Project description:Acute Pten loss initiates prostate tumorigenesis characterized by cellular senescence response. Here we examine the cellular senescence response in epithelial individual cells, by single-cell RNA sequencing (scRNAseq) in Ptenpc-/- and Ptenpc-/-; Timp1-/- GEMMs. ScRNAseq analysis determines a cluster of senescent cells expressing the senescence-related genes. A significant positive correlation is observed between the senescence score and Bcl2 expression. This provides the rational for targeting senescent cells using Bcl2 inhibitor.
Project description:Cellular senescence is associated with the progression of chronic kidney disease (CKD), and accelerated tubular cell senescence promotes the pathogenesis of renal fibrosis. We established three animal models related to Chronic Kidney Disease, including aristolochic acid nephropathy (AAN), bilateral ischemia/reperfusion injury (BIRI) and unilateral ureter obstruction (UUO). By RNA sequencing analysis in AAN, BIRI and UUO mice, we observed significant changes of senescence and fibrosis related genes.
Project description:Kurozu is a traditional Japanese rice vinegar. During fermentation and aging of the Kurozu liquid in an earthenware jar over 1 year, solid residue called Kurozu Moromi is produced. In the present study, we evaluated whether concentrated Kurozu or Kurozu Moromi could ameliorate cognitive dysfunction in the senescence accelerated P8 mouse. Senescence accelerated P8 mice were fed 0.25% (w/w) concentrated Kurozu or 0.5% (w/w) Kurozu Moromi for 4 or 25 weeks. Kurozu suppressed cognitive dysfunction and amyloid accumulation in the brain, while Kurozu Moromi showed a tendency to ameliorate cognitive dysfunction, but the effect was not significant. We hypothesize that concentrated Kurozu has an antioxidant effect, however, the level of lipid peroxidation in the brain did not differ in senescence accelerated P8 mice. DNA microarray analysis indicated that concentrated Kurozu increased HSPA1A mRNA expression, a protein that prevents protein misfolding and aggregation. The increase in HSPA1A expression by Kurozu was confirmed using quantitative real-time PCR and immunoblotting methods. Therefore, the suppression of amyloid accumulation by concentrated Kurozu may be associated with HSPA1A induction. However, concentrated Kurozu could not increase HSPA1A expression in mouse primary neurons, suggesting it may not directly affect neurons. Ten-times concentrated Kurozu (CK) was made from Kurozu liquid (Sakamoto Kurozu, Fukuyama, Kagoshima, Japan) by repeated vacuum distillation. The CK diet included 0.25% (w/w) CK in CE-2 basic rodent diet (Nihon CLEA, Tokyo, Japan). Senescence resistance (R1) and senescence accelerated P8 (P8) mice were purchased from Japan SLC (Shizuoka, Japan). Mice were housed at 25±2°C with 55±10% humidity on a 12-h light/dark cycle (lighting time 08:00-20:00). All mice were housed in independent cages and had free access to food and water. All procedures were compliant with the guidelines of the Kagoshima University Animal Ethics Committee (A10030). Ten-week old R1 mice (n=16) were fed a control CE2 diet and P8 mice were divided into three groups as follows: control CE2 diet group (n=9), KM diet group (n=9) or CK diet group (n=9). Feeding of the experimental diet started from 12 weeks of age until sacrificed. All mice were sacrificed under anesthesia at 17 weeks old (4 months old). The left side of the hippocampus region was excised from brains of 4 mice selected at random in each group, and then subjected to microarray analysis.