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Roles of Melatonin in Maintaining Mitochondrial Welfare
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Feres José Mocayar Marón, Emiliano Diez, Russel J. Reiter, Walter Manucha
The kidney intracellular protection was associated with an elevated number of mitochondria and upregulation of the prosurvival genes such as nicotinamide phosphoribosyltransferase (Nampt) and sirtuin 3 (Sirt3)121. Sirt3 is a member of the family that is localized mostly to the mitochondria and protects against inflammation and oxidative stress-related diseases, including hypertension. Melatonin elevated Sirt3 stimulated SOD activity and suppressed mitochondrial oxidative stress through AMPK122 (Figure 2). Melatonin’s high concentrations and multiple actions as an anti-inflammatory/antioxidant provide substantial protection to mitochondria which are exposed to injury22.
Micronutrients in the Prevention and Improvement of the Standard Therapy for Alzheimer’s Disease
Published in Kedar N. Prasad, Micronutrients in Health and Disease, 2019
Treatment with nicotinamide mononucleotide enhanced expression of miR-34a reduced the levels of its target protein NAPT (nicotinamide phosphoribosyltransferase, a rate-limiting enzyme in the biosynthesis of NAD+ in the liver of obese individuals.133 Increased expression of miR-34a leads to reduction in the levels of SIRT1, a NAD+-dependent deacetylase. Reduction in SIRT1 activity enhanced the transcription of its target proteins, such as PGC-1 alpha, NF-kB, and SREBP-1c (sterol Regulatory Element-Binding Transcriptional Factor-1).
Anti-Aging and Regenerative Medicine
Published in Aruna Bakhru, Nutrition and Integrative Medicine, 2018
Biosynthesis of NAD(+) is mediated by SIRT1 and nicotinamide phosphoribosyltransferase (NAMPT), that jointly regulate circadian rhythm as well as metabolism. It has been seen that NAD(+) increase can mediate extension of health and lifespan. Similarly, reciprocal studies have also shown that defective NAD(+) levels maintenance and a decline in sirtuin activity might drive the normal process of aging. Supplementation of NAD(+) along with sirtuin activation is being researched as an effective method to reverse age-related pathologies (Imai and Guarente 2014).
Targeting p21-activated kinase 4 (PAK4) with pyrazolo[3,4-d]pyrimidine derivative SPA7012 attenuates hepatic ischaemia-reperfusion injury in mice
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Yuancheng Mao, Eun Lee, Xiaohui Yang, Eun Ju Bae, Raok Jeon, Byung-Hyun Park
Several PAK4 inhibitors have been described over the last decade. PF-3758309 was first developed by Pfizer as a pan-PAK inhibitor through structure-based design combined with high-throughput screening and displayed anti-tumour effects against several types of cancers.10,11 PF-3758309 was evaluated in clinical trials (NCT00932126); however, further investigation was terminated due to undesirable pharmacokinetic properties and poor bioavailability.12 A second compound, KPT-9274, a dual inhibitor of PAK4 and nicotinamide phosphoribosyltransferase,13 is currently in clinical trials (NCT02702492) for the treatment of patients with refractory/relapsed haematologic and solid tumours. Recently, Guo et al. developed PAK4 inhibitor as a prodrug form (CZh-226) and observed improved pharmacokinetic and tissue distribution and well tolerability in a rat model of cancers.13,14 Unfortunately, use of the aforementioned PAK4 inhibitors has been limited by their weak potency and lack of PAK4 selectivity. Based on our previous study confirming PAK4 as a negative regulator of Nrf2-ARE pathways,9 we closely examined our newly identified PAK4-specific inhibitor SPA7012 for application as a therapeutic for the treatment of hepatic I/R injury. We further examined the molecular basis underlying the protective activities of this small molecule against oxidative stress in cultured hepatocytes with hypoxia-reoxygenation (H/R) and in mice with hepatic I/R.
Cellular senescence in liver fibrosis: Implications for age-related chronic liver diseases
Published in Expert Opinion on Therapeutic Targets, 2021
Wanvisa Udomsinprasert, Abhasnee Sobhonslidsuk, Jiraphun Jittikoon, Sittisak Honsawek, Usa Chaikledkaew
Alterations in the abundance of mitochondrial metabolites have been reportedly implicated in the regulation of senescence and the SASP [110]. During the TCA cycle and oxidation of fatty and amino acids, NAD+ is transformed to NADH and needed for poly-ADP ribose polymerase (PARP) activity as a foremost governor of DNA repair and nuclear factor-kappa B (NF-κB) activity [111]. On the basis of its property, recent studies have unveiled that NAD+/NADH ratios were reduced in senescent cells, causing mitochondrial dysfunction [96,112]. Concurrently, replicative senescence in human vascular smooth muscle cells has been linked to a decrease in the activity of nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting enzyme responsible for NAD+ salvage. Along with this, NAMPT overexpression previously enhanced the activity of sirtuin1 (SIRT1) being not only an important modulator of NF-κB activity, but also an inducer of p53 degradation. Besides, it has been shown to prolong the replicative lifespan of cells [113].
Visfatin and global histone H3K9me levels in colon cancer
Published in Annals of Medicine, 2021
Eman A. Al Abdulsalam, Rowyda N. Al Harithy
Over the last few decades, adipokines have established a reputation for playing a part in carcinogenesis and tumour progression [2–5]. Visfatin is an adipokine that was first discovered as a pre-B-cell colony-enhancing factor (PBEF) that is highly expressed in visceral fat [6]. It has been known as nicotinamide phosphoribosyltransferase (NAMPT), encoded by the NAMPT gene, and found to be synthesized and released by a wide variety of tissue types [7,8]. Visfatin has been shown to have endocrine, autocrine, and paracrine functions [9]. Of visfatin’s many functions, it is important to note the part it plays in the production of nicotinamide adenine dinucleotide (NAD), in the activation of the insulin signalling cascade, in increasing glucose uptake, and in inhibiting glucose release [8–10]. Furthermore, visfatin is a regulatory protein in several inflammatory disorders [11–13].