The pathway causing CD4 T-cell death in HIV-infected hosts remains poorly understood. Apoptosis has been proposed as the key mechanism for CD4 T-cell loss. We now show that caspase-3-mediated apoptosis accounts for the death of only a small fraction of productively infected cells. The remaining >95% of quiescent lymphoid CD4 T-cells die by caspase-1-mediated pyroptosis triggered by abortive viral infection. Pyroptosis corresponds to an intensely inflammatory form of programmed cell death where cytoplasmic contents and pro-inflammatory cytokines including IL-1β, are released. This death pathway thus links the two signature events in HIV infection––CD4 T-cell depletion and chronic inflammation––and creates a vicious pathogenic cycle where dying CD4 T-cells release inflammatory signals that attract more cells to die. This cycle can be broken by caspase-1 inhibitors shown to be safe in humans, raising the possibility of a new class of “anti-AIDS” therapeutics targeting the host rather than the virus.

The progressive depletion of quiescent “bystander” CD4 T-cells, which are non-permissive to HIV infection, is a principal driver of the acquired immunodeficiency syndrome (AIDS). These cells undergo abortive infection characterized by the cytosolic accumulation of incomplete HIV reverse transcripts. These viral DNAs are sensed by an unidentified host sensor that triggers an innate immune response, leading to caspase-1 activation and pyroptosis. Using unbiased proteomic and targeted biochemical approaches as well as two independent methods of lentiviral shRNA-mediated gene knockdown in primary CD4 T-cells, we identify Interferon gamma Inducible protein 16 (IFI16) as a host DNA sensor required for CD4 T-cell death due to abortive HIV infection. These findings provide insights into a key host pathway that plays a central role in CD4 T-cell depletion during disease progression to AIDS.

During apoptosis, dying cells are swiftly removed by phagocytes. How apoptotic cells are recognized by phagocytes is not fully understood. Here we report the identification and characterization of the C. elegans ttr-52 gene, which is required for efficient cell corpse engulfment and encodes a transthyretin-like protein. The TTR-52 protein is expressed in and secreted from C. elegans endoderm and clusters around apoptotic cells. Genetic analysis indicates that TTR-52 acts in the cell corpse engulfment pathway mediated by CED-1, CED-6, and CED-7 and affects clustering of the phagocyte receptor CED-1 around apoptotic cells. Interestingly, TTR-52 recognizes surface exposed phosphatidylserine (PS) in vivo and binds to both PS and the extracellular domain of CED-1 in vitro. Therefore, TTR-52 is the first bridging molecule identified in C. elegans that mediates recognition of apoptotic cells by cross-linking the PS “eat me” signal with the phagocyte receptor CED-1.

The mechanism by which gastroesophageal reflux promotes metaplasia→dysplasia→ carcinoma is unknown. The aim of the study is to determine if repeated exposure to acid and bile confers a tumorigenic phenotype in a telomerase (hTERT)-immortalized benign Barrett’s cell line, BAR-T. BAR-T cells were exposed to acid (pH 4) (A) and bile salt (200µM glycochenodeoxycholic acid) (B) daily for 5 min up to 65+ wks. The control cells were grown in parallel without any A or B treatment. Cell morphology, proliferation, transformation, and molecular changes in the gene expression for COX-2, TC22, p53 and p53 target genes were analyzed at 8–12 wks intervals. At 46 wks BAR-T cells exposed to (A+B) showed distinct phenotypic changes: forming clusters and acini, and at 65 wks displayed foci in monolayer, and formed distinct colonies in soft agar. Untreated cells did not show any such changes. In A+B treated BAR-T cells, COX-2 mRNA increased 10-20-fold, TC22 mRNA increased by 2-3-fold at 22 – 65 wks, p53, MDM2, PERP and p21mRNA increased 2.5-, 6.4-, 4- and 2.6- fold respectively when compared to untreated cells at 34 weeks. However, at 58 wks onward, there was a sharp decline of p53 and its target genes to the baseline level. At 65 weeks A+B treated BAR-T cells formed tumor in nude mice whereas untreated cells did not. We demonstrate a novel in-vitro model of transformation of a benign Barrett’s cell line following repeated exposure to A+B over the course of 65 wks.

No abstract

Infection with the hepatitis B virus (HBV) promotes the development of hepatitis, cirrhosis, and hepatocellular carcinoma (HCC) and is a leading cause of morbidity and mortality worldwide. HBV X protein (HBx) is an important effector for HBV pathogenesis, but its cellular targets and acting mechanisms remain elusive. We show here that HBx interacts with the anti-apoptotic proteins Bcl-2 and Bcl-xL through a Bcl-2 homology 3 (BH3)-like motif in mammalian cells. Importantly, mutations in the BH3-like motif that prevent HBx binding to Bcl-2 and Bcl-xL abrogate cytosolic calcium elevation and cell death induced by HBx expression in hepatocytes and severely impair HBV viral replication, which can be substantially rescued by restoring cytosolic calcium. These results suggest that HBx binding to Bcl-2 family members and subsequent elevation of cytosolic calcium are important for HBV viral replication. Consistently, RNAi knockdown of Bcl-2 or Bcl-xL results in reduced calcium elevation by HBx and decreased viral replication in hepatocytes. Our results suggest that HBx targets Bcl-2 proteins through its BH3-like motif to promote cytosolic calcium elevation, cell death, and viral replication during HBV pathogenesis, which presents an excellent therapeutic intervention point in treating patients with chronic HBV.calcium signaling | apoptosis | necrosis

Aging is a biological process characterized by a progressive functional decline in tissues and organs, which eventually leads to mortality. Telomeres, the repetitive DNA repeat sequences at the end of linear eukaryotic chromosomes protecting chromosome ends from degradation and illegitimate recombination, play a crucial role in cell fate and aging. Due to the mechanism of replication, telomeres shorten as cells proliferate, which consequently contributes to cellular senescence and mitochondrial dysfunction. Cells are the basic unit of organismal structure and function, and mitochondria are the powerhouse and metabolic center of cells. Therefore, cellular senescence and mitochondrial dysfunction would result in tissue or organ degeneration and dysfunction followed by somatic aging through multiple pathways. In this review, we summarized the main mechanisms of cellular senescence, mitochondrial malfunction and aging triggered by telomere attrition. Understanding the molecular mechanisms involved in the aging process may elicit new strategies for improving health and extending lifespan.

A global DNA hypomethylation might activate oncogene transcription, thus promoting carcinogenesis and tumor development. S-Adenosylmethionine (SAM) serves as a major methyl donor in biological transmethylation events. The object of this study is to explore the influence of SAM on the status of methylation at the promoter of the oncogenes c-myc, H-ras and tumor-suppressor gene p16 (INK4a), as well as its inhibitory effect on cancer cells. The results indicated that SAM treatment inhibited cell growth in gastric cancer cells and colon cancer cells, and the inhibition efficiency was significantly higher than that in the normal cells. Under standard growth conditions, C-myc and H-ras promoters were hypomethylated in gastric cancer cells and colon cancer cells. SAM treatment resulted in a heavy methylation of these promoters, which consequently downregulated mRNA and protein levels. In contrast, there was no significant difference in mRNA and protein levels of p16 (INK4a) with and without SAM treatment. SAM can effectively inhibit the tumor cells growth by reversing the DNA hypomethylation on promoters of oncogenes, thus down-regulating their expression. With no influence on the expression of the tumor suppressor genes, such as P16, SAM could be used as a potential drug for cancer therapy.