Is Senescence Important in Hepatic Diseases?

Aging is a condition in which a person gradually loses the ability to maintain homeostasis, due to structural alteration or dysfunction. Aging changes biological processes in many organs and tissues. The loss of regenerative capacity is the most dramatic age-associated alteration in the liver. Cellular damage, if not repaired, leads to apoptosis or senescence. The presence of permanent cell cycle arrest, the acquisition of major morphological change, and expression of senescence-associated β-galactosidase (SA-β-gal) are the characteristics of cellular senescence (CS). Interestingly, CS plays a crucial role in aging of both individual organs and the entire organism; consequently, senescent cells accumulate in organs and decline in organ function. Senescent cells have considerable influence on their microenvironment and exert both beneficial and detrimental effects through secretory associated senescent phenotype (SASP) factors. CS has attracted considerable recent interest with recognition of pathways linking aging, malignancy, and insulin resistance and the current focus on therapeutic interventions to extend healthspan. There are major implications for hepatology in the field of fibrosis and cancer, where cellular senescence of hepatocytes, cholangiocytes, stellate cells, and immune cells has been implicated in chronic liver disease progression

Anti-proliferative effect of extremely low frequency electromagnetic field on preneoplastic lesions formation in the rat liver

<p>Abstract</p> <p>Background</p> <p>Recently, extremely low frequency electromagnetic fields (ELF-EMF) have been studied with great interest due to their possible effects on human health. In this study, we evaluated the effect of 4.5 mT - 120 Hz ELF-EMF on the development of preneoplastic lesions in experimental hepatocarcinogenesis.</p> <p>Methods</p> <p>Male Fischer-344 rats were subjected to the modified resistant hepatocyte model and were exposed to 4.5 mT - 120 Hz ELF-EMF. The effects of the ELF-EMF on hepatocarcinogenesis, apoptosis, proliferation and cell cycle progression were evaluated by histochemical, TUNEL assay, caspase 3 levels, immunohistochemical and western blot analyses.</p> <p>Results</p> <p>The application of the ELF-EMF resulted in a decrease of more than 50% of the number and the area of γ-glutamyl transpeptidase-positive preneoplastic lesions (<it>P </it>= 0.01 and <it>P </it>= 0.03, respectively) and glutathione S-transferase placental expression (<it>P </it>= 0.01). The number of TUNEL-positive cells and the cleaved caspase 3 levels were unaffected; however, the proliferating cell nuclear antigen, Ki-67, and cyclin D1 expression decreased significantly (<it>P </it>≤ 0.03), as compared to the sham-exposure group.</p> <p>Conclusion</p> <p>The application of 4.5 mT - 120 Hz ELF-EMF inhibits preneoplastic lesions chemically induced in the rat liver through the reduction of cell proliferation, without altering the apoptosis process.</p

The Elephant

https://hsrc.himmelfarb.gwu.edu/artshow_gallery_2012/1032/thumbnail.jp

Sunset Fishing

Oil painting.https://hsrc.himmelfarb.gwu.edu/artshow_gallery_2014/1033/thumbnail.jp

The Cat

https://hsrc.himmelfarb.gwu.edu/artshow_gallery_2012/1031/thumbnail.jp

Inside the Cave

Oil on canvas.https://hsrc.himmelfarb.gwu.edu/artshow_gallery_2013/1061/thumbnail.jp

Akt1 and Akt2 Isoforms Play Distinct Roles in Regulating the Development of Inflammation and Fibrosis Associated with Alcoholic Liver Disease.

Akt kinase isoforms (Akt1, Akt2, and Akt3) have generally been thought to play overlapping roles in phosphoinositide 3-kinase (PI3K)-mediated-signaling. However, recent studies have suggested that they display isoform-specific roles in muscle and fat. To determine whether such isoform-specificity is observed with respect to alcoholic liver disease (ALD) progression, we examined the role of Akt1, Akt2, and Akt3 in hepatic inflammation, and pro-fibrogenic proliferation and migration using Kupffer cells, hepatic stellate cells (HSC), and hepatocytes in an ethanol and lipopolysaccharide (LPS)-induced two-hit model in vitro and in vivo. We determined that siRNA-directed silencing of Akt2, but not Akt1, significantly suppressed cell inflammatory markers in HSC and Kupffer cells. Although both Akt1 and Akt2 inhibited cell proliferation in HSC, only Akt2 inhibited cell migration. Both Akt1 and Akt2, but not Akt3, inhibited fibrogenesis in hepatocytes and HSC. In addition, our in vivo results show that administration of chronic ethanol, binge ethanol and LPS (EBL) in wild-type C57BL/6 mice activated all three Akt isoforms with concomitant increases in activated forms of phosphoinositide dependent kinase-1 (PDK1), mammalian target-of-rapamycin complex 2 (mTORC2), and PI3K, resulting in upregulation in expression of inflammatory, proliferative, and fibrogenic genes. Moreover, pharmacological blocking of Akt2, but not Akt1, inhibited EBL-induced inflammation while blocking of both Akt1 and Akt2 inhibited pro-fibrogenic marker expression and progression of fibrosis. Our findings indicate that Akt isoforms play unique roles in inflammation, cell proliferation, migration, and fibrogenesis during EBL-induced liver injury. Thus, close attention must be paid when targeting all Akt isoforms as a therapeutic intervention