20 research outputs found
DNA-Free Recombinant SV40 Capsids Protect Mice from Acute Renal Failure by Inducing Stress Response, Survival Pathway and Apoptotic Arrest
Viruses induce signaling and host defense during infection. Employing these natural trigger mechanisms to combat organ or tissue failure is hampered by harmful effects of most viruses. Here we demonstrate that SV40 empty capsids (Virus Like Particles-VLPs), with no DNA, induce host Hsp/c70 and Akt-1 survival pathways, key players in cellular survival mechanisms. We postulated that this signaling might protect against organ damage in vivo. Acute kidney injury (AKI) was chosen as target. AKI is critical, prevalent disorder in humans, caused by nephrotoxic agents, sepsis or ischemia, via apoptosis/necrosis of renal tubular cells, with high morbidity and mortality. Systemic administration of VLPs activated Akt-1 and upregulated Hsp/c70 in vivo. Experiments in mercury-induced AKI mouse model demonstrated that apoptosis, oxidative stress and toxic renal failure were significantly attenuated by pretreatment with capsids prior to the mercury insult. Survival rate increased from 12% to >60%, with wide dose response. This study demonstrates that SV40 VLPs, devoid of DNA, may potentially be used as prophylactic agent for AKI. We anticipate that these finding may be projected to a wide range of organ failure, using empty capsids of SV40 as well as other viruses
Levels of DNA methylation vary at CpG sites across the BRCA1 promoter, and differ according to triple negative and "BRCA-like" status, in both blood and tumour DNA
Triple negative breast cancer is typically an aggressive and difficult to treat subtype. It is
often associated with loss of function of the BRCA1 gene, either through mutation, loss of
heterozygosity or methylation. This study aimed to measure methylation of the BRCA1
gene promoter at individual CpG sites in blood, tumour and normal breast tissue, to assess
whether levels were correlated between different tissues, and with triple negative receptor
status, histopathological scoring for BRCA-like features and BRCA1 protein expression.
Blood DNA methylation levels were significantly correlated with tumour methylation at 9 of
11 CpG sites examined (p<0.0007). The levels of tumour DNA methylation were significantly
higher in triple negative tumours, and in tumours with high BRCA-like histopathological
scores (10 of 11 CpG sites; p<0.01 and p<0.007 respectively). Similar results were
observed in blood DNA (6 of 11 CpG sites; p<0.03 and 7 of 11 CpG sites; p<0.02 respectively).
This study provides insight into the pattern of CpG methylation across the BRCA1
promoter, and supports previous studies suggesting that tumours with BRCA1 promoter
methylation have similar features to those with BRCA1 mutations, and therefore may be
suitable for the same targeted therapies