1. Autophagic-lysosomal pathway functions in the masseter and tongue muscles in the klotho mouse, a mouse model for aging
Ryo-hei Iida, Syuhei Kanko, Takeo Suga, Mitsuhiko Morito, Akira Yamane Mol Cell Biochem. 2011 Feb;348(1-2):89-98. doi: 10.1007/s11010-010-0642-z. Epub 2010 Nov 17.
Klotho mutant (kl/kl) mice, a type of short-lived mouse models, display several aging-related phenotypes. To investigate whether the atrophy of skeletal muscles is induced in these mice via activation of the ubiquitin-proteasomal pathway and/or the autophagic-lysosomal pathway through an alteration of insulin/IGF-I signaling, we analyzed the activity of the two pathways for protein degradation and components of the insulin/IGF signaling pathway in their skeletal muscles. The masseter, tongue, and gastrocnemius muscles in kl/kl showed marked reductions in muscle weight and in myofiber diameter compared with +/+. The autophagic-lysosomal pathway in kl/kl was activated in the masseter and tongue, but not in the gastrocnemius, compared with that in +/+, whereas the ubiquitin-proteasomal pathway in these three muscles of kl/kl was not altered. No marked difference in the phosphorylation levels of insulin/IGF-I signaling components, such as insulin/IGF-I receptor, Akt, and FoxO in three muscles studied were found between kl/kl and +/+, but the phosphorylation levels of signaling component at the downstream of mTOR such as 4E-BP1 and p70 S6K were suppressed in the masseter and tongue of kl/kl compared with +/+. Deficiency of essential amino acids is reported to activate the autophagy-lysosomal pathway through the down-regulation of mTOR, not through IGF-Akt-FoxO. The masseter and tongue seem to be more actively moved than limb muscles in kl/kl, because they are essential for survival activities such as mastication, swallowing, and respiration. Thus, the deficiency of amino acid by the active movement of the masseter and tongue seems to stimulate the autophagic-lysosomal pathway via the down-regulation of mTOR signalling pathway.
2. WJ9708012 exerts anticancer activity through PKC-α related crosstalk of mitochondrial and endoplasmic reticulum stresses in human hormone-refractory prostate cancer cells
Ting-chun Kuo, Wei-jan Huang, Jih-hwa Guh Acta Pharmacol Sin. 2011 Jan;32(1):89-98. doi: 10.1038/aps.2010.173. Epub 2010 Dec 6.
Aim: To investigate the anticancer mechanism of a methoxyflavanone derivative, WJ9708012, highlighting its role on a crosstalk between endoplasmic reticulum (ER) and mitochondrial stress. Methods: Cell proliferation was examined using sulforhodamine B assay. Cell-cycle progression, Ca(2+) mobilization and mitochondrial membrane potential (ΔΨ(m)) were detected using flow cytometric analysis. Protein expression was detected using Western blot. Results: WJ9708012 displayed an antiproliferative and apoptotic activity in human hormone-refractory prostate cancer cells with IC(50) values of 6.4 and 5.3 μmol/L in PC-3 and DU-145 cells. WJ9708012 induced a prompt increase of cytosolic Ca(2+) level and activation of protein kinase C (PKC)-α. The cleavage of μ-calpain was also induced by WJ9708012. Furthermore, WJ9708012 induced cell-cycle arrest at G(1)-phase associated with down-regulation of cyclin D1, cyclin E and cyclin-dependent kinase-4 expressions. It also caused a rapid and time-dependent decrease of phosphorylation level of mTOR (Ser(2448)), 4E-BP1 (Thr(37)/Thr(46)/Thr(70)) and p70S6K (Thr(389)), indicating the inhibition of mTOR-mediated translational pathways. The ER stress was activated by the identification of up-regulated GADD153 and glucose-regulated protein-78 protein levels. The subsequent mitochondrial stress was also identified by the observation of a decreased Bcl-2 and Bcl-xL expressions, an increased truncated Bid and Bad and a loss of ΔΨ(m). Conclusion: WJ9708012 induces an increase of cytosolic Ca(2+) concentration and activation of PKC-α. Subsequently, a crosstalk between ER stress and mitochondrial insult is induced, leading to the inhibition of mTOR pathways and arrest of the cell-cycle at G(1) phase. The apoptosis is ultimately induced by a severe damage of mitochondrial function.
3. Mesenchymal Stem Cells with Granulocyte Colony-Stimulating Factor Reduce Stress Oxidative Factors in Parkinson's Disease
Laya Ghahari, Manouchehr Safari, Khojaste Rahimi Jaberi, Behnaz Jafari, Katayoun Safari, Mahmoodreza Madadian Iran Biomed J. 2020 Mar;24(2):89-98. doi: 10.29252/ibj.24.2.89. Epub 2019 Nov 2.
Background: Recent studies have shown that bone marrow mesenchymal stem cells (BMSCs) have a putative ability to promote neurogenesis and produce behavioral and functional improvement. Our previous study demonstrated that co-treatment of granulocyte colony-stimulating factor (G-CSF) and BMSCs have beneficial effects on Parkinson's models. The main purpose of this research was to investigate the effects of these two factors on oxidative stress factors in the brain of Parkinson's rat. Methods: Adult male Wistar rats (weighing 200-250 g) were used and randomly divided into five groups of seven each. To create the Parkinson's model, 6-OHDA was injected into the left substantia nigra pars compacta. The BMSCs (2 × 106) and G-CSF (75 µg/kg) were used for treatment after creating the PD model. After four weeks, the brains of rats were removed and processed for immunohistochemical studies, such as tyrosine hydroxylase-positive neurons as well as analysis of oxidative stress factors. Results: The results showed that the injected BMSCs could cross the BBB. The injected cells are also able to settle in different areas of the brain. Analyses of the brain oxidative stress factors showed that G-CSF and BMSCs reduced the expression of malondialdehyde and induced the activity of superoxide dismutase, glutathione, and peroxidase ferric reducing ability of plasma. Conclusion: Co-administration of G-CSF and BMSC reduced the expression of pro-inflammatory cytokines and induced the activity of antioxidant enzymes; however, neurogenesis increased in the brain.
