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Molecular adaptations to endurance exercise and skeletal muscle fibre plasticity
Published in Adam P. Sharples, James P. Morton, Henning Wackerhage, Molecular Exercise Physiology, 2022
Even though shifts in MyHC can occur over a long period of continuous training, other changes occur within skeletal muscle over a much shorter time frame, including increases in mitochondrial mass, capillary density, fat oxidation enzymes and insulin sensitivity. Many of these muscular responses to endurance exercise lie down stream of a single transcriptional co-activator, PGC (peroxisome proliferator-activated receptor-gamma co-activator) -1α. Most importantly, in response to exercise PGC-1α mRNA is increased, with much of the increase the result of activation in the alternative promoter (59) discussed in Chapter 6, with this form of the gene known as PGC-1α2/3. PGC-1α acts as an effector by increasing the transcriptional activity of transcription factors. In other words, transcription factors, like the nuclear respiratory factor 1 (NRF1), the estrogen-related receptor α (ERRα) and the peroxisome proliferator-activated receptor-delta (PPARδ), bind DNA in a sequence-specific manner to increase the expression of mitochondrial, angiogenic and fat oxidation genes, respectively. By contrast, a co-activator like PGC-1α does not bind DNA. Instead, it binds to transcription factors and helps them open DNA around, and recruit polymerase II to, the promoter of the gene. In this section, the regulation and downstream effects of PGC-1α will be discussed in detail.
Mitochondrial Dysfunction in Huntington Disease
Published in Abhai Kumar, Debasis Bagchi, Antioxidants and Functional Foods for Neurodegenerative Disorders, 2021
Md. Hafiz Uddin, Marufa Rumman, Tasnuva Sarowar
The underlying mechanism of PGC-1α suppression in HD is not clear. However, studies have shown that a cofactor of PGC-1α, the peroxisome proliferator-activated receptor-delta (PPAR-δ), interacts with both wild type and mHTT and enhances PGC-1α activity. An overexpression study has confirmed improved behavior and neuroprotection in the HD mouse model, whereas, its inhibition in the striatum of mice produces an HD-like phenotype (Dickey et al. 2016). The PPAR-δ activators are in clinical trials for metabolic disorders (Vazquez-Carrera 2016) and are an exciting avenue for therapeutic development in HD.
Effects of Retinoids at the Cellular Level (Differentiation, Apoptosis, Autophagy, Cell Cycle Regulation, and Senescence)
Published in Ayse Serap Karadag, Berna Aksoy, Lawrence Charles Parish, Retinoids in Dermatology, 2019
The effects of RA on cells are mediated by RA responsive receptors (RAR): retinoic acid receptor alpha (RARA or RAR-α), beta (RARB or RAR-β), and gamma (RARG or RAR-γ) and the peroxisome proliferator-activated receptor beta and delta (PPARB or PPAR-β and PPARD or PPAR-δ) which belong to the nuclear receptor superfamily (6). They function as RA ligand-dependent transcription factors which form heterodimers with the retinoid X receptors (RXRs), and mediate transcription by binding to DNA. Heterodimers RAR/RXR bind to cis acting RA response elements (RAREs), while PPAR/RXR heterodimers bind to peroxisome proliferator response element (PPRE) (Figure 8.1) (7–9). The precise control of RARs is necessary for the correct balance between self-renewal and differentiation of tissue stem cells. The loss, accumulation, mutations, or aberrant modifications of RARs results in oncogenic transformation with disturbance in differentiation and uncontrolled proliferation of cells (10). The targets of RA and RARs/PPAR-β/δ include many structural genes, oncogenes, transcription factors, and cytokines.
Ginsenoside Rh2 mitigates myocardial damage in acute myocardial infarction by regulating pyroptosis of cardiomyocytes
Published in Clinical and Experimental Hypertension, 2023
Hong Peng, Li Chen, Yi Deng, Xin Liao, Yi Yang
In traditional Chinese medicine, ginseng is the first choice of drug to correct the disrupted balance and is rich in several pharmacologically active ingredients, with ginsenoside deemed the most important (11). Ginsenoside Rh2 can inhibit the nuclear factor (NF)-κB signaling pathway and reduce the inflammatory response by enhancing the expression of transforming growth factor (TGF)-β1 (12). Ginsenoside Rh2 has been shown to afford a protective effect against CVDs. It can improve cardiac function and fibrosis by enhancing the peroxisome proliferator-activated receptor delta (PPARδ) signaling pathway and is a promising alternative therapy for cardiac fibrosis (13). Furthermore, ginsenoside Rh2 can improve the inflammatory microenvironment by enhancing exosome protection against myocardial injury (14). Recently, ginsenoside Rh2 was found to play an anti-inflammatory role in alleviating AMI by regulating cardiomyocyte pyroptosis in rats (15). However, further in vitro and in vivo studies are required to establish its protective effects and elucidate the underlying molecular mechanisms.
Inclisiran inhibits oxidized low-density lipoprotein-induced foam cell formation in Raw264.7 macrophages via activating the PPARγ pathway
Published in Autoimmunity, 2022
Zhaoping Wang, Xiangyu Chen, Jingxing Liu, Yingcui Wang, Suhua Zhang
Peroxisome proliferator activated receptors (PPARs) are ligand-activated transcription factors comprising three related ligand-dependent transcription factors: PPARα, PPARγ, and PPAR β/δ, which are encoded by PPARA, PPARG, and PPARD genes, respectively [15,16]. These three PPARs are key ligand-inducible transcription factors that play significant roles in glucose and lipid metabolism. They influence the cardiovascular system and are involved in the pathogenesis of AS and hypertension [17]. As a genetic sensor of fatty acids, PPARγ is responsible for controlling fatty acid uptake and lipogenesis [18]. PPARγ is highly expressed in activated macrophages stimulated with interleukin (IL)-4 [19,20]. Moreover, PPARγ is involved in macrophage cholesterol metabolism and inflammatory responses that control AS development [21,22]. Thiazolidinediones, agonists of PPARγ, are widely known to exert cardioprotective effects by inhibiting cytokine release, LDL oxidization, and ox-LDL uptake by macrophages [23].
Dietary Choices Modulate Colorectal Cancer Stem Cells: A Role of FXR Nuclear Receptor
Published in Nutrition and Cancer, 2021
Nilesh Kumar Sharma, Sachin C. Sarode, Gargi S Sarode, Shankargouda Patil, Jayanta K. Pal
Currently, the existence of CSCs as a key cellular heterogeneity within the tumor microenvironment is denoted as a seeding factor, as well as contributors of several tumor hallmarks, including resistance and relapse of tumors (8–27,42). In a clear role of high fat diet in the promotion of Lgr5(+) intestinal CSCs, Beyaz and Yilmaz (42) delineate the molecular mechanisms of action by high dietary fat to augment peroxisome proliferator-activated receptor delta (PPAR-δ) signature in intestinal stem cells. In this case, PPAR-δ is known as a nuclear receptor transcription factor. However, the role of PPAR-δ in colorectal cancer mediated by high dietary fat components is shown as a factor to modulate intestinal CSCs. A recent work also supports the contribution of high-fat diet in the promotion of colon CSC self-renewal by activating the expression of LGR5 and stimulated by retinoic acid 6 (STRA6) receptors (23). In addition to the clear role of high-fat diet in intestinal CSCs, Hermetet et al. (26) show that stemness power of hematopoietic stem cells is disrupted by the high fat diet through the Smad2/3-dependent-TGF-β signaling axis.