, prostate cancer and sarcoma) relative to their normal counterparts. In these cells, expression was not restored by heat shock, but rather by the demethylating agent 5-aza-2'-deoxycytidine (Aza-C).