Cells
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2024
·Vol. 13
·期 21
·1799
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IF 5.1
Seongsu Kang,Jiwon Park,Zhihong Cheng,Sanghyun Ye,Seung-Hyun Jun,Nae-Gyu Kang
Nicotinamide adenine dinucleotide (NAD + ) is indispensable for the regulation of biological metabolism. Previous studies have revealed its role in aging and degenerative diseases, while crucially showing that supplementation with NAD + or its precursors could ameliorate or reverse the progression of aging. Despite extensive evidence for the role and action of NAD + in aging, its pharmacological activity on the skin, or even its mechanism, has not been elucidated. In this study, we established a novel approach to effectively utilize NAD + for skin anti-aging by enhancing the pharmacological efficacy of exogenous NAD + using a phytochemical complex consisting of quercetin, and enoxolone through inhibition of CD38. Through the comprehensive in vitro experiments based on human fibroblasts, we observed that exogenous NAD + could exert protective effects against both extrinsic aging induced by ultraviolet light exposure and intrinsic aging. Additionally, we found that its effects were significantly boosted by quercetin and enoxolone. In this in-depth study, we demonstrated that these beneficial effects are mediated by improved sirtuin activation, autophagy, and mitochondrial functionality. Our approach is expected to verify the applicability of the topical application of NAD + and offer more effective solutions for the unmet needs of patients and consumers who demand more effective anti-aging effects.
研究领域:
生物化学
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药理学
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皮肤科学
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PubMed
高影响因子
Antioxidants
·
2024
·Vol. 13
·期 7
·859
·
IF 6
Ruifeng Wang,Anping Ding,Jiaye Wang,Jiaxue Wang,Yujie Zhou,Miao Chen,Shuang Ju,Mingpu Tan,Zengxu Xiang
Astragalin (AG), a typical flavonoid found inThesium chinenseTurcz (T. chinense), is abundant in various edible plants and possesses high nutritional value, as well as antioxidant and antibacterial effects. In this study, we initially predicted the mechanism of action of AG with two anti-aging and antioxidant-related protein targets (CD38 and IGFR) by molecular docking and molecular dynamics simulation techniques. Subsequently, we examined the anti-aging effects of AG inCaenorhabditis elegans(C. elegans), the antioxidant effects in zebrafish, and verified the related molecular mechanisms. InC. elegans, AG synergistically extended the lifespan ofC. elegansby up-regulating the expression ofdaf-16through inhibiting the expression ofdaf-2/IGFRand also activating the AMPK and MAPK pathways to up-regulate the expression ofsir-2.1,sir-2.4, andskn-1. In oxidatively damaged zebrafish embryos, AG demonstrated a synergistic effect in augmenting the resistance of zebrafish embryos to oxidative stress by up-regulating the expression levels ofSIRT1andSIRT6within the zebrafish embryos system via the suppression of CD38 enzymatic activity and then inhibiting the expression ofIGFRthrough high levels ofSIRT6. These findings highlight the antioxidant and anti-aging properties of AG and indicate its potential application as a supplementary ingredient in aquaculture for enhancing fish health and growth.
研究领域:
分子生物学
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老年医学
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营养科学
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水产养殖
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PubMed
高影响因子
JOURNAL OF PROTEOME RESEARCH
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2013
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IF 5.056
Yadong Hu,Helin Wang,Qingtao Wang,Haiteng Deng
Nicotinamide adenine dinucleotide (NAD) is a coenzyme found in all living cells and mediates multiple cellular signaling pathways. In the present study, a 35% decrease of cellular NAD level is achieved by stable expression of the N-terminal truncated CD38, a NAD hydrolase. CD38-expressing (CD38(+)) cells have the lower growth rate and are more susceptive to oxidative stress than the wild type cells and empty vector-transfected (CD38(−)) cells. Quantitative proteomic analysis shows that 178 proteins are down-regulated in CD38(+) cells, which involve in diverse cellular processes including glycolysis, RNA processing and protein synthesis, antioxidant, and DNA repair. Down regulation of six selected proteins is confirmed by Western blotting. However, down-regulation of mRNA expressions of genes associated with glycolysis, antioxidant, and DNA repair is less significant than the corresponding change in protein expression, suggesting the low NAD level impairs the protein translational machinery in CD38(+) cells. Down-regulation of antioxidant protein and DNA-repair protein expression contributes to the susceptibility of CD38(+) cells to oxidative stress. Taken together, these results demonstrate that CD38(+) cells are a useful model to study effects of the cellular NAD levels on cellular processes and establish a new linker between cellular NAD levels and oxidative stress.
研究领域:
分子生物学
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细胞生物学
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生物化学
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PubMed
高影响因子
Mucosal Immunology
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2024
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IF 7.9
Jinzhe Tong,Simiao Chen,Xinyue Gu,Xuanqi Zhang,Fang Wei,Yingying Xing
Tissue-resident memory T cells (T RM ) can be induced by infection and vaccination, and play a key role in maintaining long-term protective immunity against mucosal pathogens. Our studies explored the key factors and mechanisms affecting the differentiation, maturation, and stable residence of gastric epithelial CD4 + T RM induced by Helicobacter pylori (Hp) vaccine and optimized Hp vaccination to promote the generation and residence of T RM .CD38 regulated mitochondrial activity and enhanced TGF-β signal transduction to promote the differentiation and residence of gastric epithelial CD4 + T RM by mediating the expression of CD105. Extracellular nucleotides influenced the long-term maintenance of T RM in gastric epithelium by P2RX7. Vitamin D3 and Gram-positive enhancer matrix particles (GEMs)as immune adjuvants combined with Hp vaccination promoted the production of CD69 + CD103 + CD4 + T RM .
研究领域:
免疫学
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微生物学
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分子生物学
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疫苗学
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DOI
PubMed
高影响因子
MOLECULES
·
2026
·Vol. 31
·期 5
·864
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IF 5.1
Xinyu Shi,Ze Liang,Wentao Meng,Guang Yang,Lei Yan
CD38 is a multifunctional enzyme that plays a pivotal role in NAD+metabolism and calcium signaling, and its abnormal activity is closely associated with multiple myeloma, age-related metabolic decline, neurodegenerative diseases, and other disorders. Although monoclonal antibodies such as daratumumab have been approved for clinical application, their inherent limitations necessitate the development of novel small-molecule CD38 inhibitors. In this study, we employed DNA-encoded library (DEL) technology for the high-throughput screening of CD38 inhibitors, using a DEL library containing more than 100,000 unique compounds to screen against recombinant human CD38. A total of 1043 enriched compounds were initially identified, and after rigorous validation and screening to exclude non-specific binding and previously reported active compounds, eight hit compounds with diverse chemical scaffolds were obtained, among which Fenbendazole—a clinically approved antiparasitic drug—was included. Surface plasmon resonance (SPR) assays confirmed the direct binding of these hit compounds to CD38, with dissociation constants (KD) ranging from 7.74 × 10−5M to 2.15 × 10−4M. Fluorescence-based enzymatic activity assays demonstrated that these compounds exert dose-dependent inhibitory effects on both the hydrolase (with ε-NAD as substrate) and cyclase (with NGD as substrate) activities of CD38. Further structure–activity relationship (SAR) analysis of Fenbendazole analogues revealed the critical structural features that regulate CD38 inhibitory potency, and Flubendazole was found to exhibit excellent inhibitory activity, with an IC50of 14.78 ± 4.21 μM against CD38 hydrolase and 26.31 ± 3.40 μM against cyclase. Molecular docking and 100 ns molecular dynamics (MD) simulations further elucidated the molecular mechanism of CD38 inhibition by lead compounds, confirming that van der Waals interactions are the main driving force for the binding of small-molecule ligands to CD38, with conserved aromatic residues in the active site mediating ligand recognition. This study validates DEL technology as an efficient and reliable platform for the discovery of CD38 inhibitors, and the identified lead compounds—especially Fenbendazole and its analog Flubendazole—provide valuable molecular scaffolds for the further structural optimization of CD38 inhibitors. These findings lay a solid foundation for the development of novel therapeutic agents for the treatment of CD38-associated diseases.
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高影响因子
REDOX REPORT
·
2025
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IF 7.4
Fang Cheng,Minzhu Zhao,Qi Wang,Hongli Xiong,Kai Yu,Chong Chen,Ying Zhu,Yemiao Chen,Jianbo Li
Objectives Doxorubicin (DOX) induces dose-dependent cardiotoxicity, primarily through oxidative stress and metabolic dysregulation. Although NAD+ deficiency has been implicated in cardiovascular pathology, its role in DOX-induced cardiotoxicity (DIC) remains poorly understood. This study investigated NAD+ metabolism dysregulation as a redox-sensitive mechanism in DIC pathogenesis.Methods Human cardiomyocytes (AC16), mouse atrial myocytes (HL-1), and C57BL/6 mice were used to establish the DIC model. The role and mechanism of NAD+ in DIC were investigated using a range of methods.Results Using integrated in vitro and in vivo models, we demonstrated that DOX induces myocardial oxidative damage accompanied by NAD+ depletion. Exogenous NAD+ supplementation mitigated the DOX-induced cardiomyocyte death and redox imbalance. Mechanistically, pharmacological CD38 inhibition with 78C or genetic silencing failed to restore the NAD+ pool, whereas nicotinamide mononucleotide adenylyltransferase 3 (NMNAT3) overexpression, combined with nicotinamide mononucleotide (NMN) administration, effectively rescued NAD+ levels and attenuated oxidative stress. Computational and functional analyses identified FOXO1 as a transcriptional repressor of NMNAT3 following DOX exposure.Conclusion This study establishes the dysregulation of the FOXO1-NMNAT3 axis as a key mechanism underlying NAD+ depletion in DIC. Targeting this axis through NAD+ replenishment, particularly by activating NMNAT3, offers a novel redox-based therapeutic strategy against DIC.
研究领域:
心血管病理学
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分子生物学
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药理学
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氧化应激
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代谢调控
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转化医学
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药物毒性
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PubMed
高影响因子
Journal of Materials Chemistry B
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2024
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IF 6.1
Jing Hong,Zhanchi Zhu,Leisha Cui,Zhaojun Wang,Ying Hao,Xiaopeng Tian,Guosheng Cheng
Hematopoietic stem cell (HSC) expansion offers a key strategy to address the source limitation and donor shortages of HSCs for the treatment of various blood disorders. Specific remodeling of the complex bone marrow microenvironment that contributes to efficient in vitro expansion of HSCs remains challenging. Here, inspired by the regions with different stiffness levels in the bone marrow niche, a three dimensional (3D) bone marrow-mimicking composite scaffold created based on gelatin–hyaluronic acid (Gel–HA) hydrogels and graphene foams (GFs) was engineered to support the in vitro expansion of HSCs. The composite scaffold was prepared by forming a photo-cross-linked Gel–HA hydrogel surrounding the GF. The “soft” Gel–HA hydrogel and “stiff” GF replicate the structure and stiffness of the vascular niche and endosteal niche in the bone marrow, respectively. Furthermore, HSCs cultured in the Gel–HA/GF scaffold proliferated well and retained the CD34+CD38− immunophenotype and pluripotency, suggesting that the Gel–HA/GF composite scaffold supported the in vitro expansion of HSCs, maintaining the primitive phenotype and the ability to differentiate into functional blood cells. Thus, the hydrogel/graphene composite scaffold offers a means of facilitating HSC expansion through structurally and mechanically mimicking bone marrow niches, demonstrating great promise for HSC transplantation.
研究领域:
生物材料
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组织工程
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干细胞生物学
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生物医学工程
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PubMed
高影响因子
Marine Drugs
·
2025
·Vol. 23
·期 8
·294
·
IF 5.4
Jing Lu,Pujing Shi,Yutian Cao,Bingxin Shi,Huilin Shen,Shuai Zhao,Yuchen Gao,Huibing Chi,Lei Wang,Yawei Shi
Mussels are nutrient-rich but perishable, resulting in substantial resource loss. A protease-producing strain (Bacillus velezensisZ-1,Mytilus edulis) isolated from marine sludge was used to hydrolyze mussels, producing Y-1, a hydrolysate with antioxidant activity. In this study, ultrafiltration, gel chromatography, and LC-MS/MS were employed to isolate and identify bioactive peptides from the hydrolysate. The results revealed that the hydrolysate exhibited antioxidant activity, pancreatic cholesterol esterase inhibitory activity, pancreatic lipase inhibitory activity, and α-glucosidase inhibitory activity. Molecular docking using AutoDock Tools 1.5.6 was performed to analyze the interactions of peptides with CD38 and Keap1, leading to the identification of five potentially bioactive peptides: VPPFY, IMLFP, LPFLF, FLPF, and FPRIM. These peptides formed hydrogen bonds and hydrophobic interactions with CD38 and Keap1, demonstrating strong DPPH radical scavenging and superoxide anion radical scavenging capacities. This study highlights the multifunctional bioactive potential of these peptides, offering insights into their therapeutic applications. The findings provide a novel approach for the effective utilization of mussel resources and highlight their potential application value in the development of functional foods.
研究领域:
海洋生物技术
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食品科学
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生物化学
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药理学
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生物技术
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PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2026
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IF 6.8
Teng Wang,Weilin Liu,Chunyi Lyu,Yunxiao Luo,Xinyu Tang,Chen Han,Ruirong Xu
Ethnopharmacological relevance Realgar is an arsenic-containing mineral medicine and a key component of Realgar-Indigo naturalis formula, an oral traditional Chinese medicine preparation clinically used in China for acute promyelocytic leukemia (APL), a biologically distinct subtype of acute myeloid leukemia (AML). Realgar Transforming Solution (RTS) is a microbially processed realgar preparation. Its activity in AML stem cell-like contexts outside APL remains insufficiently defined, particularly in cell-line-derived CD34 + CD38 − LSC-like models. Aim of the study: To evaluate whether RTS suppresses stemness-associated phenotypic features in KG-1a-derived CD34 + CD38 − LSC-like cells and to explore its association with endoplasmic reticulum stress (ERS), mitochondrial injury, and mitophagy-related alterations. Materials and methods CD34 + CD38 − LSC-like cells were enriched from KG-1a cells and used as a cell-line-derived in vitro model. Cell viability, apoptosis, cell cycle, CD34 + CD38 − fraction, colony formation, and TIM3/ HAVCR2 expression were assessed after RTS treatment. RNA sequencing, Ca 2+ measurement, ROS detection, mitochondrial membrane potential assay, MDC staining, western blotting, RT-qPCR, immunofluorescence, and transmission electron microscopy were performed. 4-phenylbutyric acid and Mdivi-1 were used as pharmacological rescue agents. Results RTS reduced the CD34 + CD38 − fraction, colony formation, and TIM3/ HAVCR2 expression, while inducing apoptosis in KG-1a-derived LSC-like cells. Transcriptomics implicated ER protein processing, unfolded protein response, apoptosis, autophagy, and mitophagy-related pathways. RTS increased Ca 2+ levels, ROS accumulation, mitochondrial depolarization, PERK-eIF2α-ATF4-CHOP signaling, and PINK1/Parkin-associated mitophagy-like marker changes. 4-phenylbutyric acid and Mdivi-1 partially rescued RTS-impaired LSC-like phenotypic features, supporting pathway involvement. Conclusions RTS suppressed stemness-associated phenotypic features in a KG-1a-derived CD34 + CD38 − LSC-like model. These effects were associated with ERS, mitochondrial injury, and PINK1/Parkin-related mitophagy-like alterations.
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高影响因子
MOLECULAR & CELLULAR PROTEOMICS
·
2018
·Vol. 17
·期 10
·2005-2017
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IF 5.236
Weixuan Wang,Yadong Hu,Changmei Yang,Songbiao Zhu,Xiaofei Wang,Zhenyu Zhang,Haiteng Deng
Nicotinamide adenine dinucleotide (NAD) plays an essential role in all aspects of human life. NAD levels decrease as humans age, and supplementation with NAD precursors plays a protective role against aging and associated disease. Less is known about the effects of decreased NAD on cellular processes, which is the basis for understanding the relationship between cellular NAD levels and aging-associated disease. In the present study, cellular NAD levels were decreased by overexpression of CD38, a NAD hydrolase, or by treating cells with FK866, an inhibitor of nicotinamide phosphoribosyltransferase (NAMPT). Quantitative proteomics revealed that declining NAD levels downregulated proteins associated with primary metabolism and suppressed cell growth in culture and nude mice. Decreased glutathione synthesis caused a 4-fold increase in cellular reactive oxygen species levels, and more importantly upregulated proteins related to movement and adhesion. In turn, this significantly changed cell morphology and caused cells to undergo epithelial to mesenchymal transition (EMT). Secretomic analysis also showed that decreased NAD triggered interleukin-6 and transforming growth factor beta (TGFβ) secretion, which activated integrin-β-catenin, TGFβ-MAPK, and inflammation signaling pathways to sustain the signaling required for EMT. We further revealed that decreased NAD inactivated sirtuin 1, resulting in increased signal transducer and activator of transcription 3 (STAT3) acetylation and phosphorylation, and STAT3 activation. Repletion of nicotinamide or nicotinic acid inactivated STAT3 and reversed EMT, as did STAT3 inhibition. Taken together, these results indicate that decreased NAD activates multiple signaling pathways to promote EMT and suggests that age-dependent decreases in NAD may contribute to tumor progression. Consequently, repletion of NAD precursors has potential benefits for inhibiting cancer progression.
研究领域:
细胞生物学
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分子生物学
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癌症研究
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衰老研究
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高影响因子
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