Cao Kimberly, Chowdhury Nityananda, Wellslager Bridgette, Hill William D, Yilmaz Özlem, Yu Hong
Department of Biomedical and Community Health Sciences, College of Dental Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.
Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.
Int J Mol Sci. 2025 Jun 26;26(13):6180. doi: 10.3390/ijms26136180.
CD38, a nicotinamide adenine dinucleotide (NAD) glycohydrolase, increases in old murine macrophages after infection compared to young controls. We aimed to determine whether the increase in CD38 in old murine macrophages after infection is directly associated with enhanced inflammation induced by the oral pathogens () or () when compared to young controls. Additionally, we determined the effects of a specific CD38 inhibitor (78c) on CD38, NAD, interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α expressions, and anti-oxidative responses in old murine macrophages induced by oral pathogens. Old and young murine macrophages were either uninfected or infected with the oral pathogens or for 1 to 24 h. Protein levels of CD38 and protein kinases, including nuclear factor kappa-B (NF-κB), phosphoinositide 3-kinase (PI3K), and mitogen-activated protein kinases (MAPKs), NAD, and inflammatory cytokine (IL-1β, IL-6, TNF-α) levels were evaluated. Additionally, old murine macrophages were treated with a vehicle or a CD38 inhibitor (78c) and cells were either uninfected or infected with or . CD38, NAD, cytokine (IL-1β, IL-6, TNF-α) levels, reactive oxygen species (ROS), NAPDH oxidase 1 (Nox1), and anti-oxidative enzymes, including superoxide dismutase1 (Sod1), glutathione peroxidase 4 (Gpx4), Peroxiredoxin 1 (Prdx1), thioredoxin reductase 1 (Txnrd1), and catalase (Cat), were evaluated. The results showed that old murine macrophages significantly enhanced CD38 and reduced NAD levels 24 h after or infection compared to young controls. This enhanced CD38 in old murine macrophages was not directly correlated with the activation of protein kinases (NF-κB, PI3K, and MAPKs), nor the (IL-1β, IL-6, TNF-α) levels in macrophages. The inhibition of CD38 by 78c reduced CD38, enhanced NAD levels, attenuated IL-1β, IL-6 and TNF-α pro-inflammatory cytokine levels, reduced ROS and Nox1 expressions, and enhanced expressions of Sod1, Gpx4, Prdx1, Txnrd1, and Cat in old murine macrophages infected with or . These results suggest that the inhibition of CD38 by 78c is a promising therapeutic strategy to treat aging-associated periodontitis.
CD38是一种烟酰胺腺嘌呤二核苷酸（NAD）糖水解酶，与年轻对照组相比，老年小鼠巨噬细胞在感染后其水平会升高。我们旨在确定感染后老年小鼠巨噬细胞中CD38的增加是否与口腔病原体（ ）或（ ）诱导的炎症增强直接相关，与年轻对照组相比。此外，我们还确定了一种特异性CD38抑制剂（78c）对口腔病原体诱导的老年小鼠巨噬细胞中CD38、NAD、白细胞介素（IL）-1β、IL-6、肿瘤坏死因子（TNF）-α表达以及抗氧化反应的影响。将老年和年轻小鼠巨噬细胞分别不进行感染或用口腔病原体 或 感染1至24小时。评估CD38和蛋白激酶的蛋白水平，包括核因子κB（NF-κB）、磷酸肌醇3激酶（PI3K）和丝裂原活化蛋白激酶（MAPK）、NAD以及炎性细胞因子（IL-1β、IL-6、TNF-α）水平。此外，用载体或CD38抑制剂（78c）处理老年小鼠巨噬细胞，细胞分别不进行感染或用 或 感染。评估CD38、NAD、细胞因子（IL-1β、IL-6、TNF-α）水平、活性氧（ROS）、NADPH氧化酶1（Nox1）以及抗氧化酶，包括超氧化物歧化酶1（Sod1）、谷胱甘肽过氧化物酶4（Gpx4）、过氧化物酶1（Prdx1）、硫氧还蛋白还原酶1（Txnrd1）和过氧化氢酶（Cat）。结果显示，与年轻对照组相比，老年小鼠巨噬细胞在 或 感染24小时后CD38显著升高而NAD水平降低。老年小鼠巨噬细胞中这种升高的CD38与蛋白激酶（NF-κB、PI3K和MAPK）的激活以及巨噬细胞中的（IL-1β、IL-6、TNF-α）水平均无直接关联。78c对CD38的抑制降低了CD38、提高了NAD水平、减弱了IL-1β、IL-6和TNF-α促炎细胞因子水平、降低了ROS和Nox1表达，并增强了感染 或 的老年小鼠巨噬细胞中Sod1、Gpx4、Prdx1、Txnrd1和Cat的表达。这些结果表明，78c对CD38的抑制是治疗与衰老相关的牙周炎的一种有前景的治疗策略。
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