角质形成细胞中的 HG 和 KdPT 的影响

Summary 糖尿病是一种常见病,影响全世界数百万人。它表现为血液和身体内的葡萄糖浓度增高。慢性足部溃疡是糖尿病最严重的并发症之一,影响高达 10% 的糖尿病患者。这类溃疡依然难以治疗,导致医疗保健系统成本高昂和患者中的死亡率增高。这项来自德国的研究旨在了解高血糖对表皮角质形成细胞的影响,这种细胞是皮肤最外层的细胞,也是伤口愈合的关键细胞。此外,该研究还调查了一种称为 KdPT 的小分子能否使角质形成细胞免于葡萄糖引发应激和毒性的伤害。作者们在有或无 KdPT 的情况下,通过细胞培养物模型和来自健康受试者的皮肤活检标本调查了角质形成细胞在高糖条件下的各种功能。高糖可减少角质形成细胞的细胞增殖和活力(意味着导致细胞数量减少和健康细胞数量减少)以及迁移(细胞运动)。它还改变了细胞大小和弹性。除了上述发现,还观察到对细胞具有毒性的活性氧簇数量增加和细胞内应激。但是,KdPT 缓解了高血糖的部分负面影响。作者们的这些发现强调了 KdPT 的一种新作用,即,可能被用于开发针对糖尿病皮肤溃疡的新疗法。 Linked Article: Gkogkolou et al. Br J Dermatol 2019; 180:836–84

HG in keratinocytes and the impact of KdPT

Summary Diabetes is a common disease affecting millions of people worldwide. It is characterized by increased glucose concentrations in the blood and body. Chronic foot ulcers are one of the most serious complications in diabetes, affecting up to 10% of diabetic patients. Treatment of these ulcers remains difficult, resulting in high costs for healthcare systems as well as increased mortality in patients. This study from Germany aimed to characterize the effects of high glucose on epidermal keratinocytes, the cells of the outermost layer of the skin and a key cell type for wound healing. Furthermore, it examined if a small molecule, called KdPT, can protect keratinocytes from glucose‐induced stress and toxicity. The authors investigated various functions of keratinocytes under high‐glucose conditions with or without KdPT in cell culture models as well as in skin biopsies from healthy subjects. High glucose reduced cell proliferation and viability (meaning it caused a decrease in the number of cells, and a decrease in the number of healthy cells), and migration (cellular movement) of keratinocytes. It also altered the cell size and elasticity. Parallel to these changes, increased amounts of reactive oxygen species, which are toxic to cells, as well as intracellular stress were observed. However, KdPT reduced some of these negative effects of high glucose. The authors’ findings highlight a novel effect of KdPT, which could be used to develop new treatments for diabetic skin ulcers. Linked Article: Gkogkolou et al. Br J Dermatol 2019; 180:836–84

The genetic basis for most patients with pustular skin disease remains elusive

Background Rare variants in the genes IL36RN, CARD14 and AP1S3 have been identified to cause or contribute to pustular skin diseases, primarily generalized pustular psoriasis (GPP). Objectives To better understand the disease relevance of these genes, we screened our cohorts of patients with pustular skin diseases [primarily GPP and palmoplantar pustular psoriasis (PPP)] for coding changes in these three genes. Carriers of single heterozygous IL36RN mutations were screened for a second mutation in IL36RN. Methods Coding exons of IL36RN, CARD14 and AP1S3 were sequenced in 67 patients – 61 with GPP, two with acute generalized exanthematous pustulosis and four with acrodermatitis continua of Hallopeau. We screened IL36RN and AP1S3 for intragenic copy‐number variants and 258 patients with PPP for coding changes in AP1S3. Eleven heterozygous IL36RN mutations carriers were analysed for a second noncoding IL36RN mutation. Genotype–phenotype correlations in carriers/noncarriers of IL36RN mutations were assessed within the GPP cohort. Results The majority of patients (GPP, 64%) did not carry rare variants in any of the three genes. Biallelic and monoallelic IL36RN mutations were identified in 15 and five patients with GPP, respectively. Noncoding rare IL36RN variants were not identified in heterozygous carriers. The only significant genotype–phenotype correlation observed for IL36RN mutation carriers was early age at disease onset. Additional rare CARD14 or AP1S3 variants were identified in 15% of IL36RN mutation carriers. Conclusions The identification of IL36RN mutation carriers harbouring additional rare variants in CARD14 or AP1S3 indicates a more complex mode of inheritance of pustular psoriasis. Our results suggest that, in heterozygous IL36RN mutation carriers, there are additional disease‐causing genetic factors outside IL36RN