Porcine <scp>CD</scp>38 exhibits prominent secondary <scp>NAD</scp><sup>+</sup> cyclase activity

Ting, Kai Yiu; Leung, Christina Fp; Graeff, Richard; Lee, Hon Cheung; Hao, Quan; Kotaka, Masayo

doi:10.1002/pro.2859

Cited by 6 publications

(6 citation statements)

References 33 publications

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“…CD38 not only degrades NAD + but also degrades NAD + precursors such as NMN and NR [ 25 ]. Overactivation of the NAD + degrading enzyme CD38 is thought to be one of the main reasons for the rapid decrease in NAD + observed during aging.…”

Section: Resultsmentioning

confidence: 99%

Aβ promotes CD38 expression in senescent microglia in Alzheimer’s disease

Huang

Xing

et al. 2022

Biol Res

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Background In Alzheimer’s disease (AD), the neuroinflammatory response mediated by the activation of senescent microglia is closely related to energy dysmetabolism. However, the mechanism underlying the interaction between the energy metabolism of aging microglia and neuroinflammation remains unclear. Methods We used biochemical methods, enzyme-linked immunosorbent assay (ELISA), immunofluorescence, and western blot to determine the effects and mechanism of CD38 knockdown on energy metabolism and neuroinflammation in Aβ1-40 injured BV2 cells. Using AD model mice, we detected CD38 enzyme activity, energy metabolism factors (ATP, NAD +, and NAD + /NADH), and neuroinflammatory factors (IL-1β, IL-6, and TNF-α) following the addition of CD38 inhibitor. Using a combination of biochemical analysis and behavioral testing, we analyzed the effects of the CD38 inhibitor on energy metabolism disorder, the neuroinflammatory response, and the cognition of AD mice. Results Following Aβ1-40 injury, SA-β-Gal positive cells and senescence-related proteins P16 and P21 increased in BV2 cells, while energy-related molecules (ATP, NAD +, and NAD + /NADH) and mitochondrial function (mitochondrial ROS and MMP) decreased. Further studies showed that CD38 knockdown could improve Aβ1-40-induced BV2 cells energy dysmetabolism and reduce the levels of IL-1β, IL-6, and TNF-α. In vivo results showed an increase in senile plaque deposition and microglial activation in the hippocampus and cortex of 34-week-old APP/PS1 mice. Following treatment with the CD38 inhibitor, senile plaque deposition decreased, the number of Iba1 + BV2 cells increased, the energy metabolism disorder was improved, the proinflammatory cytokines were reduced, and the spatial learning ability was improved. Conclusions Our results confirm that senescent microglia appeared in the brain of 34-week-old APP/PS1 mice, and that Aβ1-40 can induce senescence of BV2 cells. The expression of CD38 increases in senescent BV2 cells, resulting in energy metabolism disorder. Therefore, reducing CD38 expression can effectively improve energy metabolism disorder and reduce proinflammatory cytokines. Following intervention with the CD38 inhibitor in APP/PS1 mice, the energy metabolism disorder was improved in the hippocampus and cortex, the level of proinflammatory cytokines was reduced, and cognitive impairment was improved.

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Section: Resultsmentioning

confidence: 99%

Aβ promotes CD38 expression in senescent microglia in Alzheimer’s disease

Huang

Xing

et al. 2022

Biol Res

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“…CD38 is a transmembrane glycoprotein that, in addition to having functions as an ectoenzyme, serves as a receptor associated with the extracellular domain. It is responsible for mobilizing the Ca 2+ at the intracellular level and the production of ADPR, which can covalently bind to many proteins and modify their functions [20][21][22][23][24]. CD38 is made up of 300 amino acids, and their multiple enzymatic functions are executed in a single active site that presents the critical residues Glu 226, Trp 125, Trp 189, and Glu 116 [25].…”

Section: Resultsmentioning

confidence: 99%

Identification of Novel Molecular Targets of Four Microcystin Variants by High-Throughput Virtual Screening

et al. 2022

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Highly toxic microcystins (MCs) perform complex interactions with many proteins that induce cellular dysregulation, leading to the development of several diseases including cancer. There is significant diversity and chemical complexity among MC congeners, which makes it difficult to identify structure-dependent toxicity outcomes and their long-term effects. The aim of this study was to exploratory identify likely molecular targets of the main MC variants (MC-LA, MC-LR, MC-RR, and MC-LY) by conducting a computational binding affinity analysis using AutoDock Vina to evaluate the interaction of the toxins with 1000 proteins related to different biological functions. All four variants showed strong in silico interactions with proteins that regulate metabolism/immune system, CD38 (top scoring hit, −11.5 kcal/mol); inflammation, TLR4 (−11.4 kcal/mol) and TLR8 (−11.5 kcal/mol); neuronal conduction, BChE; renin–angiotensin signaling, (ACE); thyroid hormone homeostasis (TTR); and cancer-promoting processes, among other biochemical activities. The results show MCs have the potential to bind onto distinct molecular targets which could generate biochemical alterations through a number of signal transduction pathways. In short, this study broadens our knowledge about the mechanisms of action of different variants of microcystins and provides information for future direct experimentation.

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“…At neutral pH, CD38 can hydrolyze NAD + to adenosine diphosphate ribose (ADPR) and cyclic adenosine diphosphate ribose (cADPR), in which cADPR can also be hydrolyzed to ADPR. However, since the hydrolase activity is stronger than the cyclase activity, CD38 prefers to hydrolyze NAD + to ADPR [9]. Besides, CD38 can convert nicotinic acid (NA) to nicotinic acid adenosine dinucleotide phosphate (NAADP) in an acidic pH environment [9].…”

Section: Introductionmentioning

confidence: 99%

“…However, since the hydrolase activity is stronger than the cyclase activity, CD38 prefers to hydrolyze NAD + to ADPR [9]. Besides, CD38 can convert nicotinic acid (NA) to nicotinic acid adenosine dinucleotide phosphate (NAADP) in an acidic pH environment [9]. All these products of CD38 are very efficient second messengers, which can cause the migration of Ca 2+ [10].…”

Section: Introductionmentioning

confidence: 99%

CD38 Enhances TLR9 Expression and Activates NLRP3 Inflammasome after Porcine Parvovirus Infection

Zheng

et al. 2022

Viruses

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(1) Background: Porcine Parvovirus (PPV) is a single-stranded DNA virus without envelope which causes great harm in relation to porcine reproductive disorders in clinic. Cluster of Differentiation 38 (CD38) is a transmembrane protein widely existing in mammals. Its various functions make it a very popular research object, including in the viral infection field. (2) Methods: Western blotting and an EdU Cell Proliferation Kit were used to evaluate the effect of CD38-deficient cells. Relative quantitative real-time RT-PCR was used to detect the transcription levels of cytokines after PPV infection. The renilla luciferase reporter gene assay was used to verify the activation function of CD38 on downstream factors. The fluorescence probe method was used to detect the level of intracellular reactive oxygen species (ROS). (3) Results: This study found that the loss of CD38 function inhibited the up-regulated state of Toll-like Receptor 9 (TLR9), Interferon-α (IFN-α), and Myxovirus Resistance 1 (Mx1) after PPV infection. The luminescence of the group transfected with both CD38 expression plasmid and TLR9 promoter renilla luciferase reporter plasmid was significantly up-regulated compared with the control, suggesting that CD38 may activate the promoter of TLR9. In addition, CD38 deficiency not only activated the transcription of Sirtuin-1 (SIRT1), but also inhibited ROS level and the transcription of NLR Family Pyrin Domain Containing 3 (NLRP3). (4) Conclusion: (i) CD38 may participate in the TLR9/IFN-α/Mx1 pathway by activating the expression of TLR9 after PPV infected PK-15 cells; (ii) CD38 may activate the NLRP3/CASP1 pathway by increasing ROS level; (iii) CD38 deficiency activates the expression of SIRT1 and can prevent the normal proliferation of PPV.

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Porcine CD38 exhibits prominent secondary NAD⁺ cyclase activity

Cited by 6 publications

References 33 publications

Aβ promotes CD38 expression in senescent microglia in Alzheimer’s disease

Aβ promotes CD38 expression in senescent microglia in Alzheimer’s disease

Identification of Novel Molecular Targets of Four Microcystin Variants by High-Throughput Virtual Screening

CD38 Enhances TLR9 Expression and Activates NLRP3 Inflammasome after Porcine Parvovirus Infection

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Porcine CD38 exhibits prominent secondary NAD+ cyclase activity

Cited by 6 publications

References 33 publications

Aβ promotes CD38 expression in senescent microglia in Alzheimer’s disease

Aβ promotes CD38 expression in senescent microglia in Alzheimer’s disease

Identification of Novel Molecular Targets of Four Microcystin Variants by High-Throughput Virtual Screening

CD38 Enhances TLR9 Expression and Activates NLRP3 Inflammasome after Porcine Parvovirus Infection

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Porcine CD38 exhibits prominent secondary NAD⁺ cyclase activity