Autophagy
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2024
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IF 14.6
Qingyuan Zhang,Chunhui Chen,Ye Ma,Xinyi Yan,Nianhong Lai,Hao Wang,Baogui Gao,Anna Meilin Gu,Qinrui Han,Qingling Zhang,Lei La,Xuegang Sun
Regressing the accelerated degradation of skeletal muscle protein is a significant goal for cancer cachexia management. Here, we show that genetic deletion of Pgam5 ameliorates skeletal muscle atrophy in various tumor-bearing mice. pgam5 ablation represses excessive myoblast mitophagy and effectively suppresses mitochondria meltdown and muscle wastage. Next, we define BNIP3 as a mitophagy receptor constitutively associating with PGAM5. bnip3 deletion restricts body weight loss and enhances the gastrocnemius mass index in the age- and tumor size-matched experiments. The NH2-terminal region of PGAM5 binds to the PEST motif-containing region of BNIP3 to dampen the ubiquitination and degradation of BNIP3 to maintain continuous mitophagy. Finally, we identify S100A9 as a pro-cachectic chemokine via activating AGER/RAGE. AGER deficiency or S100A9 inhibition restrains skeletal muscle loss by weakening the interaction between PGAM5 and BNIP3. In conclusion, the AGER-PGAM5-BNIP3 axis is a novel but common pathway in cancer-associated muscle wasting that can be targetable. Abbreviation: AGER/RAGE: advanced glycation end-product specific receptor; BA1: bafilomycin A1; BNIP3: BCL2 interacting protein 3; BNIP3L: BCL2 interacting protein 3 like; Ckm-Cre: creatinine kinase, muscle-specific Cre; CM: conditioned medium; CON/CTRL: control; CRC: colorectal cancer; FUNDC1: FUN14 domain containing 1; MAP1LC3A/LC3A: microtubule associated protein 1 light chain 3 alpha; PGAM5: PGAM family member 5, mitochondrial serine/threonine protein phosphatase; S100A9: S100 calcium binding protein A9; SQSTM1/p62: sequestosome 1; TOMM20: translocase of outer mitochondrial membrane 20; TIMM23: translocase of inner mitochondrial membrane 23; TSKO: tissue-specific knockout; VDAC1: voltage dependent anion channel 1.
研究领域:
肿瘤学
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细胞生物学
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肌肉生物学
✓ 已验证
DOI
PubMed
高影响因子
Oxidative Medicine and Cellular Longevity
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2022
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IF 7.31
Pingjun Zhu,Junyan Wang,Wenjuan Du,Jun Ren,Ying Zhang,Fei Xie,Guogang Xu
Mitochondrial dysfunction and necroptosis have been perceived as the primary molecular mechanisms underscoring acute lung injury. Meanwhile, nuclear receptor subfamily 4 group A member 1 (NR4A1) is considered a regulator of inflammation-related endothelial injury in lung tissue although the downstream molecular events remain elusive. In this study, we employed NR4A1-/- mice to decipher the role of NR4A1 in the onset and progression of acute lung injury with a focus on mitochondrial damage and necroptosis. Our results demonstrated that NR4A1 was significantly upregulated in lipopolysaccharide- (LPS-) treated lung tissues. Knockout of NR4A1 overtly improved lung tissue morphology, inhibited inflammation, and reduced oxidative stress in LPS-treated lung tissue. A cell signaling study suggested that NR4A1 deletion repressed levels of PGAM5 and attenuated LPS-mediated necroptosis in primary murine alveolar epithelial type II (ATII) cells, the effects of which were mitigated by PGAM5 overexpression. Moreover, LPS-mediated mitochondrial injury including mitochondrial membrane potential collapse and mitochondrial oxidative stress was drastically improved by NR4A1 deletion. Furthermore, NR4A1 deletion preserved mitochondrial homeostasis through activation of Opa1-related mitochondrial fusion. Silencing of Opa1 triggered mitochondrial dysfunction in NR4A1-deleted ATII cells. Taken together, our data identified NR4A1 as a novel regulator of LPS-related acute lung injury through regulation of mitochondrial fusion and necroptosis, indicating therapeutic promises of targeting NR4A1 in the treatment of acute lung injury in clinical practice.
研究领域:
分子生物学
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免疫学
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呼吸病学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2026
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IF 6.8
Qianqian Du,Zhimei Chen,Xian Ma,Yayu Zhang,Yongqiang Fan
Ethnopharmacological relevance Notoginsenoside R1 (NGR1), a primary bioactive constituent of P. notoginseng , has potent anti-inflammatory and immunomodulatory functions, but its role and mechanism in UC remain incompletely understood and warrant further exploration. The global prevalence of ulcerative colitis (UC) is rising steadily, threatening human health. Despite advances in modern therapies, UC treatments remain limited. Aim of the study This work investigated whether NGR1 alleviates DSS-induced colitis by inhibiting the PGAM5-NEK7 interaction and NLRP3 inflammasome activation in macrophages, providing new mechanistic insights and therapeutic targets for UC. Materials and methods UC model was established via 3% DSS administration to assess the protective efficacy of NGR1. Disease activity index (DAI), body weight and colon length were determined to assess disease severity and intestinal injury. HE staining, ELISA and immunofluorescence assays were employed to assess pathological changes in the colon and liver. Macrophages were depleted via tail vein injection of clodronate liposomes. RT-qPCR, ELISA, immunofluorescence and WB were performed to quantify macrophage markers, pro-inflammatory genes and NLRP3 inflammasome-related proteins. In vitro , LPS/ATP-stimulated bone marrow-derived macrophages (BMDMs) demonstrated that NGR1 exerts a potent inhibitory effect on NLRP3 inflammasome activation. After cell treatment, CCK-8, ELISA, RT-qPCR, and WB assays were performed to detect cell viability, inflammatory cytokine levels, and the expression of related genes and proteins. Meanwhile, molecular docking was utilized to verify the interactions among PGAM5, NEK7 and NLRP3. Co-IP in 293T cells overexpressing PGAM5, NEK7 and NLRP3 further verified their interplay. Results Compared with the Model group, NGR1 intervention markedly reduced the DAI scores, ameliorated body weight loss and colon shortening, alleviated colonic and hepatic pathological damage, upregulated the expression of intestinal barrier tight junction proteins (ZO-1, Occludin and Claudin-1), and decreased LPS levels and the release of TNF-α, IL-1β and IL-6 in serum and tissues. Macrophage depletion was observed to markedly abolish protective effects of NGR1, and reduced PGAM5, NEK7, NLRP3, Caspase-1, C-Caspase-1 levels. In vitro , NGR1 inhibited inflammatory factor secretion and NLRP3 inflammasome activation in LPS/ATP-stimulated BMDMs, these effects were partially blocked after PGAM5 or NEK7 gene silencing. Co-IP assays confirmed endogenous interactions between PGAM5, NEK7 and NLRP3. And the molecular docking showed NGR1 could bind to PGAM5, and NGR1 intervention significantly suppressed the expression of the ternary complex formed by the three proteins. Conclusion This study revealed that NGR1 disrupted the PGAM5-NEK7 interaction, restrained NLRP3 inflammasome assembly in macrophages, and relieved colonic damage triggered by DSS, providing a novel target for UC treatment.
✓ 已验证
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
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2024
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IF 13.3
Lei Xu,Jiahe Hu,Xiuwei Yan,Hongtao Zhao,Mo Geng,Jiheng Zhang,Chunxiao Zhou,Zhihui Liu,Bo Li,Shaoshan Hu
Photodynamic therapy (PDT) is an effective treatment for glioblastoma (GBM) that activates photosensitizers to produce reactive oxygen species (ROS) while minimizing harm to normal tissues. However, the therapeutic outcomes of PDT are often unsatisfactory. This limitation arises partly from the challenges posed by the blood–brain barrier (BBB) in transporting photosensitizers and partly from the excessive levels of glutathione (GSH) in the tumor microenvironment (TME), which can neutralize ROS. Hypericin (HYP) has emerged as a promising photosensitizer for PDT due to its excellent photosensitizing properties and antitumor activity. Dysregulated iron metabolism is a hallmark of numerous cancers, including GBM. In this study, biodegradable tetra-sulfide-bound dendritic mesoporous organosilicas nanocomposite (NCs) modified with bovine serum albumin (BSA) were synthesized. NCs penetrates the BBB and selectively targets GBM by binding to secreted acidic protein acidic and rich in cysteine (SPARC), an albumin-binding receptor that is prominently expressed in both the BBB and GBM. Upon degradation in response to high GSH concentrations in the TME, the NCs release their payload while concurrently depleting GSH. Under laser irradiation, the ROS-generating agent HYP, loaded within the NCs, is combined with the ferroptosis inducer erastin to achieve a synergistic anti-GBM effect via PDT/ferroptosis. Additionally, the NCs induces oxeiptosis by regulating KEAP1/PGAM5/AIFM1 pathway. Consequently, NC inhibits GBM growth by inducing ferroptosis and oxeiptosis through excessive ROS production. This study demonstrates the potential of NCs to enhance the effectiveness of PDT, offering a promising therapeutic strategy for GBM patients.
研究领域:
肿瘤学
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纳米技术
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治疗学
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神经科学
✓ 已验证
产品关联
DOI
高影响因子
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