SummaryConcomitant hepatocyte apoptosis and regeneration is a hallmark of chronic liver diseases (CLDs) predisposing to hepatocellular carcinoma (HCC). Here, we mechanistically link caspase-8-dependent apoptosis to HCC development via proliferation- and replication-associated DNA damage. Proliferation-associated replication stress, DNA damage, and genetic instability are detectable in CLDs before any neoplastic changes occur. Accumulated levels of hepatocyte apoptosis determine and predict subsequent hepatocarcinogenesis. Proliferation-associated DNA damage is sensed by a complex comprising caspase-8, FADD, c-FLIP, and a kinase-dependent function of RIPK1. This platform requires a non-apoptotic function of caspase-8, but no caspase-3 or caspase-8 cleavage. It may represent a DNA damage-sensing mechanism in hepatocytes that can act via JNK and subsequent phosphorylation of the histone variant H2AX.
Deletion of the Casp8 gene in epithelial tissues of mice results in severe inflammatory pathologies. Its ubiquitous deletion, or its specific deletion in endothelial cells, results in intrauterine death associated with capillary damage. These pathologies are all preventable by co-deletion of Casp8 and the genes encoding either the RIPK1 or the RIPK3 protein kinase. Since activation of RIPK3 in Caspase-8-deficient cells can trigger necroptotic cell death, and since RIPK1 can activate RIPK3, it is widely assumed that the inflammatory states resulting from Caspase-8 deficiency occur as a consequence of RIPK3-induced necroptosis. Here, we report that although on a Ripk3-null background Casp8 deletion in mice does not result in outright pathological changes, it triggers enhanced expression of a variety of inflammatory genes in utero, which gradually subsides after birth. Deletion of Ripk1, or even of only one of its two alleles, obliterates this activation. Resembling the embryonic pathology observed in RIPK3-expressing cells, the activation of inflammatory genes observed on a Ripk3-null background seems to be initiated in endothelial cells. Analysis of endothelial cells isolated from livers of Caspase-8-deficient embryos revealed neither an increase in the amount of RIPK1 in these cells after Casp8 deletion, nor triggering of RIPK1 phosphorylation. These findings indicate that the triggering of inflammation by Casp8 deletion in mice occurs, in part, independently of necroptosis or other functions of RIPK3, and rather reflects enhanced RIPK1-dependent signaling for activation of inflammatory genes.
BackgroundKorean mistletoe (Viscum album coloratum) is a semi-parasitic plant that grows on various trees and has a diverse range of effects on biological functions, being implicated in having anti-tumor, immunostimulatory, anti-diabetic, and anti-obesity properties. Recently, we also reported that Korean mistletoe extract (KME) improves endurance exercise in mice, suggesting its beneficial roles in enhancing the capacity of skeletal muscle.MethodsWe examined the expression pattern of several genes concerned with muscle physiology in C2C12 myotubes cells to identify whether KME inhibits muscle atrophy or promotes muscle hypertrophy. We also investigated these effects of KME in denervated mice model.ResultsInterestingly, KME induced the mRNA expression of SREBP-1c, PGC-1α, and GLUT4, known positive regulators of muscle hypertrophy, in C2C12 cells. On the contrary, KME reduced the expression of Atrogin-1, which is directly involved in the induction of muscle atrophy. In animal models, KME mitigated the decrease of muscle weight in denervated mice. The expression of Atrogin-1 was also diminished in those mice. Moreover, KME enhanced the grip strength and muscle weight in long-term feeding mice.ConclusionsOur results suggest that KME has beneficial effects on muscle atrophy and muscle hypertrophy.
Mistlero C was shown to be non-genotoxic in a series of genotoxicity tests, including a bacterial reverse mutation test and a combined in vivo mammalian erythrocyte micronucleus test. In a bacterial reverse mutation assay, no significant increases in the number of revertant colonies, compared to the negative control, was detected in 5,000 ㎍/plate of Mistlero C. In addition, with Mistlero C, no changes were shown in the number of micronucleated polychromatic erythrocytes (MNPCE) among 2,000 polychromatic erythrocytes compared to the negative control. Mistlero C was administered orally in rats to investigate acute toxicity. The LD 50 values in rats were above 2,000 ㎎/㎏. In a repeated dose, 13-week, oral toxicity study conducted in rats, no compound-related adverse effects were shown at doses of Mistlero C of up to 1,000 ㎎/㎏ body weight/day. The results of these studies support the safe use of Mistlero C in food for human consumption.
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