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Pharmacologic Ascorbate Influences Multiple Cellular Pathways Preferentially in Cancer Cells
Published in Qi Chen, Margreet C.M. Vissers, Cancer and Vitamin C, 2020
Qi Chen, Kishore Polireddy, Ping Chen, Ramesh Balusu, Tao Wang, Ruochen Dong
Tubulin acetylation is under the control of balanced enzymatic activities of acetyltransferases (α-tubulin acetyltransferase [α-TAT]) and deacetylases (histone deacetylase 6 [HDAC6] and Sirtuin 2 [Sirt-2]). Sirt-2 is a NAD+-dependent protein deacetylase, whereas HDAC6 is a Zn+2 dependent protein deacetylase. Both Sirt-2 and HDAC6 predominantly localize to the cytoplasm and have deacetylase activity for αK40 [43–45]. Ascorbate has no effect on the expression levels of α-TAT and Sirt-2 but slightly decreased HDAC6 expression. However, overexpression of HDAC6 in pancreatic cancer cell lines failed to rescue ascorbate-mediated α-tubulin acetylation, suggesting that HDAC6 has a minimal role in this process despite its expression being influenced by ascorbate. While the influence of ascorbate on α-TAT is less studied, the current studies demonstrated the importance of Sirt-2. Ascorbate enhances α-tubulin acetylation mainly by inhibiting Sirt-2 activity, as a consequence of NAD+ depletion. Supplementation of NAD+ prevented the ascorbate-mediated α-tubulin acetylation. Results from these studies are critical for defining the synergistic effect of ascorbate and tubulin-stabilizing anticancer drugs, such as paclitaxel [4].
Micronutrients in Prevention and Improvement of the Standard Therapy in Hearing Disorders
Published in Kedar N. Prasad, Micronutrients in Health and Disease, 2019
Age-related hearing loss is caused by the cochlear degeneration. Overexpression of miR-29b induced degeneration of cochlear hair cells by decreasing the levels of its target proteins. These key proteins are (a) silent mating type information regulation 2 homolog 1 (SIRT1), a NAD+ dependent protein deacetylase, which downregulates inflammatory processes, and (b) proliferator-activated receptor-gamma coactivator 1α (PGC-1α). PGC-1alpha is a stimulator of mitochondrial biogenesis and a regulator of energy metabolism, whose inhibition can lead to impaired mitochondrial function and cochlear hair cell apoptosis in mice.111 This study was confirmed by the opposite experiment in which inhibition of miR-29b increased the levels of SIRT1 and PGC-1aα, and deceased apoptosis of cochlear hair cells (HEI-OC1 inner ear cell line).
Early Life Nutrition, Epigenetics, and Later Cardiometabolic Health
Published in Nathalie Bergeron, Patty W. Siri-Tarino, George A. Bray, Ronald M. Krauss, Nutrition and Cardiometabolic Health, 2017
Mark H. Vickers, Clare M. Reynolds, Clint Gray, Nathalie Bergeron, Patty W. Siri-Tarino, George A. Bray, Ronald M. Krauss
Work in the primate has shown that, in addition to DNA methylation changes, obesity induced by a calorie-dense maternal diet can lead to alterations in fetal chromatin structure via covalent histone modifications (Aagaard-Tillery et al. 2008). Hepatic metabolism in the neonate can be altered in the setting of a maternal HFD, albeit in a sex-specific manner, and these differences, in association with histone modifications, may contribute to the known sexual dimorphism in oxidative balance (Strakovsky et al. 2014). Further work in the nonhuman primate has shown that a maternal HFD can modulate sirtuin 1 (SIRT1) histone and protein deacetylase activity in the fetus. This implicates SIRT1 as a likely mediator of the fetal epigenome and metabolome in the setting of maternal obesity (Suter et al. 2012). Via regulatory loops, miRNAs can cause histone modifications and altered DNA methylation of promoter sites, which affect the expression of target genes (Hawkins and Morris 2008, Tan et al. 2009). Further, in an ovine model of maternal obesity, miRNA expression in fetal muscle is altered and therefore may be a mechanism by which intramuscular adipogenesis is enhanced during early muscle development (Yan et al. 2013).
Logistic role of carnitine shuttle system on radiation-induced L-carnitine and acylcarnitines alteration
Published in International Journal of Radiation Biology, 2022
CACT is located to the inner mitochondrial membrane as a carrier that transports acylcarnitines across the membrane in exchange for free L-carnitine that exits from the mitochondrial matrix (Figure 2). It can also transport the carnitine shuttle system intermediates acylcarnitines out of the mitochondria (Bennett 2007). The enzyme has high activity in most cell types, and the activity obviously exceeds of β-oxidation flux requirement greatly. Thus, CACT is not usually thought to play a role in regulating the β-oxidation flux. However, one study found that acetylation of CACT decreased the transport activity, which indicated CACT may be a possible regulatory site of β-oxidation pathway (Eaton 2002). The acetylation level plays an additional role in the control of CACT function and is affected by acetyl-CoA level and the activity of sirtuin-3. This NAD+‐dependent protein deacetylase is a member of the silent information regulator 2 family. This mechanism represents a control of the influx of fatty acyl groups into mitochondria in response to intramitochondrial acetyl-CoA level. The role of CACT on alteration of carnitine profile can be acquainted in some literature. For example, the level of palmitoylcarnitine was elevated in the CACT deficiency patients (Yamada and Taketani 2019; Houten et al. 2020).
Patients with ankylosing spondylitis have high risk of irritable bowel syndrome: a long-term nationwide population-based cohort study
Published in Postgraduate Medicine, 2022
Hao-Yuan Feng, Chi-Ho Chan, Yu-Cheng Chu, Xin-Man Qu, Yu-Hsun Wang, James Cheng-Chung Wei
Unlike rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE), there were still no specific autoantibodies as markers for AS. However, autoantibodies do exist in the serum of AS patients [33,34]. In recent, a higher positive rate of autoantibody targeting NAD-dependent protein deacetylase sirtuin-1(SIRT-1) was detect in a relatively high proportion of AS patients [35]. The function of SIRT-1 was demonstrated to regulate the homeostasis of microbiota of GI tract and prevent GI inflammation in mouse experiments [36]. Therefore, altering the activity of SIRT-1 by its autoantibody might disrupt the microbiota ecosystem. Expression of SIRT-1 also improved endoplasmic reticulum stress-mediated apoptosis of intestinal epithelial cells in ulcerative colitis [37]. In addition, the presence of anti-enteric neuronal antibodies in autoimmune patients that attack the neuron in GI has also been reported [38], hence why there was a higher risk of IBS in AS patients. Therefore, the reasons why AS patients have high risks of IBS might be attributed to multiple factors.
Inflammation, oxidative stress and altered heat shock response in type 2 diabetes: the basis for new pharmacological and non-pharmacological interventions
Published in Archives of Physiology and Biochemistry, 2022
Gabriela Elisa Hirsch, Thiago Gomes Heck
Once again, NF-κB is also related to other complications of diabetes, such as in hepatic and renal dysfunctions. As a multi-task nuclear factor signal, NF-κB interferes in the cellular response to various stimuli such as stress and free radicals (Melloul 2008, Ghosh and Hayden 2012), which, once augmented, interact with various biomolecules causing changes in cellular functions and structure, such as loss of membrane integrity, structural/functional protein changes and genetic mutations (Memisogullari et al.2003, Vincent et al.2004). The NAD-dependent protein deacetylase sirtuin-1 (SIRT1), an enzyme responsible for the deacetylation of proteins involved in cellular regulation of diverse processes such as fatty acid oxidation and control of cellular metabolic balance (Baur 2010, Nogueiras et al.2012), also appears to be involved in the control of glucose plasma levels through the regulation of insulin secretion (Dong et al.2011, Gillum et al.2011, Turkmen et al.2014). The metabolic unbalance effects of DM2 can be related to inhibition of SIRT1 activity, which in turns is related with decreases in HSPs synthesis, by metabolic changes that promotes a decrease in 5′-adenosine monophosphate kinase (AMPK) activity, as physical inactivity, obesity and aging (Miragem and Homem de Bittencourt 2017).