Tregs depletion aggravates activation of astrocytes by modulating IL-10/GXP4 following cerebral infarction.

Background: Tregs plays a critical role in the development of secondary injuries in diseases. Accumulating evidence suggests an association between ischemic stroke and renal dysfunction; however, the underlying mechanisms remain unclear. This study aimed to investigate the potential of Tregs in inhibiting the activation of astrocytes after focal cerebral infarction. Methods: This study aimed to investigate the renal consequences of focal cerebral ischemia by subjecting a mouse model to transient middle cerebral artery occlusion (tMCAO). Subsequently, we assessed renal fibrosis, renal ferroptosis, Treg infiltration, astrocyte activation, as well as the expression levels of active GPX4, FSP1, IL-10, IL-6, and IL-2 after a 2-week period. Results: In the tMCAO mouse model, depletion of tregs protected against activation of astrocyte and significantly decreased FSP1, IL-6, IL-2, and NLRP3 expression levels, while partially reversing the changes in Tregs. Mechanistically, tregs depletion attenuates renal fibrosis by modulating IL-10/GPX4 following cerebral infarction. Conclusion: Tregs depletion attenuates renal fibrosis by modulating IL-10/GPX4 following cerebral infarction.

The molecular basis for impaired hypoxia-induced VEGF expression in diabetic tissues.

Diabetes is associated with poor outcomes following acute vascular occlusive events. This results in part from a failure to form adequate compensatory microvasculature in response to ischemia. Since vascular endothelial growth factor (VEGF) is an essential mediator of neovascularization, we examined whether hypoxic up-regulation of VEGF was impaired in diabetes. Both fibroblasts isolated from type 2 diabetic patients, and normal fibroblasts exposed chronically to high glucose, were defective in their capacity to up-regulate VEGF in response to hypoxia. In vivo, diabetic animals demonstrated an impaired ability to increase VEGF production in response to soft tissue ischemia. This resulted from a high glucose-induced decrease in transactivation by the transcription factor hypoxia-inducible factor-1alpha (HIF-1alpha), which mediates hypoxia-stimulated VEGF expression. Decreased HIF-1alpha functional activity was specifically caused by impaired HIF-1alpha binding to the coactivator p300. We identify covalent modification of p300 by the dicarbonyl metabolite methylglyoxal as being responsible for this decreased association. Administration of deferoxamine abrogated methylglyoxal conjugation, normalizing both HIF-1alpha/p300 interaction and transactivation by HIF-1alpha. In diabetic mice, deferoxamine promoted neovascularization and enhanced wound healing. These findings define molecular defects that underlie impaired VEGF production in diabetic tissues and offer a promising direction for therapeutic intervention.

C3 Assignment: Camera Cubemap Color Assignment for Creative Interior Design.

Color design for 3D indoor scenes is a challenging problem due to many factors that need to be balanced. Although learning from images is a commonly adopted strategy, this strategy may be more suitable for natural scenes in which objects tend to have relatively fixed colors. For interior scenes consisting mostly of man-made objects, creative yet reasonable color assignments are expected. We propose C3 Assignment, a system providing diverse suggestions for interior color design while satisfying general global and local rules including color compatibility, color mood, contrast, and user preference. We extend these constraints from the image domain to [Formula: see text], and formulate 3D interior color design as an optimization problem. The design is accomplished in an omnidirectional manner to ensure a comfortable experience when the inhabitant observes the interior scene from possible positions and directions. We design a surrogate-assisted evolutionary algorithm to efficiently solve the highly nonlinear optimization problem for interactive applications, and investigate the system performance concerning problem complexity, solver convergence, and suggestion diversity. Preliminary user studies have been conducted to validate the rule extension from 2D to 3D and to verify system usability.

Akt-mediated mechanotransduction in murine fibroblasts during hypertrophic scar formation.

Although numerous factors are implicated in skin fibrosis, the exact pathophysiology of hypertrophic scarring remains unknown. We recently demonstrated that mechanical force initiates hypertrophic scar formation in a murine model, potentially enhancing cellular survival through Akt. Here, we specifically examined Akt-mediated mechanotransduction in fibroblasts using both strain culture systems and our murine scar model. In vitro, static strain increased fibroblast motility, an effect blocked by wortmannin (a phosphoinositide-3-kinase/Akt inhibitor). We also demonstrated that high-frequency cyclic strain was more effective at inducing Akt phosphorylation than low frequency or static strain. In vivo, Akt phosphorylation was induced by mechanical loading of dermal fibroblasts in both unwounded and wounded murine skin. Mechanically loaded scars also exhibited strong expression of α-smooth muscle actin, a putative marker of pathologic scar formation. In vivo inhibition of Akt increased apoptosis but did not significantly abrogate hypertrophic scar development. These data suggest that although Akt signaling is activated in fibroblasts during mechanical loading of skin, this is not the critical pathway in hypertrophic scar formation. Future studies are needed to fully elucidate the critical mechanotransduction components and pathways which activate skin fibrosis.

Mechanical load initiates hypertrophic scar formation through decreased cellular apoptosis.

Hypertrophic scars occur following cutaneous wounding and result in severe functional and esthetic defects. The pathophysiology of this process remains unknown. Here, we demonstrate for the first time that mechanical stress applied to a healing wound is sufficient to produce hypertrophic scars in mice. The resulting scars are histopathologically identical to human hypertrophic scars and persist for more than six months following a brief (one-week) period of augmented mechanical stress during the proliferative phase of wound healing. Resulting scars are structurally identical to human hypertrophic scars and showed dramatic increases in volume (20-fold) and cellular density (20-fold). The increased cellularity is accompanied by a four-fold decrease in cellular apoptosis and increased activation of the prosurvival marker Akt. To clarify the importance of apoptosis in hypertrophic scar formation, we examine the effects of mechanical loading on cutaneous wounds of animals with altered pathways of cellular apoptosis. In p53-null mice, with down-regulated cellular apoptosis, we observe significantly greater scar hypertrophy and cellular density. Conversely, scar hypertrophy and cellular density are significantly reduced in proapoptotic BclII-null mice. We conclude that mechanical loading early in the proliferative phase of wound healing produces hypertrophic scars by inhibiting cellular apoptosis through an Akt-dependent mechanism.

MicroRNA-187 promotes growth and metastasis of gastric cancer by inhibiting FOXA2.

MicroRNAs (miRNAs) play an active role in the pathogenesis of gastric cancer. The expression and biological function for miR-187 in gastric cancer remains unknow. In the present study, we demonstrated that miR-187 expression was increased in gastric cancer (GC) tissues and cells. Increased expression level of miR-187 was associated with adverse clinical features including tumor size, lymph metastasis and TNM stage, and decreased overall survival and disease-free survival of GC patients. Functionally, overexpression miR-187 could promote while inhibition of miR-187 could suppress, the proliferation, migration and invasion of GC cells in vitro. In vivo experiments showed that overexpression of miR-187 promoted the growth and lung metastasis of SGC-7901 cells in nude mice. Mechanically, we confirmed that FOXA2 was the downstream target of miR-187 in GC cells using luciferase assay, qRT-PCR and western blot analysis. Moreover, overexpression of FOXA2 abrogated the promoting effects of miR-187 overexpression on SGC-7901 cell proliferation, migration and invasion, while inhibition of FOXA2 reversed the inhibitory effects of miR-187 downregulation on these biological functions of AGS cells, suggesting that FOXA2 was a functional mediator of miR-187 in GC. Therefore, this study indicates that miR-187 is potentially a biomarker and treatment target for GC patients.

[Performance and Mechanism Study of Visible Light-driven C3N4/BiOBr Composite Photocatalyst].

Efficient visible light-driven C3N4/BiOBr composite photocatalysts were prepared via a facile hydrothermal method and characterized by X-ray diffraction, Fourier transform infrared, scanning electron microscopy, UV-Vis diffuse reflectance spectra and photoluminescence spectra for the phase composition and optical property. Taking rhodamine B (RhB) as the target pollutant, the photocatalytic activity and stability of photocatalysts were studied under visible light irradiation. Furthermore, the mechanism in the process of photocatalytic degradation was discussed by electron spin resonance spectroscopy analysis and the trapping experiment of generated radicals. The results indicated that C3N4/BiOBr composite photocatalysts had excellent crystallization performance. Composited by C3N4, BiOBr exhibited considerably higher photocatalytic activity by reducing the rate of electron-hole recombination. Among prepared composites with various C3N4 contents, 15% C3N4/BiOBr exhibited the best efficiency for the degradation of RhB. After irradiation for 18 minutes, the degradation rate of RhB was 100%, which was 1.5 times higher than that using pure BiOBr. The results also suggested that holes and ·O2- were the main reactive species in the photocatalytic process for the RhB degradation, and holes played the leading role.

Assessment of pancreatic islet mass after islet transplantation using in vivo bioluminescence imaging.

BACKGROUND: Pancreatic islet transplantation is an emerging therapy for type 1 diabetes, but it is difficult to assess islets after transplantation and thus to design interventions to improve islet survival. METHODS: To image and quantify islets, the authors transplanted luciferase-expressing murine or human islets (by adenovirus-mediated gene transfer) into the liver or beneath the renal capsule of immunodeficient mice and quantified the in vivo bioluminescence imaging (BLI) of mice using a cooled charge-coupled device camera and digital photon-counting image analysis. To account for variables that are independent of islet mass such as transplant site, animal positioning, and wound healing, the BLI of transplanted islets was calibrated against measurement of luminescence of an implanted bead emitting a constant light intensity. RESULTS: BLI of mice bearing islet transplants was seen in the expected anatomic location, was stable for more than 8 weeks after transplantation, and correlated with the number of islets transplanted into the liver or kidney. BLI of the luminescent bead and of transplanted islets in the kidney was approximately four times greater than when transplanted in the liver, indicating that photon emission is dependent on optical absorption of generated light and thus light source location. CONCLUSION: In vivo BLI allows for quantitative, serial measurements of pancreatic islet mass after transplantation and should be useful in assessing interventions to sustain or increase islet survival of transplanted islets.

A large-scale fabrication of flower-like submicrometer-sized tungsten whiskers via metal catalysis.

Tungsten powder mixed with an appropriate amount of nickel and iron powders is used as raw material to fabricate large-scale tungsten whisker-like structure. The morphology, microstructure and composition of the whisker-like tungsten are observed and tested by scanning electron microscope and FESEM, transmission electron microscopy, X-ray spectroscopy, and X-ray diffraction, respectively. The main component of the tungsten whisker-like structure is tungsten, which has the axial growth along the <100 > direction with large aspect ratio and possesses flower-like structure. Large-scale submicrometer-sized whisker-like tungsten was fabricated via vapor phase deposition approach with the aid of metal catalysts at 800°C by holding for 6 h in the appropriate atmosphere. The growth procedure of flower-like tungsten whisker is probably based on the vapor-liquid-solid mechanism at beginning of the formation of tungsten nuclei, then vapor-solid mechanism is dominant.

HIF-1alpha dysfunction in diabetes.

Diabetic wounds are a significant public health burden, with slow or nonhealing diabetic foot ulcers representing the leading cause of non-traumatic lower limb amputation in developed countries. These wounds heal poorly as a result of compromised blood vessel formation in response to ischemia. We have recently shown that this impairment in neovascularization results from a high glucose-induced defect in transactivation of hypoxia-inducible factor-1alpha (HIF-1alpha), the transcription factor regulating vascular endothelial growth factor (VEGF) expression. HIF-1 dysfunction is the end result of reactive oxygen species-induced modification of its coactivator p300 by the glycolytic metabolite methylglyoxal. Use of the iron chelator-antioxidant deferoxamine (DFO) reversed these effects and normalized healing of humanized diabetic wounds in mice. Here, we present additional data demonstrating that HIF-1alpha activity, not stability, is impaired in the high glucose environment. We demonstrate that high glucose-induced impairments in HIF-1alpha transactivation persist even in the setting of constitutive HIF-1alpha protein overexpression. Further, we show that high glucose-induced hydroxylation of the C-terminal transactivation domain of HIF-1alpha (the primary pathway regulating HIF-1alpha/p300 binding) does not alter HIF-1alpha activity. We extend our study of DFO's therapeutic efficacy in the treatment of impaired wound healing by demonstrating improvements in tissue viability in diabetic mice with DFO-induced increases in VEGF expression and vascular proliferation. Since DFO has been in clinical use for decades, the potential of this drug to treat a variety of ischemic conditions in humans can be evaluated relatively quickly.

CARP: fishing for novel mechanisms of neovascularization.

Gene expression profiling of mouse skin wounds has led to the discovery of numerous target genes that may have therapeutic or diagnostic value. Among these, cardiac ankyrin repeat protein (CARP, ankrd1) expression was markedly and persistently elevated in several cutaneous compartments. This review summarizes the current state of knowledge of CARP and its regulation in biological systems. In addition to its role as a nuclear transcription cofactor in many cell types including vascular endothelium, CARP is also a structural component of the sarcomere. CARP transcripts are prominent in cardiogenesis and muscle injury, and they are under complex regulation by cytokines, hypoxia, doxorubicin, and other forms of stress. CARP overexpression in wounds by adenoviral gene transfer leads to a high vascular density, and CARP exerts effects on endothelial behavior. The unusual cellular distribution and actions of CARP make it a novel candidate gene in tissue repair.

CARP, a cardiac ankyrin repeat protein, is up-regulated during wound healing and induces angiogenesis in experimental granulation tissue.

Cardiac ankyrin repeat protein (CARP) was identified by subtractive hybridization as one of a group of genes that are rapidly modulated by acute wounding of mouse skin. Quantitative RT-PCR showed that CARP was strongly induced during the first day after wounding (157.1-fold), and the high level persisted for up to 14 days. Immunohistochemistry and in situ hybridization revealed that CARP was expressed in skeletal muscle, vessel wall, hair follicle, inflammatory cells, and epidermis in the wound area. To examine the effects of CARP on wound healing, we developed an adenoviral CARP vector to treat subcutaneously implanted sponges in either rats or Flk-1(LacZ) knock-in mice. Four days after infection, CARP-infected sponges in rats showed a remarkable increase in the vascular component in granulation tissue as compared to Ad-LacZ controls. This result was confirmed by CD34 immunostaining. By 7 days post-infection of sponge implants in Flk-1(LacZ) knock-in mice, granulation tissue showed many more LacZ-positive cells in Ad-CARP-infected sponges than in virus controls. Ad-CARP treatment also induced neovascularization and increased blood perfusion in rabbit excisional wounds in and ischemic rat wounds. These findings indicate that CARP could play a unique role in therapeutic angiogenesis during wound healing.