An update of the defensive barrier function of skin

Skin, as the outermost organ in the human body, continuously confronts the external environment and serves as a primary defense system. The protective functions of skin include UV-protection, anti-oxidant and antimicrobial functions. In addition to these protections, skin also acts as a sensory organ and the primary regulator of body temperature. Within these important functions, the epidermal permeability barrier, which controls the transcutaneous movement of water and other electrolytes, is probably the most important. This permeability barrier resides in the stratum corneum, a resilient layer composed of corneocytes and stratum corneum intercellular lipids. Since the first realization of the structural and biochemical diversities involved in the stratum corneum, a tremendous amount of work has been performed to elucidate its roles and functions in the skin, and in humans in general. The perturbation of the epidermal permeability barrier, previously speculated to be just a symptom involved in skin diseases, is currently considered to be a primary pathophysiologic factor for many skin diseases. In addition, much of the evidence provides support for the idea that various protective functions in the skin are closely related or even co-regulated. In this review, the recent achievements of skin researchers focusing on the functions of the epidermal permeability barrier and their importance in skin disease, such as atopic dermatitis and psoriasis, are introduced.     

Pioglitazone does not increase cerebral glucose utilisation in a murine model of Alzheimer’s disease and decreases it in wild-type mice

Aims/hypothesis Clinical trials are in progress to test thiazolidinediones in neurodegenerative diseases such as Alzheimer’s disease that involve deficiencies in brain glucose metabolism. While thiazolidinediones enhance glucose uptake in non-cerebral tissues, their impact on brain energy metabolism has not been investigated in vivo. We thus determined whether the thiazolidinedione pioglitazone reverses the decrease in cerebral glucose utilisation (CGU) in a model of brain metabolic deficiency related to Alzheimer’s disease. Results are relevant to diabetes because millions of diabetic patients take pioglitazone as an insulin-sensitising drug, and diabetes increases the risk of developing Alzheimer’s disease.Materials and methods The regional pattern of CGU was measured with the 2-deoxy [¹⁴C] glucose autoradiographic technique in adult awake mice overexpressing transforming growth factor β1 (TGFβ1), and in wild-type littermates. Mice were treated with pioglitazone for 2 months.Results Measurement of CGU in 27 brain regions confirmed that TGFβ1 overexpression induced hypometabolism across the brain. Pioglitazone did not reverse the effect of TGFβ1 overexpression and decreased regional CGU in control animals by up to 23%. The extent of the regional CGU decrease induced by pioglitazone, but not that induced by TGFβ1, correlated strongly with basal CGU, suggesting that the higher the local metabolic rate the greater the reduction of CGU effected by pioglitazone.Conclusions/interpretation In contrast to its stimulatory effect in non-cerebral tissues, chronic treatment with pioglitazone decreases CGU in vivo. This evidence does not support the hypothesis that pioglitazone could act as a metabolic enhancer in Alzheimer’s disease, and raises the question of how thiazolidinediones could be beneficial in neurodegenerative diseases.     

Carcinogenesis in mouse stomach by simultaneous activation of the Wnt signaling and prostaglandin E2 pathway

BACKGROUND & AIMS: Accumulating evidence indicates that prostaglandin E(2) (PGE(2)), a downstream product of cyclooxygenase 2 (COX-2), plays a key role in gastric tumorigenesis. The Wnt pathway is also suggested to play a causal role in gastric carcinogenesis. However, the molecular mechanism remains poorly understood of how the Wnt and PGE(2) pathways contribute to gastric tumorigenesis. To investigate the role of Wnt and PGE(2) in gastric cancer, we have generated transgenic mice that activate both pathways and examined their phenotypes. METHODS: We constructed K19-Wnt1 transgenic mice expressing Wnt1 in the gastric mucosa using the keratin 19 promoter. We then crossed K19-Wnt1 mice with another transgenic line, K19-C2mE, to obtain K19-Wnt1/C2mE compound transgenic mice. The K19-C2mE mice express COX-2 and microsomal prostaglandin E synthase-1 (mPGES-1) in the stomach, showing an increased gastric PGE(2) level. We examined the gastric phenotypes of both K19-Wnt1 and K19-Wnt1/C2mE mice. RESULTS: K19-Wnt1 mice had a significant suppression of epithelial differentiation and developed small preneoplastic lesions consisting of undifferentiated epithelial cells with macrophage accumulation. Importantly, additional expression of COX-2 and mPGES-1 converted the preneoplastic lesions in the K19-Wnt1 mice into dysplastic gastric tumors by 20 weeks of age. Notably, we found mucous cell metaplasia in the glandular stomach of the K19-Wnt1/C2mE mice as early as 5 weeks of age, before the dysplastic tumor development. CONCLUSIONS: Wnt signaling keeps the gastric progenitor cells undifferentiated. Simultaneous activation of both Wnt and PGE(2) pathways causes dysplastic gastric tumors through the metaplasia-carcinoma sequence.     

The emerging roles of hydrogen sulfide in the gastrointestinal tract and liver

Hydrogen sulfide, like nitric oxide, was best known as a toxic pollutant before becoming recognized as a key regulator of several physiologic processes. In recent years, evidence has accumulated to suggest important roles for hydrogen sulfide as a mediator of several aspects of gastrointestinal and liver function. Moreover, alterations in hydrogen sulfide production could contribute to disorders of the gastrointestinal tract and liver. For example, nonsteroidal anti-inflammatory drugs can reduce production of hydrogen sulfide in the stomach, and this has been shown to contribute to the generation of mucosal injury. Hydrogen sulfide has also been shown to play a key role in modulation of visceral hyperalgesia. Inhibitors of hydrogen sulfide synthesis and drugs that can generate safe levels of hydrogen sulfide in vivo have been developed and are permitting interventional studies in experimental models and, in the near future, humans.