BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
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2022
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IF 5.011
Xijie Yu,Xiaoxiao Xu,Wei Dong,Chang Yang,Yao Luo,Ying He,Chenxi Jiang,Yanru Wu,Jiawei Wang
Endoplasmic reticulum (ER) stress is an evolutionarily conserved cellular stress response related to multiple diseases, including temporomandibular joint (TMJ) cartilage-related diseases. Recent studies have indicated that DDIT3/CHOP (a downstream transcription factor of ER stress) is an important effector in mediating ER stress to inhibit chondrogenesis . However, the underlying mechanism by which DDIT3 regulates chondrogenesis remains unclear. In this study, tunicamycin (an ER stress agonist)-induced ER stress inhibited chondrocyte differentiation and matrix synthesis in vitro and led to an osteoarthritis-like phenotype in mouse TMJ cartilage. Meanwhile, DDIT3 expression in chondrocytes was robustly upregulated. Loss-of-function experiments validated the inhibiting effect of DDIT3 on chondrocyte differentiation and matrix synthesis. Mechanistically, the inhibiting effect was attributed to the direct and indirect regulatory effect of DDIT3 on SIRT1 (sirtuin1, silent mating type information regulation protein type 1, a member of NAD+ dependent class III histone deacetylases). On one hand, DDIT3 directly promoted the transcription of SIRT1. On the other hand, DDIT3 indirectly increased the expression of SIRT1 by promoting AMPKα phosphorylation and activation. Furthermore, activation of AMPKα or SIRT1 with the corresponding agonist AICAR or resveratrol in the DDIT3-knockdown cells partially restored the inhibiting effect of DDIT3 on chondrocyte differentiation and matrix synthesis. Collectively, these novel findings indicate that DDIT3 regulates the inhibitory effect of ER stress on chondrocyte differentiation and matrix synthesis partially via the AMPKα-SIRT1 pathway. A thorough understanding of ER stress in regulating chondrocyte homeostasis and its role in the onset of osteoarthritis may be promising to develop therapeutic targets and prevent condyle cartilage destruction.
研究领域:
细胞生物学
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分子生物学
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骨科
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病理学
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DOI
PubMed
高影响因子
Journal of Orthopaedic Translation
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2026
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IF 7.8
Chang Yang,Jin Ke,Qiongdong Xu,Wei Dong,Wenqian Yu,Yan Wang,Jiawei Wang
Objective Emerging evidence has shown that inflammatory synovial macrophage and anabolism-impaired chondrocytes play essential roles in osteoarthritis (OA). The present work aims at uncovering the pathogenic mechanism of how the damage-associated molecular patterns (DAMPs) released from inflammatory synovial macrophage promote extracellular matrix (ECM) degradation of chondrocytes and developing feasible strategies to counter its detrimental effects. Methods We identified pyroptosis of synovial macrophages in the synovium of OA human and mouse. The effect and mechanism of mitochondrial DNA (mtDNA) released from pyroptotic synovial macrophage in ECM degradation of chondrocytes and cartilage degeneration was further explored in cellular and animal models. Finally, the ameliorative effect of folic acid-modified poly (lactic-co-glycolic acid) (PLGA) nanoparticles in OA was elucidated by in vivo experiments. Results Mitochondrial dysfunction in synovial macrophages leads to the release of mtDNA into the cytoplasm, which promotes macrophage pyroptosis, thereby facilitating extracellular release of mtDNA and creating an inflammatory microenvironment unfavorable to cartilage in OA. DDIT3 deficiency inhibits mtROS production by enhancing PINK1/Parkin-dependent mitophagy, which constraining the mtDNA release into the cytoplasm. The decreased cytosolic mtDNA, in turn, dampens macrophage pyroptosis. In vivo , DDIT3 deficiency significantly alleviates synovial inflammation and cartilage degeneration in OA progression, and targeting inhibition of macrophage pyroptosis by folic acid-modified PLGA nanoparticles mimics the protective effects of DDIT3 deficiency against OA progression. Conclusions Our findings identified the pathological role of mtDNA released from pyroptotic synovial macrophages through DDIT3-mediated mitophagy in OA, and demonstrated the efficacy of using folic acid-modified PLGA nanoparticles as a delivery for OA treatment. The translational potential of this article This study highlights the pivotal role of mtDNA released from pyroptotic synovial macrophages through DDIT3-mediated mitophagy in OA. Targeting inhibition of macrophage pyroptosis by folic acid-modified PLGA nanoparticles might serve as a potential therapeutic target for alleviating cartilage degeneration in OA.
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PubMed
高影响因子
CANCER LETTERS
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2024
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IF 9.1
Huimin Huang,Shitong Wang,Hongping Xia,Xingling Zhao,Kaiyuan Chen,Guihua Jin,Shipeng Zhou,Zhaoliang Lu,Tongke Chen,Huajun Yu,Xiaoqun Zheng,Haishan Huang,Linhua Lan
The aim of this study was to investigate the underlying molecular mechanism behind the promotion of cell survival under conditions of glucose deprivation by l -lactate. To accomplish this, we performed tissue microarray and immunohistochemistry staining to analyze the correlation between the abundance of pan-Lysine lactylation and prognosis. In vivo evaluations of tumor growth were conducted using the KPC and nude mice xenograft tumor model. For mechanistic studies, multi-omics analysis, RNA interference, and site-directed mutagenesis techniques were utilized. Our findings robustly confirmed that l -lactate promotes cell survival under glucose deprivation conditions, primarily by relying on GLS1-mediated glutaminolysis to support mitochondrial respiration. Mechanistically, we discovered that l -lactate enhances the NMNAT1-mediated NAD + salvage pathway while concurrently inactivating p-38 MAPK signaling and suppressing DDIT3 transcription. Notably, Pan-Kla abundance was significantly upregulated in patients with Pancreatic adenocarcinoma (PAAD) and associated with poor prognosis. We identified the 128th Lysine residue of NMNAT1 as a critical site for lactylation and revealed EP300 as a key lactyltransferase responsible for catalyzing lactylation. Importantly, we elucidated that lactylation of NMNAT1 enhances its nuclear localization and maintains enzymatic activity, thereby supporting the nuclear NAD + salvage pathway and facilitating cancer growth. Finally, we demonstrated that the NMNAT1-dependent NAD + salvage pathway promotes cell survival under glucose deprivation conditions and is reliant on the activity of Sirt1. Collectively, our study has unraveled a novel molecular mechanism by which l -lactate promotes cell survival under glucose deprivation conditions, presenting a promising strategy for targeting lactate and NAD + metabolism in the treatment of PAAD.
研究领域:
癌症生物学
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代谢
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
Italian Journal of Animal Science
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2021
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IF 2.217
Yi Ma,Mawda Elmhadi,Chao Wang,Hao Zhang,Hongrong Wang
Several studies have demonstrated that high-concentrate (HC) diet with thiamine supplementation can alleviate rumen epithelium inflammation and protecting the barrier function in goats. This study aimed to investigate the effects of dietary supply of thiamine on mitophagy and endoplasmic reticulum stress (ERS) during high-concentrate diet feeding. Twenty-four Boer goats (35.62 ± 2.4 kg) were used in this study, goats were subsequently assigned to 3 treatment groups (8 goats in each group) as follows: a low-concentrate diet (CON; concentrate: forage 30:70), a high-concentrate diet (HC; concentrate: forage 70:30) and high-concentrate diet with 200 mg thiamine/kg DMI (HCT; concentrate: forage 70:30) for 12 weeks. Compared with the HC group, the goats of HCT group had a markedly higher final weight, net weight gain, and average daily gain (ADG). The blood physiological and biochemical results showed that the HCT group expressed a lower the content of lymphocytes and leukocytes but a higher total protein and monocytes compared with that of HC group. The rumen epithelial mitochondrial membrane potential change (ΔΨm), relative mitochondrial DNA (mtDNA) content, adenosine triphosphate (ATP) level, together with the activities of the respiratory complexes I, III, and IV were markedly higher in the HCT group relative to HC ones. Relative to the HC group, the unc-51 like autophagy activating kinase 1 (ULK1), microtubule-associated protein 1 light chain 3 (LC3), autophagy-related 5 (ATG5), autophagy related 7 (ATG7), Beclin1, PTEN induced putative kinase 1 (PINK1), PERK (PKR-Endoplasmic Reticulum Kinase), activating transcription factor 4 (ATF4), activating transcription factor 6 (ATF6), X-box binding protein 1 (XBP1), heat shock 70 kDa protein 5 (HSPA5), DNA damage-inducible transcript 3 (DDIT3) and DNA damage-inducible transcript 4 (DDIT4) mRNA levels were decreased, but the breast cancer 1 (BRCA1), ataxia telangiectasia mutated (ATM), heat shock factor binding protein 1 (HSBP1) were increased in rumen epithelium of the HCT group. The results of transmission electron micrographs showed that the cell structure of the HCT group was higher integrity than that in the HC group, and the damage degree of mitochondria as well as endoplasmic reticulum being lower than the HC group. These results demonstrated that dietary thiamine could enhance rumen epithelial integrity by suppressing the responses of ERS and mitophagy during long-term HC diet feeding.HIGHLIGHTSThis study is the first to demonstrate that the reduction of inflammatory response is related to the down-regulation of autophagy and endoplasmic reticulum stress in goats.Thiamine has good anti-inflammatory and anti-oxidation properties, which can be applied in intensive industry to reduce the negative effects caused by long-term high-concentrate diet.
研究领域:
动物营养
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分子生物学
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兽医学
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营养基因组学
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DOI
高影响因子
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