In light of these results, we conclude that the SENS-IS assay is able to correctly identify the presence of sensitizers in medical devices extracts.Renal fibrosis is characterized by chronic inflammation and excessive accumulation of extracellular matrix and progressively leads to functional insufficiency and even total loss of kidney function. In this study we investigated the anti-fibrotic potential of two highly selective and potent SK2 inhibitors, SLM6031434 and HWG-35D, in unilateral ureter obstruction (UUO), a model for progressive renal fibrosis, in mice. In both cases, treatment with SLM6031434 or HWG-35D resulted in an attenuated fibrotic response to UUO in comparison to vehicle-treated mice as demonstrated by reduced collagen accumulation and a decreased expression of collagen-1 (Col1), fibronectin-1 (FN-1), connective tissue growth factor (CTGF), and α-smooth muscle actin (α-SMA). Similar to our previous study in Sphk2-/- mice, we found an increased protein expression of Smad7, a negative regulator of the pro-fibrotic TGFβ/Smad signalling cascade, accompanied by a strong accumulation of sphingosine in SK2 inhibitor-treated kidneys. Treatment of primary renal fibroblasts with SLM6031434 or HWG-35D dose-dependently increased Smad7 expression and ameliorated the expression of Col1, FN-1 and CTGF. In summary, these data prove the anti-fibrotic potential of SK2 inhibition in a mouse model of renal fibrosis, thereby validating SK2 as pharmacological target for the treatment of fibrosis in chronic kidney disease.The intervertebral disc and cartilage are specialized, extracellular matrix-rich tissues critical for absorbing mechanical loads, providing flexibility to the joints, and longitudinal growth in the case of growth plate cartilage. Specialized niche conditions in these tissues, such as hypoxia, are critical in regulating cellular activities including autophagy, a lysosomal degradation pathway that promotes cell survival. M3814 research buy Mounting evidence suggests that dysregulation of autophagic pathways underscores many skeletal pathologies affecting the spinal column, articular and growth plate cartilages. Many lysosomal storage disorders characterized by the accumulation of partially degraded glycosaminoglycans (GAGs) due to the lysosomal dysfunction thus affect skeletal tissues and result in altered ECM structure. Likewise, pathologies that arise from mutations in genes encoding ECM proteins and ECM processing, folding, and post-translational modifications, result in accumulation of misfolded proteins in the ER, ER stress and autophagy dysregulation. These conditions evidence reduced secretion of ECM proteins and/or increased secretion of mutant proteins, thereby impairing matrix quality and the integrity of affected skeletal tissues and causing a lack of growth and degeneration. In this review, we discuss the role of autophagy and mechanisms of its regulation in the intervertebral disc and cartilages, as well as how dysregulation of autophagic pathways affects these skeletal tissues.
Numerous studies suggest that cytomegalovirus (CMV) infection may act as isolated risk factor in the development of cardiac allograft vasculopathy (CAV). Viral G protein-coupled receptors (GPCRs) are thought to contribute to the pathogenic changes associated with CMV infection. The aim of this study was to investigate the role of murine cytomegalovirus GPCR M33 in the development of CAV in a murine aortic allograft model.

MHC I-mismatched aortas of C.B10 (H2
) mice were transplanted into BALB/c (H2
) recipients, which were either mock-infected, infected with wild type (WT) MCMV or MCMV with a deleted M33-receptor gene (delM33). Persistence of cytomegalovirus infection was confirmed by qPCR and by luciferase assay to ensure active viral replication. Grafts were harvested on days 21 and 37 for intragraft mRNA expression and histological analysis.

Active viral replication was demonstrated and MCMV presence was confirmed by PCR within spleen, liver, salivary glands, lung and the aortic transplant. Infection with delM33 resulted in significantly less intimal proliferation compared to WT-MCMV but more pronounced proliferation than in mock-infected allografts (32.19% [delM33] vs. 41.71% [WT-MCMV] vs. 24.33% [MCMV-]). Intragraft expression of most analyzed genes was significantly increased in infected mice. VCAM-1, ICAM-1, PDGFβ, CXCR3 and Granzyme B were distinctly less expressed in grafts of delM33 infected compared to WT infected mice. Cellular infiltration revealed reduced dendritic cells and T cells in grafts infected with delM33 compared to WT MCMV.

These data suggest that the MCMV encoded receptor M33 plays an important role as a viral effector mechanism contributing to the development of CAV in a murine aortic transplant model.
These data suggest that the MCMV encoded receptor M33 plays an important role as a viral effector mechanism contributing to the development of CAV in a murine aortic transplant model.Dermacoccus abyssi strain HZAU 226 is a spoilage bacterium isolated from eggs. So far, there are still few genomic resources available on the Dermacoccus abyssi. Here, we reported the complete genome sequence of Dermacoccus abyssi strain HZAU 226. High-quality DNA was extracted using the Qiagen kit, then single-molecule sequencing was performed by GridION sequencer. The raw data was quality-controlled and assembled to obtain the final genome, which consisted of a complete genome of 2,992,060 bp circular chromosome and a 64,524 bp plasmid. The structural and functional annotations of the genome were achieved through the analysis of different available databases, including antibiotic resistance genes, secondary metabolite synthesis genes and stress-related genes. Meanwhile, comparative genomic analyses of the strains were also performed. This is the first report on the complete genome of Dermacoccus abyssi, which will provide genomic resources for the study of spoilage bacteria in eggs.Breast cancer is the most frequently diagnosed and the leading cause of cancer-related deaths in women worldwide. However, the role of circSLC8A1 in breast cancer remains elusive. Herein, a cohort of 77 breast tumors and paired adjacent normal mammary tissues were collected. We demonstrated that circSLC8A1 was significantly down-regulated in breast cancer tissues and cell lines, of which expression was negatively correlated with clinical severity and dismal prognosis. Overexpression of circSLC8A1 suppressed cell proliferation, migration and invasion in vitro, and inhibited tumor growth in vivo. CircSLC8A1 directly targeted miR-671 to execute tumor suppressive activities via regulating PI3k/Akt signaling. Krüppel-like factor 16 (KLF16), a transcriptional activator of PTEN, was identified as a target of miR-671. Furthermore, circSLC8A1 could sponge miR-671 to suppress breast tumor growth via PTEN/PI3k/Akt signaling in vivo. In summary, circSLC8A1/miR-671 regulates breast cancer progression through PTEN/PI3k/Akt signaling, which may provide efficient therapeutic target for this devastating cancer.M3814 research buy