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Exercise-Induced Mitochondrial Biogenesis: Molecular Regulation, Impact of Training, and Influence on Exercise Performance
Published in Peter M. Tiidus, Rebecca E. K. MacPherson, Paul J. LeBlanc, Andrea R. Josse, The Routledge Handbook on Biochemistry of Exercise, 2020
Hashim Islam, Jacob T. Bonafiglia, Cesare Granata, Brendon J. Gurd
Similar to PPARβ, the oestrogen-related receptor (ERR) family of nuclear receptors are known regulators of oxidative metabolism, and their transcriptional activity is dependent on their interactions with various co-regulators (e.g., PGC-1a) (62). However, transgenic rodent studies suggest that oxidative remodelling of skeletal muscle by the gamma-isoform of this family (ERRg) may also occur independently from PGC-1a (25). Overexpression of ERRg in murine skeletal muscle increases mitochondrial content, oxidative enzyme activities, and exercise capacity (62). Most compellingly, ERRg overexpression in murine skeletal muscle devoid of both PGC-1 isoforms (PGC-1a/β) significantly improves defects in mitochondrial content and respiratory function associated with the loss of PGC-1a/β both basally and in response to exercise training (25). These findings implicate ERRg as an additional player in the transcriptional control of mitochondrial biogenesis beyond its established role as a downstream binding partner of PGC-1a.
Protein Degradation Inducers SNIPERs and Protacs against Oncogenic Proteins
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Norihito Shibata, Nobumichi Ohoka, Takayuki Hattori, Mikihiko Naito
To improve the protein knockdown activity of PRORACs, Dr. Crews’ group developed hydroxyproline-based small molecules targeting VHL (Buckley et al., 2012a; Buckley et al., 2012b; Galdeano et al., 2014; Frost et al., 2016). They synthesized all small molecule PROTACs consisting of VHL032 (a VHL ligand) and a ligand of estrogen-related receptor a (ERRα) or receptor-interacting serine-threonine kinase 2 (RIPK2) (Bondeson et al., 2015). These novel VHL-recruiting PROTACs induce significant degradation of ERRα and RIPK2 at 100 and 3 nM, respectively. In addition, the VHL-recruiting PROTAC against ERRα provides broad tissue distribution and knockdown of ERRα protein in a tumor xenograft model. Using the VHL ligand or its derivative, potent PROTACs were also developed against oncogenic proteins such as BRD4 (Raina et al., 2016), TRIM24 (Gechijian et al., 2018), and receptor tyrosine kinases (epidermal growth factor receptor, HER2, and c-MET) (Burslem et al., 2018).
Organic Chemicals
Published in William J. Rea, Kalpana D. Patel, Reversibility of Chronic Disease and Hypersensitivity, Volume 4, 2017
William J. Rea, Kalpana D. Patel
The mean uBPA concentration in our study was 3.65 ng/mL with an assumption of an average 24-hour urine volume for adults of 1600 mL, a 100% excretion rate, and a total blood volume of 6 L, which would give an estimated BPA blood concentration in the nanograms per milliliter range. BPA shows relatively weak estrogenic agonist activities against both human estrogen receptor-α and receptor-β subtypes (ERα, ERβ) that control many estrogen-mediated activities. The half-maximal inhibitory concentration for receptor binding of BPA to human ERα and ERβ is in the low micromolar range when calculated in vitro and, if extrapolated directly to the in vivo situation (without considering competitive binding to serum-binding proteins, for instance), this would imply low ER occupancy rates in blood and potential target tissues. However, BPA binds to other estrogen-related receptors with high affinity, including the estrogen-related receptor-γ (ERRγ), for which optimal receptor binding is in the nanomolar range.277 A recent study has reported positive associations between increased BPS exposure and in vivo estrogenic gene expression in adults, including ERβ and the estrogen-related receptor α (ERRα).278 ERRα is an orphan nuclear receptor involved in estrogenic signaling and energy homeostatis that is coordinately regulated with ERRγ. It is relevant to note that expression of ERRα is highest in tissues that preferentially use fatty acids as energy sources, including adipose tissue, skeletal muscle, and heart.
Kidney and lipids: novel potential therapeutic targets for dyslipidemia in kidney disease?
Published in Expert Opinion on Therapeutic Targets, 2022
Konrad Zuzda, Wiktoria Grycuk, Jacek Małyszko, Jolanta Małyszko
In another model of diabetic DBA/2 J and db/db mice, Wang et al. [178] reported that the nuclear hormone receptor farnesoid X receptor (FXR) and G protein–coupled receptor TGR5 have renoprotective roles in diabetes- and obesity-related kidney diseases. Administration of the dual FXR/TGR5 agonist INT-767 improved proteinuria and prevented podocyte injury, mesangial expansion, and tubulointerstitial fibrosis. This agent affects multiple pathways, including stimulation of a signaling cascade involving AMP-activated protein kinase, sirtuin 1, PGC-1α (peroxisome proliferator-activated receptor-gamma coactivator), sirtuin 3, estrogen-related receptor-α, and Nrf-1, inhibition of endoplasmic reticulum stress, and inhibition of enhanced renal fatty acid and cholesterol metabolism. In addition, in mice with diet-induced obesity, a dual FXR/TGR5 agonist prevents mitochondrial dysfunction, oxidative stress, and kidney fibrosis. The authors suggested that INT-767 could be a promising agent for the treatment of renal complications in diabetes and obesity. As angiotensin II exacerbates mitochondrial reactive oxygen species synthesis and mitochondrial fragmentation in podocytes, both in vivo and in vitro, Zhu et al. [179] recently showed that mitoquinone, a mitochondria-targeted antioxidant, can reverse injury caused by angiotensin II.
Low bone mass is associated with carotid calcification plaque in Chinese postmenopausal women: the Chongqing osteoporosis study
Published in Climacteric, 2020
D. Liu, L. Chen, S. Dong, H. Yang, L. Li, J. Liu, H. Zhou, R. Zhou
Vascular calcification is now considered to be an active process with common characteristics with bone remodeling48–51. The study has suggested that heparanase may play an important role in vascular calcification, which may be related to the enhancement of mineralization and osteogenic differentiation of vascular smooth muscle cells7. Dynamic protein-related protein 1 (DRP1) is a key regulator of mitochondrial division. The data demonstrated a new function of DRP1 in regulating cardiovascular calcification, and supported a role of mitochondrial dynamics in regulating oxidative stress-mediated arterial calcium accrual and bone loss52. Vascular calcification which refers to ectopic mineralization in vascular cells is associated with atherosclerosis53. The present results indicated that estrogen-related receptor (ERR) γ played a key role in vascular calcification by upregulating the BMP2 signaling pathway. ERRγ promoted dedifferentiation of vascular smooth muscle cells to an osteogenic phenotype during the vascular calcification process. Runt-related transcription factor 2 (Runx2) is a key osteogenic transcription factor; the present studies have demonstrated that Runx2 is related to calcification of vascular smooth muscle cells54. The study has determined a new causative effect of vascular smooth muscle cell-specific phosphatase on vascular calcification, and has demonstrated that FOXO1/3 (forkhead box O) plays a crucial role in Runx2 ubiquitination and vascular smooth muscle cell calcification.
Bisphenol A: A notorious player in the mosaic of autoimmunity
Published in Autoimmunity, 2018
Gali Aljadeff, Eleonora Longhi, Yehuda Shoenfeld
The BPA compound is structurally similar to steroid hormones and exhibits estrogen (E2) mimicking effects (Figure 2). Studies report that BPA exerts agonist effects on both classical (ERα and ERß) [16, 17] and non-classical (G protein-coupled receptor (GPCR) and estrogen-related receptor gamma (ERRγ)) [18] estrogen receptors. In turn, BPA has been observed to trigger cellular proliferation and molecular pathways involved in the pathogenesis of breast cancer [18, 19], endometrial cancer [20], and prostate cancer [21]. Furthermore, BPA has been shown to alter the function of several cell types critical in establishing immune tolerance, including dendritic cells, and T and B lymphocytes [22]. An additional study conducted by Balistrieri et al. [23] investigated the effect of BPA on neutrophil function in innate immunity. In vivo, antagonist binding of the estrogen receptor on the neutrophil cell membrane can downregulate production of ROS. Indeed, results of this study suggest that neutrophils exposed to BPA can induce increased ROS production by neutrophils by binding the estrogen receptor, implicating BPA estrogenic activity [23].