Psoriasis is a chronic, inflammatory skin disease involving both environmental and genetic factors. According to genome-wide association studies (GWAS), the TNIP1 gene, which encodes the TNF-α-induced protein 3-interacting protein 1 (TNIP1), is strongly linked to the susceptibility of psoriasis. TNIP1 is a widely expressed ubiquitin sensor that binds to the ubiquitin-editing protein A20 and restricts TNF- and TLR-induced signals. In our study, TNIP1 expression decreased in specimens of epidermis affected by psoriasis. Based on previous studies suggesting a role for TNIP1 in modulating cancer cell growth, we investigated its role in keratinocyte proliferation, which is clearly abnormal in psoriasis. To mimic the downregulation or upregulation of TNIP1 in HaCaT cells and primary human keratinocytes (PHKs), we used a TNIP1 specific small interfering hairpin RNA (TNIP1 shRNA) lentiviral vector or a recombinant TNIP1 (rTNIP1) lentiviral vector, respectively. Blocking TNIP1 expression increased keratinocyte proliferation, while overexpression of TNIP1 decreased keratinocyte proliferation. Furthermore, we showed that TNIP1 signaling might involve extracellular signal-regulated kinase1/2 (Erk1/2) and CCAAT/enhancer-binding protein β (C/EBPβ) activity. Intradermal injection of TNIP1 shRNA in BALB/c mice led to exaggerated psoriatic conditions in imiquimod (IMQ)-induced psoriasis-like dermatitis. These findings indicate that TNIP1 has a protective role in psoriasis and therefore could be a promising therapeutic target.

To develop a method for labeling human bone marrow mesenchymal stem cells (hMSCs) with 89Zr-oxine to characterize the biodistribution characteristics of hMSCs in normal Sprague-Dawley (SD) rats in real-time by micro-PET-computed tomography (micro-PET/CT) imaging.

Dowling-Degos disease (DDD), or reticular pigmented anomaly of the flexures, is a type of rare autosomal-dominant genodermatosis characterized by reticular hyperpigmentation and hypopigmentation of the flexures, such as the neck, axilla, and areas below the breasts and groin, and shows considerable heterogeneity. Loss-of-function mutations of keratin 5 (KRT5) have been identified in DDD individuals. In this study, we collected DNA samples from a large Chinese family affected by generalized DDD and found no mutation of KRT5. We performed a genome-wide linkage analysis of this family and mapped generalized DDD to a region between rs1293713 and rs244123 on chromosome 20 [corrected]. By exome sequencing, we identified nonsense mutation c.430G>T (p.Glu144(∗)) in POFUT1, which encodes protein O-fucosyltransferase 1, in the family. Study of an additional generalized DDD individual revealed the heterozygous deletion mutation c.482delA (p.Lys161Serfs(∗)42) in POFUT1. Knockdown of POFUT1 reduces the expression of NOTCH1, NOTCH2, HES1, and KRT5 in HaCaT cells. Using zebrafish, we showed that pofut1 is expressed in the skin and other organs. Morpholino knockdown of pofut1 in zebrafish produced a phenotype characteristic of hypopigmentation at 48 hr postfertilization (hpf) and abnormal melanin distribution at 72 hpf, replicating the clinical phenotype observed in our DDD individuals. At 48 and 72 hpf, tyrosinase activities decreased by 33% and 45%, respectively, and melanin protein contents decreased by 20% and 25%, respectively. Our findings demonstrate that POFUT1 mutations cause generalized DDD. These results strongly suggest that the protein product of POFUT1 plays a significant and conserved role in melanin synthesis and transport.

Neuropathy is the most common diabetic complication. Although the A1 and A2A adenosine receptors are important pharmacological targets in alleviating diabetic neuropathy, the role of the A3 adenosine receptor remains unknown. Because the A3 adenosine receptor regulates pain induced by chronic constriction injury or chemotherapy, its stimulation might also attenuate diabetic neuropathy. This study examines the effects of systemic treatment with the A3 adenosine receptor agonist 1-deoxy-1-[6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-N-methyl-β-d-ribofuranuronamide (IB-MECA) on diabetic neuropathy and explores the putative mechanisms underlying its pharmacological effects. We show that IB-MECA alleviated mechanical hyperalgesia and thermal hypoalgesia in mice 2 weeks but not 4 weeks after streptozocin (STZ) treatment. Furthermore, IB-MECA prevented the reduction in sciatic motor nerve conduction velocity and sensory nerve conduction velocity in diabetic mice 2 weeks but not 4 weeks after STZ treatment. Similarly, IB-MECA inhibited the activation of nuclear factor-κB and decreased the generation of tumor necrosis factor-α in the spinal cord of mice 2 weeks but not 4 weeks after STZ treatment. These phenomena were associated with reduction of A3 adenosine receptor expression in the spinal cord after long-term diabetes. Our results suggest that the A3 adenosine receptor plays a critical role in regulating diabetic neuropathy and that reduction in A3 adenosine receptor expression/function might contribute to the progression of diabetic neuropathy. © 2016 Wiley Periodicals, Inc.