The resistance of tissues to physical stress is dependent upon strong cell-cell adhesion in which desmosomes play a crucial role. We propose that desmosomes fulfil this function by adopting a more strongly adhesive state, hyper-adhesion, than other junctions. We show that the hyper-adhesive desmosomes in epidermis resist disruption by ethylene glycol bis(2-aminoethyl ether)-N,N,N′N′-tetraacetic acid (EGTA) and are thus independent of Ca2+. We propose that Ca2+ independence is the normal condition for tissue desmosomes. Ca2+ independence is associated with an organised arrangement of the intercellular adhesive material exemplified by a dense midline. When epidermis is wounded, desmosomes in the wound-edge epithelium lose hyper-adhesiveness and become Ca2+ dependent, i.e. readily dissociated by EGTA. Ca2+-dependent desmosomes lack a midline and show narrowing of the intercellular space. We suggest that this indicates a less-organised, weakly adhesive arrangement of the desmosomal cadherins, resembling classical cadherins in adherens junctions. Transition to Ca2+ dependence on wounding is accompanied by relocalisation of protein kinase C α to desmosomal plaques suggesting that an `inside-out' transmembrane signal is responsible for changing desmosomal adhesiveness. We model hyper-adhesive desmosomes using the crystal packing observed for the ectodomain of C-cadherin and show how the regularity of this 3D array provides a possible explanation for Ca2+ independence.

The desmoglein 1 (Dsg1) and desmocollin 1 (Dsc1) isoforms of the desmosomal cadherins are expressed in the suprabasal layers of epidermis, whereas Dsg3 and Dsc3 are more strongly expressed basally. This differential expression may have a function in epidermal morphogenesis and/or may regulate the proliferation and differentiation of keratinocytes. To test this hypothesis, we changed the expression pattern by overexpressing human Dsg3 under the control of the keratin 1 (K1) promoter in the suprabasal epidermis of transgenic mice. From around 12 weeks of age, the mice exhibited flaking of the skin accompanied by epidermal pustules and thinning of the hair. Histological analysis of affected areas revealed acanthosis, hypergranulosis, hyperkeratosis, localized parakeratosis, and abnormal hair follicles. This phenotype has some features in common with human ichthyosiform diseases. Electron microscopy revealed a mild epidermal spongiosis. Suprabasally, desmosomes showed incorporation of the exogenous protein by immunogold labeling but were normal in structure. The epidermis was hyperproliferative, and differentiation was abnormal, demonstrated by expression of K14 in the suprabasal layer, restriction of K1, and strong induction of K6 and K16. The changes resembled those found in previous studies in which growth factors, cytokines, and integrins had been overexpressed in epidermis. Thus our data strongly support the view that Dsg3 contributes to the regulation of epidermal differentiation. Our results contrast markedly with those recently obtained by expressing Dsg3 in epidermis under the involucrin promoter. Possible reasons for this difference are considered in this paper.

Desmosomes are intercellular junctions that provide strong adhesion or hyper-adhesion in tissues. Here, we discuss the molecular and structural basis of this with particular reference to the desmosomal cadherins (DCs), their isoforms and evolution. We also assess the role of DCs as regulators of epithelial differentiation. New data on the role of desmosomes in development and human disease, especially wound healing and pemphigus, are briefly discussed, and the importance of regulation of the adhesiveness of desmosomes in tissue dynamics is considered.

New insights have been added to identification, behavior and cellular properties of embryonic and tissue-specific stem cells over the last few years. The modes of stem cell division, asymmetric vs. symmetric, are tightly regulated during development and regeneration. The proper choice of a stem cell to divide asymmetrically or symmetrically has great consequences for development and disease because inappropriate asymmetric division disrupts organ morphogenesis, whereas uncontrolled symmetric division induces tumorigenesis. Therefore, understanding the behavior of lung stem cells could identify innovative solutions for restoring normal morphogenesis and/or regeneration of different organs. In this concise review, we describe recent studies in our laboratory about the mode of division of lung epithelial stem cells. We also compare asymmetric cell division (ACD) in the lung stem cells with other tissues in different organisms.

The Eya1 gene encodes a transcriptional co-activator that acts with Six1 to control the development of different organs. However, Six1-Eya1 interactions and functional roles in mesenchymal cell proliferation and differentiation as well as alveolarization during the saccular stage of lung development are still unknown. Herein, we provide the first evidence that Six1 and Eya1 act together to regulate mesenchymal development as well as alveolarization during the saccular phase of lung morphogenesis. Deletion of either or both Six1 and Eya1 genes results in a severe saccular phenotype, including defects of mesenchymal cell development and remodeling of the distal lung septae and arteries. Mutant lung histology at the saccular phase shows mesenchymal and saccular wall thickening, and abnormal proliferation of α-smooth muscle actin-positive cells, as well as increased mesenchymal/fibroblast cell differentiation, which become more sever when deleting both genes. Our study indicates that SHH but not TGF-β signaling pathway is a central mediator for the histologic alterations described in the saccular phenotype of Eya1(-/-) or Six1(-/-) lungs. Indeed, genetic reduction of SHH activity in vivo or inhibition of its activity in vitro substantially rescues lung mesenchymal and alveolar phenotype of mutant mice at the saccular phase. These findings uncover novel functions for Six1-Eya1-SHH pathway during the saccular phase of lung morphogenesis, providing a conceptual framework for future mechanistic and translational studies in this area.

Patients with chronic, painful diseases often seek alternative therapy. The purpose of this study was to investigate the potential of hydroalcoholic extract of Zingiber officinale rhizomes ( Z. officinale extract) to ameliorate inflammatory process in rat collagen-induced arthritis. Our results show that Z. officinale extract in doses higher than 50 mg/kg/day intraperitoneally starting from the dose of booster immunization and for 26 days can ameliorate the clinical scores, disease incidence, joint temperature and swelling, and cartilage destruction, together with reduction of serum levels of interleukin (IL)-1 β , IL-2, IL-6, tumour necrosis factor-α , and anti-CII antibodies. Moreover, Z. officinale extract at the dose of 200 mg/kg/day was superior to 2 mg/kg/day of indomethacin at most of the measured parameters. These observations might make Z. officinale extract a good alternative to non-steroidal anti-inflammatory drugs for patients with rheumatoid arthritis.

SummaryLittle is known about the regulatory mechanisms underlying lung epithelial tight junction (TJ) assembly, which is inextricably linked to the preservation of epithelial polarity, and is highly coordinated by proteins that regulate epithelial cell polarity, such as aPKCf. We recently reported that Eya1 phosphatase functions through aPKCf-Notch1 signaling to control cell polarity in the lung epithelium. Here, we have extended these observations to TJ formation to demonstrate that Eya1 is crucial for the maintenance of TJ protein assembly in the lung epithelium, probably by controlling aPKCf phosphorylation levels, aPKCf-mediated TJ protein phosphorylation and Notch1-Cdc42 activity. Thus, TJs are disassembled after interfering with Eya1 function in vivo or during calcium-induced TJ assembly in vitro. These effects are reversed by reintroduction of wild-type Eya1 or partially inhibiting aPKCf in Eya1siRNA cells. Moreover, genetic activation of Notch1 rescues Eya1 2/2 lung epithelial TJ defects. These findings uncover novel functions for the Eya1-aPKCf-Notch1-Cdc42 pathway as a crucial regulatory mechanism of TJ assembly and polarity of the lung epithelium, providing a conceptual framework for future mechanistic and translational studies in this area.

To assess the effect of seminal redox status on lipid peroxidation)LPO(, apoptosis and integrity of sperm DNA in infertile males. Methods: In this case-control study, the total antioxidant status)TAS(and reactive oxygen species)ROS(levels were analyzed within the seminal plasma of fertile normozoospermic, n=40 and infertile)asthenozoospermic, n=30; oligoasthenoteratozoospermic, n=30(males. Additionally, the level of 4-hydroxynonenal)4-HNE(, DNA fragmentation, and caspase-3 activity were estimated in the spermatozoa. Original Article Results: Significantly)p<0.001(increased seminal ROS level with decreased TAS scores was observed in the infertile groups compared to normozoospermics. The infertile males showed marked elevated)p<0.001(levels of 4-HNE, DNA fragmentation and caspase-3 activity compared to normozoospermics, which was positively correlated to increased seminal ROS levels and negatively to the TAS score in the studied groups. Seminal ROS level was significantly inverse correlated to the semen parameters. Additionally, a strong negative correlation between DNA fragmentation, LPO, caspase-3activity and seminal parameters were observed. Conclusion: Seminal oxidative stress is a potential risk factor for LPO, DNA damage, and apoptosis in spermatozoa, which can affect semen quality and male fertility. Thus, in addition to conventional seminological parameters, measurement of seminal oxidative stress and sperm DNA integrity may also be employed to investigate the functional integrity of spermatozoa at the molecular level.