CASP8
Caspase-8 precursor (EC 3.4.22.61) (CASP-8) (Apoptotic cysteine protease) (Apoptotic protease Mch-5) (CAP4) (FADD-homologous ICE/ced-3-like protease) (FADD-like ICE) (FLICE) (ICE-like apoptotic protease 5) (MORT1-associated ced-3 homolog) (MACH) [Contains: Caspase-8 subunit p18; Caspase-8 subunit p10] [MCH5]
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Innate immune response and particularly terminal complement complex (TCC) deposition are thought to be involved in the pathogenesis of posttraumatic osteoarthritis. However, the possible role of TCC in regulated cell death as well as chondrocyte hypertrophy and senescence has not been unraveled so far and was first addressed using an ex vivo human cartilage trauma-model. Cartilage explants were subjected to blunt impact (0.59 J) and exposed to human serum (HS) and cartilage homogenate (HG) with or without different potential therapeutics: RIPK1-inhibitor Necrostatin-1 (Nec), caspase-inhibitor zVAD, antioxidant N-acetyl cysteine (NAC) and TCC-inhibitors aurintricarboxylic acid (ATA) and clusterin (CLU). Cell death and hypertrophy/senescence-associated markers were evaluated on mRNA and protein level. Addition of HS resulted in significantly enhanced TCC deposition on chondrocytes and decrease of cell viability after trauma. This effect was potentiated by HG and was associated with expression of RIPK3, MLKL and CASP8. Cytotoxicity of HS could be prevented by heat-inactivation or specific inhibitors, whereby combination of Nec and zVAD as well as ATA exhibited highest cell protection. Moreover, HS HG exposition enhanced the gene expression of CXCL1, IL-8, RUNX2 and VEGFA as well as secretion of IL-6 after cartilage trauma. Our findings imply crucial involvement of the complement system and primarily TCC in regulated cell death and phenotypic changes of chondrocytes after cartilage trauma. Inhibition of TCC formation or downstream signaling largely modified serum-induced pathophysiologic effects and might therefore represent a therapeutic target to maintain the survival and chondrogenic character of cartilage cells.
Keywords
- Aurintricarboxylic acid
- Cartilage trauma
- Hypertrophy
- Regulated cell death
- Senescence
- Terminal complement complex
We performed the analysis of genotype frequency dynamics of CASP8, BCL2 and BAX genes polymorphic markers between 21 and 109 years in the group of Ethnic Tatars from Bashkortostan. Genotyping was carried out using PCR and PCR-RFLP. We found associations between age and -652(6N)I/D polymorphism of CASP8 gene (rs3834129), 140016C>T polymorphism of BCL2 gene (rs12454712) and 919A>G polymorphism of BAX gene (rs1805419). An increase of genotype frequency of BCL2*C/*C and decrease of genotype frequency of CASP8*I/*D was observed in male of senile age; and also decrease of genotype frequency of BAX*G/*G among long-livers. In female of longevity age, the number of CASP8*I/*D, BCL2*T/*T and BAX*A/*A genotype carriers was higher and number of CASP8*DI/*D, BCL2*C/*C, BAX*A/*G and BAX *G/*G genotype carriers was reduced.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Alleles
- Bashkiria
- Caspase 8
- Female
- Gene Frequency
- Genes, bcl-2
- Genotype
- Humans
- Longevity
- Male
- Middle Aged
- Polymerase Chain Reaction
- Polymorphism, Genetic
- Young Adult
- bcl-2-Associated X Protein
The abundance of a preselection of transcripts involved in inflammation, immunosenescence and stress response was compared between PBMC of healthy aged donors and aged patients in acute phase of heart failure and at recovery. This study identified 22 transcripts differentially abundant in acute phase of heart failure versus healthy aged subjects. Transcripts involved in inflammation and oxidative stress were more abundant. Those associated with T-cell functions were less abundant. The results were compared to two other major acute geriatric issues: infectious diseases and hip fracture. In acute phase, compared to healthy aged subjects, the abundance of 15/22 transcripts was also altered in both geriatric infectious diseases and hip fracture. Many variations had not vanished at the recovery phase. The abundance of CD28, CD69, LCK, HMOX1, TNFRSF1A transcripts, known to be altered in healthy aged versus healthy young subjects, was further affected in acute phase of the three geriatric diseases considered. The transcript levels of BCL2, CASP8, CCL5, [[DDIT3]], EGR3, IL10RB, IL1R2, SERPINB2 and TIMP1 were affected in all three pathological conditions compared to healthy aged, but not versus healthy young subjects. In conclusion, this work provides critical targets for therapeutic research on geriatric heart failure, infectious diseases and hip fracture.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Biomarkers
- Communicable Diseases
- Female
- Heart Failure
- Hip Fractures
- Hospitalization
- Humans
- Male
- Neutrophils
- Transcription, Genetic
Aberrant DNA methylation is an important epigenetic alteration in hepatocellular carcinoma (HCC). However, the molecular processes underlying the methylator phenotype and the contribution of hepatitis viruses are poorly understood. The current study is a comprehensive methylation analysis of human liver tissue specimens. A total of 176 liver tissues, including 77 pairs of HCCs and matching noncancerous liver and 22 normal livers, were analyzed for methylation. Methylation of 19 epigenetic markers was quantified, and the results were correlated with different disease states and the presence or absence of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. Based on methylation profiles, the 19 loci were categorized into 3 groups. Normal liver tissues showed methylation primarily in group 1 loci (HIC-1, CASP8, GSTP1, SOCS1, RASSF1A, p16, APC), which was significantly higher than group 2 (CDH1, RUNX3, RIZ1, SFRP2, MINT31) and group 3 markers (COX2, MINT1, CACNA1G, RASSF2, MINT2, Reprimo, DCC) (P < 0.0001). Noncancerous livers demonstrated increased methylation in both group 1 and group 2 loci. Methylation was significantly more abundant in HCV-positive livers compared with normal liver tissues. Conversely, HCC showed frequent methylation at each locus investigated in all 3 groups. However, the group 3 loci showed more dense and frequent methylation in HCV-positive cancers compared with both HBV-positive cancers and virus-negative cancers (P < 0.0001). Methylation in HCC is frequent but occurs in a gene-specific and disease-specific manner. Methylation profiling allowed us to determine that aberrant methylation is commonly present in normal aging livers, and sequentially progresses with advancing stages of chronic viral infection. Finally, our data provide evidence that HCV infection may accelerate the methylation process and suggests a continuum of increasing methylation with persistent viral infection and carcinogenesis in the liver.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Carcinoma, Hepatocellular
- Cellular Senescence
- DNA Methylation
- Epigenesis, Genetic
- Female
- Gene Expression Regulation, Neoplastic
- Genes, Tumor Suppressor
- Hepatitis B, Chronic
- Humans
- Liver
- Liver Neoplasms
- Male
- Middle Aged