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In the skin, repeated incidents of ischemia followed by reperfusion can result in the breakdown of the skin and the formation of a pressure ulcer. Here we gently applied paired magnets to the backs of mice to cause ischemia for 1.5 h and then removed them to allow reperfusion. The sterile inflammatory response generated within 4 h causes a stage 1 pressure ulcer with an elevation of the gap junction protein Cx43 in the epidermis. If this process is repeated the insult will result in a more severe stage 2 pressure ulcer with a breakdown of the epidermis 2–3 days later. After a single pinch, the elevation of Cx43 in the epidermis is associated with the inflammatory response with an increased number of neutrophils, HMGB1 (marker of necrosis) and RIP3 (responsible for necroptosis). Delivering Cx43 specific antisense oligonucleotides sub-dermally after a single insult, was able to significantly reduce the elevation of epidermal Cx43 protein expression and reduce the number of neutrophils and prevent the elevation of HMGB1 and RIP3. In a double pinch model, the Cx43 antisense treatment was able to reduce the level of inflammation, necroptosis, and the extent of tissue damage and progression to an open wound. This approach may be useful in reducing the progression of stage 1 pressure ulcers to stage 2. [ABSTRACT FROM AUTHOR]

Studying the Role of Cx43 during Peritoneal Adhesion Formation Mouse Cx43 antisense oligodeoxynucleotide, Cx43asODN (5'-GTAATTGCGGCAGGAGGAATTGTTTCTGTC-3') was administered to the IB peritoneal adhesion to investigate the role of Cx43 in adhesion formation [[12]]. Effect of Cx43asODN Treatment on Inflammation during Early Adhesion Formation At both 6 and 24 h post-surgery, Cx43asODN treatment showed a mild reduction in inflammation OIB ( I p i = 0.528, I p i = 0.222, respectively) and a more significant reduction WIB when compared to control ( I p i <= 0.01) (Figure 5). Inhibition of Cx43 expression in Cx43 SP +/- sp transgenic mice or through Cx43asODN treatment in CKD models significantly reduced cell adhesion markers, monocyte infiltration and interstitial renal fibrosis [[26]]. Graph: Figure 2 Cx43asODN significantly reduced Cx43 protein levels in the regions within the IB at 24 h post-surgery. Significant Upregulation of Cx43 in IB during Early Adhesion Formation Cx43 protein levels were investigated at 0, 6, and 24 h post-surgery (Figure 1A and Figure S3. [Extracted from the article]

Background: Burn wounds continue to worsen after initial injury in a process known as burn conversion, which lasts about 3-5 days. It causes burn wounds to enlarge and deepen, leading to greater morbidity. Apoptosis is one of the factors contributing to the conversion of the zone of stasis into the zone of coagulation. Suppression of apoptosis has been associated with reducing burn conversion. Connexin 43 (Cx43) gap junctions facilitate the spread of apoptotic signals from dying cells to healthy neighbouring cells in injured tissues through the bystander effect.Objectives: The study is to understand the role of Cx43 in burn conversion.Methods: In our study, 15 burn tissue samples were arranged into three groups as early (beginning of burn conversion), intermediate (extensive burn conversion) and late (established burn conversion) burns.Results: We found a striking increase in the amount of Cx43 protein expressed in the dermal fibroblasts (identified with heat shock protein 47 (HSP47) staining) in the zone of stasis in early and intermediate burns. These dermal fibroblasts also express high levels of cleaved-Caspase 3 indicating on-going apoptosis.Conclusions: Our findings suggest that elevation of Cx43 may play an active role in burn conversion spreading apoptosis in the early and intermediate burn wound. [ABSTRACT FROM AUTHOR]

Background: Cell surface sialylation is associated with tumor cell invasiveness in many cancers. Glioblastoma is the most malignant primary brain tumor and is highly infiltrative. ST3GAL1 sialyltransferase gene is amplified in a subclass of glioblastomas, and its role in tumor cell self-renewal remains unexplored. Methods: Self-renewal of patient glioma cells was evaluated using clonogenic, viability, and invasiveness assays. ST3GAL1 was identified from differentially expressed genes in Peanut Agglutinin-stained cells and validated in REMBRANDT (n = 390) and Gravendeel (n = 276) clinical databases. Gene set enrichment analysis revealed upstream processes. TGFβ signaling on ST3GAL1 transcription was assessed using chromatin immunoprecipitation. Transcriptome analysis of ST3GAL1 knockdown cells was done to identify downstream pathways. A constitutively active FoxM1 mutant lacking critical anaphase-promoting complex/cyclosome ([APC/C]-Cdh1) binding sites was used to evaluate ST3Gal1-mediated regulation of FoxM1 protein. Finally, the prognostic role of ST3Gal1 was determined using an orthotopic xenograft model (3 mice groups comprising nontargeting and 2 clones of ST3GAL1 knockdown in NNI-11 [8 per group] and NNI-21 [6 per group]), and the correlation with patient clinical information. All statistical tests on patients' data were two-sided; other P values below are one-sided. Results: High ST3GAL1 expression defines an invasive subfraction with self-renewal capacity; its loss of function prolongs survival in a mouse model established from mesenchymal NNI-11 (P < .001; groups of 8 in 3 arms: nontargeting, C1, and C2 clones of ST3GAL1 knockdown). ST3GAL1 transcriptomic program stratifies patient survival (hazard ratio [HR] = 2.47, 95% confidence interval [CI] = 1.72 to 3.55, REMBRANDT P = 1.92 x 10⁻⁸; HR = 2.89, 95% CI = 1.94 to 4.30, Gravendeel P = 1.05 x 10⁻¹¹), independent of age and histology, and associates with higher tumor grade and T2 volume (P = 1.46 x 10⁻⁴). TGFβ signaling, elevated in mesenchymal patients, correlates with high ST3GAL1 (REMBRANDT gliomacor = 0.31, P = 2.29 x 10⁻¹⁰; Gravendeel gliomacor = 0.50, P = 3.63 x 10⁻²⁰). The transcriptomic program upon ST3GAL1 knockdown enriches for mitotic cell cycle processes. FoxM1 was identified as a statistically significantly modulated gene (P = 2.25 x 10⁻⁵) and mediates ST3Gal1 signaling via the (APC/C)-Cdh1 complex. Conclusions: The ST3GAL1-associated transcriptomic program portends poor prognosis in glioma patients and enriches for higher tumor grades of the mesenchymal molecular classification. We show that ST3Gal1-regulated self-renewal traits are crucial to the sustenance of glioblastoma multiforme growth. [ABSTRACT FROM AUTHOR]