40Ni-Added Poly(polyoxometalate) Assembled by {Ni6GeW9} and {Ni8(GeW9)2} Units: Structure, Magnetic, and Heterogeneous Catalysis Properties.

A novel 40Ni-added germanotungstate, Cs8K14Na3H3{[Ni6(OH)3(H2O)6(B-α-GeW9O34)]2[Ni8(µ6-O)(µ2-OH)2 (µ3-OH)2(H2O)B2O3(OH)2(B-α-GeW9O34)2]}2·84H2O (1), was made by the reaction of the trivacant [A-α-GeW9O34]10- ({GeW9}) precursor with Ni2+ cations and B5O8-, and systematically investigated by Fourier-transform infrared spectroscopy, elemental analysis, thermogravimetric analysis, and powder X-ray diffraction. Single crystal X-ray analysis indicates that the polyoxoanion of 1 is a novel octamer constructed by {Ni6GeW9} and {Ni8(GeW9)2} structural building units via Ni-O═W linkages. The magnetic behavior shows the existence of overall ferromagnetic interactions among the Ni2+ centers in compound 1. Photocatalytic H2 production studies have implied that 1 can work as a heterogeneous catalyst for hydrogen production with decent robustness and recyclability.

The NLRP3 Inflammasome: An Important Driver of Neuroinflammation in Hemorrhagic Stroke.

Hemorrhagic stroke is a devastating clinical event with no effective medical treatment. Neuroinflammation, which follows a hemorrhagic stroke, is an important element that involves both acute brain injury and subsequent brain rehabilitation. Therefore, delineating the key inflammatory mediators and deciphering their pathophysiological roles in hemorrhagic strokes is of great importance in the development of novel therapeutic targets for this disease. The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is a multi-protein complex that is localized within the cytoplasm. This NOD-like receptor orchestrates innate immune responses to pathogenic organisms and cell stress through the activation of caspase-1 and the maturation of the proinflammatory cytokines such as interleukin-1ß (IL-1ß) and IL-18. Mounting evidence has demonstrated that when the NLRP3 inflammasome is activated, it exerts harmful effects on brain tissue after a hemorrhagic stroke. This review article summarizes the current knowledge regarding the role and the underlying mechanisms of the NLRP3 inflammasome in the pathophysiological processes of hemorrhagic strokes. A better understanding of the function and regulation of the NLRP3 inflammasome in hemorrhagic strokes will provide clues for devising novel therapeutic strategies to fight this disease.

Loss of Desmocollin 3 in skin tumor development and progression.

Desmocollin 3 (DSC3) is a desmosomal cadherin that is required for maintaining cell adhesion in the epidermis as demonstrated by the intra-epidermal blistering observed in Dsc3 null skin. Recently, it has been suggested that deregulated expression of DSC3 occurs in certain human tumor types. It is not clear whether DSC3 plays a role in the development or progression of cancers arising in stratified epithelia such as the epidermis. To address this issue, we generated a mouse model in which Dsc3 expression is ablated in K-Ras oncogene-induced skin tumors. Our results demonstrate that loss of Dsc3 leads to an increase in K-Ras-induced skin tumors. We hypothesize that acantholysis-induced epidermal hyperplasia in the Dsc3 null epidermis facilitates Ras-induced tumor development. Further, we demonstrate that spontaneous loss of DSC3 expression is a common occurrence during human and mouse skin tumor progression. This loss occurs in tumor cells invading the dermis. Interestingly, other desmosomal proteins are still expressed in tumor cells that lack DSC3, suggesting a specific function of DSC3 loss in tumor progression. While loss of DSC3 on the skin surface leads to epidermal blistering, it does not appear to induce loss of cell-cell adhesion in tumor cells invading the dermis, most likely due to a protection of these cells within the dermis from mechanical stress. We thus hypothesize that DSC3 can contribute to the progression of tumors both by cell adhesion-dependent (skin surface) and likely by cell adhesion-independent (invading tumor cells) mechanisms.

Preparation and Evaluation of Liposomes and Niosomes Containing Total Ginsenosides for Anti-Photoaging Therapy.

Ginsenosides are the principal bioactive compounds of ginseng. Total ginsenosides (GS) contain a variety of saponin monomers, which have potent anti-photoaging activity and improve the skin barrier function. To enhance the efficiency of GS transdermal absorption, GS liposomes (GSLs) and GS niosomes (GSNs) were formulated as delivery vehicles. Based on the clarified and optimized formulation process, GSL and GSN were prepared. The structure, cumulative transmittance, skin retention, total transmittance, and bioactivity of GSLs and GSNs were characterized. GSL and GSN were shown to inhibit lipid peroxidation and increase the contents of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in human keratinocytes (HaCaTs). In addition, HaCAT cell migration, proliferation, and GS cellular uptake were significantly increased. The therapeutic effects of GSL and GSN were also evaluated in a rat model of photoaging. Histopathological changes were assessed in rat skin treated with GSL, GSN, or GS by hematoxylin-eosin (H&E) and aldehyde fuchsine staining. Malondialdehyde (MDA), SOD, GSH-Px, matrix metalloproteinases (MMPs), interleukin-6 (IL-6), interleukin-1ß (IL-1ß), and tumor necrosis factor-α (TNF-α) expression levels were determined. Results indicated that the optimal formulation of GSL used soybean lecithin (SPC) as the phospholipid, with a lipid-drug ratio of 1:0.4 and a phospholipid-cholesterol ratio of 1:3.5. The optimal temperature for the preparation process of GSN by ethanol injection was 65°C, with a ratio of the organic phase to aqueous phase of 1:9. It was demonstrated that the cumulative release rate, skin retention rate, and total transmission rate of GSL-7 at 24 h were higher than those of GSN-4 and GS. GSL-7 significantly inhibited skin lipid peroxidation caused by ultraviolet (UV) radiation. In addition, GSL-7 reduced the contents of MMPs and inflammatory cytokines in skin tissue. In conclusion, GSL-7 may reduce skin aging caused by UV radiation and contribute to skin tissue repair.

Serum netrin-1 serves as a prognostic biomarker of aneurysmal subarachnoid hemorrhage.

BACKGROUND: Netrin-1 exhibits anti-inflammatory properties. Netrin-1 could alleviate brain injury of subarachnoid hemorrhage (SAH) rat. This study was designed to discern the utility of serum netrin-1 as a biomarker for assessing the severity and prognosis of patients with aneurysmal SAH. METHODS: Netrin-1 concentrations were gauged in serum from 104 patients and 104 controls. Hemorrhagic clinical and radiological severity was assessed utilizing World Federation of Neurological Surgeons (WFNS) score, modified Fisher score, and Hunt Hess score. Glasgow Outcome Scale (GOS) score was recorded at 6 months after SAH. GOS score of 1-3 was considered as a poor outcome. RESULTS: Patients showed substantially lower serum netrin-1 concentrations than controls (median, 237.9 pg/ml; interquartile range, 189.6-271.2 pg/ml vs. median, 815.4 pg/ml; interquartile range, 581.8-990.4 pg/ml). Netrin-1 concentrations were independently correlated with WNFS score, modified Fisher score, Hunt Hess score and serum C-reactive protein concentrations (t = -4.667, -3.792, -4.304 and - 3.549 respectively). Area under ROC curve was 0.837 (95% CI, 0.752-0.902) for predicting 6-month poor prognosis. Serum netrin-1 concentrations <229.3 pg/ml emerged as an independent prognostic predictor (odds ratio, 14.316; 95% confidence interval, 5.032-40.726). CONCLUSIONS: Serum netrin-1 might represent a potential biomarker for reflecting severity, inflammation and prognosis of human aneurysmal SAH.

Integrating animal models and in vitro tissue models to elucidate the role of desmosomal proteins in diseases.

Desmosomes are intercellular junctions that provide tissues with structural stability. These junctions might also act as signaling centers that transmit environmental clues to the cell, thereby affecting cell differentiation, migration, and proliferation. The importance of desmosomes is underscored by devastating skin and heart diseases caused by mutations in desmosomal genes. Recent observations suggest that abnormal desmosomal protein expression might indirectly contribute to skin disorders previously not linked to these proteins. For example, it has been postulated that reduced desmosomal protein expression occurs in patients affected by Ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (AEC), a skin fragility disorder caused by mutations in the transcription factor TP63. Currently, it is not clear how these changes in desmosomal gene expression contribute to AEC. We will discuss new approaches that combine in vitro and in vivo models to elucidate the role of desmosomal gene deregulation in human skin diseases such as AEC.

Plakoglobin as a regulator of desmocollin gene expression.

Desmosomes are cell adhesion junctions required for the normal development and maintenance of mammalian tissues and organs such as the skin, skin appendages, and the heart. The goal of this study was to investigate how desmocollins (DSCs), transmembrane components of desmosomes, are regulated at the transcriptional level. We hypothesized that differential expression of the Dsc2 and Dsc3 genes is a prerequisite for normal development of skin appendages. We demonstrate that plakoglobin (Pg) in conjunction with lymphoid enhancer-binding factor 1 (Lef-1) differentially regulates the proximal promoters of these two genes. Specifically, we found that Lef-1 acts as a switch activating Dsc2 and repressing Dsc3 in the presence of Pg. Interestingly, we also determined that NF-κB pathway components, the downstream effectors of the ectodysplasin-A (EDA)/ ectodysplasin-A receptor (EDAR)/NF-κB signaling cascade, can activate Dsc2 expression. We hypothesize that Lef-1 and EDA/EDAR/NF-κB signaling contribute to a shift in Dsc isoform expression from Dsc3 to Dsc2 in placode keratinocytes. It is tempting to speculate that this shift is required for the invasive growth of placode keratinocytes into the dermis, a crucial step in skin appendage formation.

Mouse models for blistering skin disorders.

Genetically engineered mice have been essential tools for elucidating the pathological mechanisms underlying human diseases. In the case of diseases caused by impaired desmosome function, mouse models have helped to establish causal links between mutations and disease phenotypes. This review focuses on mice that lack the desmosomal cadherins desmoglein 3 or desmocollin 3 in stratified epithelia. A comparison of the phenotypes observed in these mouse lines is provided and the relationship between the mutant mouse phenotypes and human diseases, in particular pemphigus vulgaris, is discussed. Furthermore, we will discuss the advantages and potential limitations of genetically engineered mouse lines in our ongoing quest to understand blistering skin diseases.

Loss of desmocollin 3 in mice leads to epidermal blistering.

Desmocollin 3 (DSC3) belongs to a subfamily of cadherins and is a major component of desmosomes in keratinocytes of stratified epithelia, such as the epidermis. Based on its amino acid sequence homology to classical cadherins, such as E-cadherin, it has been postulated that DSC3 functions as a cell-adhesion molecule. To test this hypothesis, we assessed the function of DSC3 in the development and maintenance of stratified epithelia, in particular the epidermis and hair follicles. Using a conditional null allele, we show that loss of Dsc3 function in the epidermis causes impaired cell-cell adhesion, leading to intra-epidermal blistering and telogen hair loss. Furthermore, the lesions in Dsc3-null skin resemble those observed in individuals with pemphigus vulgaris (PV), indicating that impaired Dsc3 function could be a potential cause of PV-like inherited or acquired skin blistering diseases.

An unexpected role for keratin 10 end domains in susceptibility to skin cancer.

Keratin 10 (K10) is a type I keratin that is expressed in post-mitotic suprabasal keratinocytes of the skin. Based on cell culture experiments and transgenic mouse studies, it has been proposed that K10 suppresses cell proliferation and tumor formation in the skin. Furthermore, the ability of K10 to suppress cell proliferation was mapped to its unique N- and C-terminal protein domains. In the present study, we modified the endogenous keratin 14 (K14) gene of mice using a knock-in approach to encode a chimeric keratin that consists of the K14 rod domain fused to the K10 head and tail domains (K1014chim). This transgene was expressed in the basal layer of the epidermis and the outer root sheath of hair follicles. Unexpectedly, we found that the K10 end domains had no effect on basal keratinocyte proliferation in vivo. Moreover, when subjected to a chemical skin carcinogenesis protocol, papilloma formation in mutant mice was accelerated instead of being inhibited. Our data suggest that the increased tumor susceptibility of K1014chim mice is in part due to a suppression of apoptosis in mutant keratinocytes. Our results support the notion that intermediate filaments, in addition to their function as cytoskeletal components, affect tumor susceptibility of epithelial cells.