E2f2 Attenuates Apoptosis of Activated T Lymphocytes and Protects from Immune-Mediated Injury through Repression of Fas and FasL

Targeted disruption of E2f2 in mice causes T-cell hyperactivation and a disproportionate cell cycle entry upon stimulation. However, E2f2−/− mice do not develop a lymphoproliferative condition. We report that E2f2 plays a Fas-dependent anti-apoptotic function in vitro and in vivo. TCR-stimulated murine E2f2−/− T cells overexpress the proapoptotic genes Fas and FasL and exhibit enhanced apoptosis, which is prevented by treatment with neutralizing anti-FasL antibodies. p53 pathway is activated in TCR-stimulated E2f2−/− lymphocytes, but targeted disruption of p53 in E2f2−/− mice does not abrogate Fas/FasL expression or apoptosis, implying a p53-independent apoptotic mechanism. We show that E2f2 is recruited to Fas and FasL gene promoters to repress their expression. in vivo, E2f2−/− mice are prone to develop immune-mediated liver injury owing to an aberrant lymphoid Fas/FasL activation. Taken together, our results suggest that E2f2-dependent inhibition of Fas/FasL pathway may play a direct role in limiting the development of immune-mediated pathologies.

Effect of Eight Weeks of Resistance Training and Consumption of Tribulus Terrestris on Androgenic Receptor-1, Fas Ligand Gene Expression, and Lipid Profiles in Rats Exposed to Stanozolol

Background: Protective effect of medicinal plants on the heart has been reported, but the effect of resistance training (RT) and Tribulus terrestris (TT) on the heart exposed to anabolic-androgenic steroids (AAS) abuse is still unknown. Objectives: The present study aimed to investigate the effect of RT and TT on androgen receptor-1 (ar-1), Fas ligand (fasl) gene expression and lipid profiles in rats exposed to stanozolol (S). Methods: Thirty-five male rats were selected and divided into 7 groups as follows: (1) sham (normal saline/Sh), (2) stanozolol (S), (3) S+100 mg/kg TT (S+TT100), (4) S+ 50 mg/kg TT (S+TT50), (5) S+RT+TT, (6) S+RT+TT100, and (7) S+RT+TT50. Over a course of eight-week period, groups 3, 4, 6, and 7 received 50 and 100 mg/kg/d doses of TT peritoneally and groups 5-7 performed three sessions of increasing RT per week. Results: RT decreased plasma cholesterol and low-density lipoprotein cholesterol (LDL-C) levels, as well as ar-1 and fasl gene expression in S-exposed rats (P<0.05). TT50, TT100, SRTT100, and SRTT50 reduced ar-1 and fasl gene expressions (P<0.05). TT50 reduced triglyceride (TG), cholesterol and increased high-density lipoprotein-cholesterol (HDL-C) (P≤0.01), and TT100 decreased LDL-C levels (P<0.05). Additionally, SRTT100 reduced TG, cholesterol, and LDL-C levels and increased HDL-C level (P<0.05), and SRTT50 decreased cholesterol level and increased HDL-C level in S-exposed rats (P<0.05). Conclusion: RT and consumption of TT appear to have protective effects on the improvement of apoptosisdependent androgen receptor-1 and lipid profile in S-exposed rats.

Adenovirus-Mediated FasL Minigene Transfer Endows Transduced Cells with Killer Potential

Fas ligand (First apoptosis signal ligand, FasL, also known as CD95L) is the common executioner of apoptosis within the tumor necrosis factor (TNF) superfamily. We aimed to induce functional FasL expression in transduced cells using an adenovirus vector, which has the advantage of strong and transient induction of the gene included in the adenoviral genome. Here, we report that the adenovirus carrying a truncated FasL gene, named FasL minigene, encoding the full-length FasL protein (Ad-gFasL) is more efficient than the adenovirus carrying FasL cDNA (Ad-cFasL) in the induction of FasL expression in transduced cells. FasL minigene (2887 bp) lacking the second intron and a part of the 3′-UTR was created to reduce the gene length due to the size limitation of the adenoviral genome. The results show that, in transduced hepatocytes, strong expression of mRNA FasL appeared after 10 h for Ad-gFasL, while for Ad-cFasL, a faint expression appeared after 16 h. For Ad-gFasL, the protein expression was noticed starting with 0.5 transfection units (TU)/cell, while for Ad-cFasL, it could not be revealed. FasL-expressing endothelial cells induced apoptosis of A20 cells in co-culture experiments. FasL-expressing cells may be exploitable in various autoimmune diseases such as graft-versus-host disease, chronic colitis, and type I diabetes.

Sheng Mai San protects H9C2 cells against hyperglycemia-induced apoptosis

Background Sheng Mai San (SMS) has been proven to exhibit cardio-protective effects. This study aimed to explore the molecular mechanisms of SMS on hyperglycaemia (HG)-induced apoptosis in H9C2 cells. Methods HG-induced H9C2 cells were established as the experimental model, and then treated with SMS at 25, 50, and 100 μg/mL. H9C2 cell viability and apoptosis were quantified using MTT and Annexin V-FITC assays, respectively. Furthermore, Bcl-2/Bax signalling pathway protein expression and Fas and FasL gene expression levels were quantified using western blotting and RT-PCR, respectively. Results SMS treatments at 25, 50, 100 μg/mL significantly improved H9C2 cell viability and inhibited H9C2 cell apoptosis (p < 0.05). Compared to the HG group, SMS treatment at 25, 50, and 100 μg/mL significantly downregulated p53 and Bax expression and upregulated Bcl-2 expression (p < 0.05). Moreover, SMS treatment at 100 μg/mL significantly downregulated Fas and FasL expression level (p < 0.05) when compared to the HG group. Conclusion SMS protects H9C2 cells from HG-induced apoptosis probably by downregulating p53 expression and upregulating the Bcl-2/Bax ratio. It may also be associated with the inhibition of the Fas/FasL signalling pathway.

The relationship between Fas and Fas ligand gene polymorphism and preeclampsia risk

Preeclampsia is an idiopathic multisystem disorder with partial genetic and immunological etiology. Several studies investigated the association between various single-nucleotide polymorphisms (SNPs) in Fas and Fas ligand (FasL) genes and the risk of preeclampsia. However, they achieved inconsistent results. Therefore, we conducted a meta-analysis by systematically searching the Cochrane Library, PubMed and Embase databases and assessed this association by calculating pooled odds ratios with 95% confidence interval to reach a more trustworthy conclusion. Subgroup analyses by genotype methods and source of controls (SOC) were also conducted. Seven citations containing nine studies were included for four SNPs (Fas -670 A/G, FasL 124A/G, FasL -844C/T, Fas -1377 G/A) in this meta-analysis. Our data suggested the G allele and genotype GG of the Fas -670 A/G polymorphism, GG genotype of the FasL 124A/G polymorphism, and TT genotype of the FasL -844C/T polymorphism increased the risk of preeclampsia. Stratification analyses by genotype methods and SOC also indicated that Fas -670 A/G polymorphism was related to increased risk for preeclampsia. In conclusion, Fas and FasL gene polymorphisms play important roles in the development of preeclampsia. Further well-designed studies in other races are needed to confirm the findings of this meta-analysis.