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Aquatic Plants Native to America
Published in Namrita Lall, Aquatic Plants, 2020
Bianca D. Fibrich, Jacqueline Maphutha, Carel B. Oosthuizen, Danielle Twilley, Khan-Van Ho, Chung-Ho Lin, Leszek P. Vincent, T. N. Shilpa, N. P. Deepika, B. Duraiswamy, S. P. Dhanabal, Suresh M. Kumar, Namrita Lall
Luteolinidin, isolated from A. caroliniana, showed potential for the treatment of schistosomiasis (bilharzia) due to its ability to inhibit Schistosoma mansoni recombinant NAD+ glycohydrolase expressed in Pichia pastoris using the continuous fluorometric method (IC50 5.9 µM) (Kuhn et al. 2010).
Streptococcus
Published in Dongyou Liu, Laboratory Models for Foodborne Infections, 2017
GAS is commonly transmitted through two routes: foodborne or airborne. Foodborne GAS epidemics often result from consumption of inappropriately prepared/cooked raw milk, cold salads, eggs, mayonnaise, tuna, potatoes, cheese, conch, and other ingredients that are inadvertently contaminated by GAS from infected animals (e.g., cows with streptococcal mastitis) or food handlers (who have sore throat, or have infected skin lesions on hands/arms, or are asymptomatic carriers) [7–9]. Airborne GAS epidemics are due to inhalation of respiratory/saliva droplets from carriers who disseminate the bacterium via sneeze or cough. Another means for GAS to spread is through person-to-person skin contact. External factors favoring GAS disease outbreaks include crowded settings (e.g., military training centers), mass consumption of contaminated foods, and hospital acquisition (e.g., puerperal sepsis). Intrinsic factors include the emergence of dominant clones [e.g., M1T1 clone that acquires three regions of heterologous DNA: a 36-kb chromosomal region encoding the toxins SLO and NAD-glycohydrolase and two bacteriophages encoding the DNase Sda1 and the superantigen SpeA (streptococcal pyrogenic exotoxin A); M3 clone that acquires prophages encoding phospholipase A2 and SpeA and the duplication of four amino acids in the N-terminal region of the M3 protein].
CD38: targeted therapy in multiple myeloma and therapeutic potential for solid cancers
Published in Expert Opinion on Investigational Drugs, 2020
Ying Jiao, Ming Yi, Linping Xu, Qian Chu, Yongxiang Yan, Suxia Luo, Kongming Wu
CD38 is identified to have three enzyme activities, NAD+ glycohydrolase (NADase), ADP-ribosyl cyclase and cyclic ADP-ribose hydrolase in 1994 [55], which accounts for the balance of NAD pool. NAD (nicotinamide adenine dinucleotide) is an important coenzyme that regulates various metabolic processes, including glycolysis, tricarboxylic acid cycle, and oxidative phosphorylation. As NADase, the main function, CD38 plays an indispensable role in catalyzing the majority of β-NAD and β-NAD derivatives, such as β-NADP and β-NMN, rather than α- NAD or NADH to produce nicotinamide (NAM) and almost stoichiometric ADPR [56,57]. Presented as ADP-ribosyl cyclase, the secondary function, CD38 can convert β-NAD and β-NAD derivatives to cyclic ADP ribosyl (cADPR) and nicotinamide [58]. Furthermore, it can convert cADPR into ADPR as cADPR hydrolase [59]. Both ADPR and cADPR, the second messengers, are involved in calcium signaling to regulate calcium mobilization [60–62]. A study indicates that adenosine catalyzed by CD38 inhibits CD8+ T cell and CD4+ T cell proliferation through the interaction with the specific adenosine receptors on T cells [63].
Biochemical mechanism and biological effects of the inhibition of silent information regulator 1 (SIRT1) by EX-527 (SEN0014196 or selisistat)
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Sylvain Broussy, Hanna Laaroussi, Michel Vidal
In addition to sirtuins, EX-527 and racemic 35 (rac-35) have been tested in vitro on other isolated enzyme and receptor targets. Overall, they displayed very little to no activity. They did not inhibit class I and II HDACs and NAD+ glycohydrolase at 100 µM15. PARP are enzymes using the NAD+ as cosubstrate for ADP-ribosyl transfer, producing nicotinamide, like sirtuins. Therefore, inhibitors targeting the nicotinamide binding pocket like EX-527 could have an inhibitory effect on PARP enzymes. No inhibition was observed on PARP1 and PARP1029,36. On cardiac potassium channels (hERG/IKr), EX-527 had an IC50 of 43 µM, with 0% inhibition at 10 µM37, and rac-35 displayed only 10% inhibition at 10 µM15. Cytochrome P450 are key enzymes involved in metabolism of drugs. They are largely evaluated in screening panels of new biologically active molecules, to identify P450 substrates or inhibitors. On cytochromes P450 (3A4, 2D6, 2C9, 2C19, 1A2, 2C8, and 2E1), both molecules had weak or no inhibitory potency at 1 µM, the highest values being 23% inhibition for 2C19 and 1A2 with rac-35. IC50 values determined for EX-527 were higher than 100 µM for all cytochromes P450 except 2C9 (62.4 µM), 2C19 (72.2 µM), and A2 (8.7 µM)15,37.
Implications of NAD metabolism in pathophysiology and therapeutics for neurodegenerative diseases
Published in Nutritional Neuroscience, 2021
Keisuke Hikosaka, Keisuke Yaku, Keisuke Okabe, Takashi Nakagawa
Several studies have revealed the molecular mechanism of SARM1-mediated axonal degeneration. SARM1 is a multi-domain protein possessing sterile alpha motif (SAM) and TIR domains [37,40]. Reportedly, SAM domain mediates multimerization of SARM1, and TIR domain is necessary for execution of axonal degeneration [40]. Importantly, SARM1 initiates axon degeneration by depleting axonal NAD levels [41,42]. Biochemical analyses have revealed that TIR domain itself has an intrinsic NAD glycohydrolase activity, which leads to cleaving NAD into ADP-ribose (ADPR) and NAM [43]. In addition, it has an NAD cyclase activity generating cyclic-ADPR from NAD [43]. TIR domain proteins are evolutionally conserved from bacteria to humans, and both bacteria and archaea TIR domain proteins have enzymatic activity to cleave NAD [44]. Therefore, TIR domain protein is considered a new class of NAD glycohydrolase. SARM1 is localized in mitochondria, and loss of mitochondrial membrane potential triggers axon degeneration by activating SARM1 [45]. Another study has shown that SARM1 activates the mitogen-activated protein kinase (MAPK) signaling pathway and regulates energy homeostasis in axons [46]. Particularly, SARM1 activates c-Jun N-terminal kinase 1 (JNK1) and JNK3 followed by ATP depletion for the execution of axon degeneration. JNK also phosphorylates SARM1 and regulates its NAD cleavage activity [47]. Oxidative stress triggers SARM1 phosphorylation by JNK and inhibits mitochondrial respiration. Increased phosphorylation in SARM1 is also observed in neuronal cells derived from a patient with familial PD [47]. Considering these results, SARM1 may negatively regulate axonal energy metabolism through mitochondria upon various stresses, and the activation of SARM1 results in the depletion of NAD and ATP, followed by axon degeneration. However, TIR domain was originally discovered as an adaptor protein for Toll-like receptors and transduced various innate immune signaling. A recent study has demonstrated that SARM1 regulates the recruitment of immune cells during traumatic axonal injury independent of axon degeneration machinery [48]. Thus, SARM1 may have more diverse roles beyond metabolic control.