Journal of Advanced Research
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2024
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IF 11.4
Sijia Lu,Quanxin Jiang,Peihui Zhou,Limin Yin,Ning Wang,Junting Xu,Qiqi Qian,Mijia Tao,Hanrui Yin,Liu Han,Yunqing Gu,Fei Gao,Junli Liu,Suzhen Chen
Introduction Promoting adipose thermogenesis is considered as a promising therapeutic intervention in obesity. However, endeavors to develop anti-obesity medications by targeting the canonical thermogenesis regulatory pathway, particularly β3-adrenergic receptor (β3-AR)-dependent mechanism, have failed due to the off-target effects of β3-AR agonists, exacerbating the risk of cardiovascular disease. Hyperforin (HPF), a natural compound extracted from the traditional herbal St. John’s Wort, binds to Dihydrolipoamide s-acetyltransferase (Dlat) and exerts effective anti-obesity properties through promoting adipose thermogenesis. Objectives The objective of this study was to investigate the oral efficacy and pharmacokinetics profile of HPF, and explore the detailed mechanism by which Dlat modulates HPF-mediated adipose thermogenesis. Methods To assess the anti-obesity efficacy of orally administered HPF in vivo , Dlat heterozygous knockout (Dlat +/- ) mice and wild-type (WT) mice, both fed a high-fat diet (HFD), underwent a validation process that involved the use of metabolic cages, NMR analysis, and infrared imaging. Sprague Dawley rats were employed to determine the pharmacokinetic parameters of HPF. Seahorse assays, JC-1 staining, qPCR, and immunoblotting were performed to evaluate cellular thermogenic efficacy of HPF and Dlat in vitro . Results Our study uncovered a non-canonical thermogenesis pathway involving Dlat, transient receptor potential vanilloid 3 (Trpv3, a calcium channel) and AMPK. Dlat interacted with Trpv3 to activate it, resulting in an increase in intracellular calcium (Ca 2+ ) and the activation of Camkkβ. Camkkβ then stimulated AMPK, leading to elevated Ucp1 expression and initiating adipose thermogenesis. HPF promoted thermogenesis in adipose tissues through enhancing the Dlat-Trpv3 interaction independently of β3-AR, causing minimal cardiac side effects. Notably, HPF’s thermogenic effects were reduced in Dlat +/- mice. Moreover, HPF exerted favorable oral bioavailability, a relatively long half-life, and extensive distribution within adipose tissues. Conclusion In summary, our study demonstrates that HPF targets a novel mechanism for promoting adipose thermogenesis and exhibits potent and safe anti-obesity efficacy.
研究领域:
药理学
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分子生物学
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代谢
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高影响因子
International Journal of Biological Sciences
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2024
·Vol. 20
·期 2
·516-536
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IF 8.2
Tian Shaoping,Wang Rui,Wang Yiting,Chen Ruibing,Lin Tianyu,Xiao Xuesong,Liu Xinyu,Ideozu Justin Eze,Geng Hua,Wang Yong,Yue Dan
A key player in mitochondrial respiration, p32, often referred to as C1QBP, is mostly found in the mitochondrial matrix. Previously, we showed that p32 interacts with DLAT in the mitochondria. Here, we found that p32 expression was reduced in ccRCC and suppressed progression and metastasis in ccRCC animal models. We observed that increasing p32 expression led to an increase in oxidative phosphorylation by interacting with DLAT, thus, regulating the activation of the pyruvate dehydrogenase complex (PDHc). Mechanistically, reduced p32 expression, in concert with DLAT, suppresses PDHc activity and the TCA cycle. Furthermore, our research discovered that p32 has a direct binding affinity for copper, facilitating the copper-induced oligomerization of lipo-DLAT specifically in ccRCC cells. This finding reveals an innovative function of the p32/DLAT/copper complex in regulating glycometabolism and the TCA cycle in ccRCC. Importantly, our research provides important new understandings of the underlying molecular processes causing the abnormal mitochondrial metabolism linked to this cancer.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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代谢紊乱
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FREE RADICAL BIOLOGY AND MEDICINE
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2025
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IF 8.2
Yangyang Lu,Yan Li,Xueying Sun,Xin Li,Shufen Zhao,Yuanyuan Fang,Wensheng Qiu,Cheng Luo,Weiwei Qi
Gastric cancer treatment remains challenging due to tumor heterogeneity and drug resistance. Cuproptosis, a novel form of cell death induced by excessive copper accumulation in mitochondria, is regulated by FDX1 and involves cytotoxic aggregation of lipoylated proteins such as DLAT. Given the markedly elevated copper levels observed in gastric cancer tissues, triggering cuproptosis represents a promising therapeutic strategy. Since cuproptosis strongly relies on active mitochondrial respiration, we hypothesized that mitochondrial uncoupling-which dissociates electron transport from oxidative phosphorylation by dissipating the proton gradient across the inner mitochondrial membrane, thereby enhancing respiratory activity-could sensitize gastric cancer cells to cuproptosis. In this study, we first established a cuproptosis model in gastric cancer cells using elesclomol combined with copper. We then systematically evaluated the enhancing effect of mitochondrial uncoupling on this process. Using the classical uncoupler FCCP and clinically relevant agents (niclosamide, nitazoxanide, and oxyclozanide), we confirmed mitochondrial uncoupling through membrane potential depolarization, an increased NAD + /NADH ratio, elevated oxygen consumption, and decreased ATP levels. Importantly, mitochondrial uncoupling significantly potentiated the cytotoxic effect of elesclomol-copper ion treatment in gastric cancer cells, which was closely associated with increased DLAT oligomerization. Mechanistic investigations revealed that mitochondrial uncoupling promotes cuproptosis susceptibility by upregulating DLAT and FDX1 protein expression and remodeling cellular metabolism. In summary, this study highlights the key role of mitochondrial uncoupling in amplifying cuproptosis and proposes a novel combination strategy based on metabolic intervention. These findings offer a new theoretical foundation and potential clinical translation prospects for gastric cancer treatment.
研究领域:
肿瘤学
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细胞生物学
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分子生物学
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癌症代谢
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药理学
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高影响因子
WORLD JOURNAL OF GASTROENTEROLOGY
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2025
·Vol. 31
·期 34
·109825
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IF 5.4
Peng-Tuo Xiao,Chang-Feng Li,Yuan-Da Liu,Jing Zhong,Xi-Lun Cui,Chang Liu,Wei Yang
BACKGROUND Colorectal cancer (CRC) is a major global health burden. B cell CLL/lymphoma 10 (BCL10), a key component of the caspase recruitment domain protein-BCL10-mucosa-associated lymphoid tissue lymphoma paracaspase complexes, is upregulated in CRC and associated with poor patient prognosis, suggesting its potential role in CRC development and progression. Cuproptosis, a novel form of programmed cell death, has emerged as a promising therapeutic strategy for cancer. AIM To explore the role of BCL10 in regulating the sensitivity of CRC cells to cuproptosis. METHODS A series of in vitro and in vivo experiments were conducted using CRC cell lines and CRC mouse models to evaluate the effects of BCL10 on CRC cell proliferation, migration, invasion, and sensitivity to copper-induced cell death. Mechanistic studies were performed to elucidate the underlying molecular pathways. RESULTS BCL10 promoted CRC cell proliferation, migration, and invasion, while its knockdown had the opposite effects. BCL10 also influenced the sensitivity of CRC cells to cuproptosis, with BCL10 overexpression enhancing resistance and its knockdown increasing sensitivity. The mechanism involved BCL10 modulating the expression of DLAT, a key protein in the copper-induced cell death pathway, through activation of the nuclear factor kappa-B (NF-κB) signaling pathway. CONCLUSION BCL10 promotes CRC growth and regulates the sensitivity of CRC cells to cuproptosis by activating the NF-κB signaling pathway and modulating DLAT expression. These findings provide a molecular basis for developing BCL10-targeted therapies for CRC.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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信号转导
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转化医学
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癌变机制
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ENVIRONMENTAL POLLUTION
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2024
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IF 7.6
Ziyan Wang,Wei Zhang,Danyang Huang,Huiwen Kang,Jingyu Wang,Ziyan Liu,Guangyu Jiang,Ai Gao
Decabromodiphenyl ether (BDE-209) has been universally detected in environmental media and animals, but its damage to ovarian function and mechanism is still unclear, and melatonin has been shown to improve mammalian ovarian function. This study aimed to investigate the toxic effects of BDE-209 on the ovary and tried to improve ovarian function with melatonin. Herein, BDE-209 was administered orally to female SD rats for 60 days. Enzyme-linked immunosorbent assay, HE staining, transcriptome analysis, qPCR and immunohistochemical staining were used to explore and verify the potential mechanism. We found that BDE-209 exposure had effects on the ovary, as shown by abnormal changes in the estrous cycle, hormone levels and ovarian reserve function in rats, while increasing the proportion of collagen fibres in ovarian tissue. In terms of mechanism, cuproptosis, a form of cell death, was identified to play a crucial role in BDE-209-induced ovarian dysfunction, with the phenotype manifested as copper salt accumulation in ovary, downregulation of glutathione pathway metabolism and copper transfer molecule ( ATP7A/B ), and upregulation of FDX1 , lipoic acid pathway ( LIAS, LIPT1 ), pyruvate dehydrogenase complex components (DLAT, PDHB, PDHA1 ), and copper transfer molecule ( SLC31A1 ). Furthermore, possible interventions were explored. Notably, a supplement with melatonin has a repair effect on the damage to ovarian function by reversing the gene expression of cuproptosis-involved molecules. Overall, this study revealed that cuproptosis is involved in BDE-209-induced ovarian damage and the beneficial effect of melatonin on ovarian copper damage, providing evidence for the prevention and control of female reproductive damage induced by BDE-209.
研究领域:
毒理学
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生殖生物学
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药理学
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分子生物学
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高影响因子
BIOMATERIALS
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2024
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IF 12.8
Xinying Yu,Bei Li,Jie Yan,Wenxi Li,Hao Tian,Guohao Wang,Songtao Zhou,Yunlu Dai
Proteotoxic stress, caused by the accumulation of abnormal unfolded or misfolded cellular proteins, can efficiently activate inflammatory innate immune response. Initiating the mitochondrial proteotoxic stress might go forward to enable the cytosolic release of intramitochondrial DNA (mtDNA) for the immune-related mtDNA–cGAS–STING activation, which however is easily eliminated by a cell self-protection, i.e., mitophagy. In light of this, a nanoinducer (PCM) is reported to trigger mitophagy-inhibited cuproptotic proteotoxicity. Through a simple metal-phenolic coordination, PCMs reduce the original Cu 2+ with the phenolic group of PEG-polyphenol-chlorin e6 (Ce6) into Cu + . Cu + thereby performs its high binding affinity to dihydrolipoamide S-acetyltransferase (DLAT) and aggregates DLAT for cuproptotic proteotoxic stress and mitochondrial respiratory inhibition. Meanwhile, intracellular oxygen saved from the respiratory failure can be utilized by PCM-conjugated Ce6 to boost the proteotoxic stress. Next, PCM-loaded mitophagy inhibitor (Mdivi-1) protects proteotoxic products from being mitophagy-eliminated, which allows more mtDNA to be released in the cytosol and successfully stimulate the cGAS–STING signaling. In vitro and in vivo studies reveal that PCMs can upregulate the tumor-infiltrated NK cells by 24% and enhance the cytotoxic killing of effector T cells. This study proposes an anti-tumor immunotherapy through mitochondrial proteotoxicity.
研究领域:
癌症生物学
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免疫学
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分子生物学
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细胞生物学
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ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2025
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IF 6.1
Huiqi Li,Qizhuan Lin,Huanpeng Liu,Zheyan Chen,Xueliang Zhang,Liyuan Jin,Renyi Peng,Huanzhi Jin
Polystyrene nanoplastics (PS-NPs) and copper ions (Cu²⁺) are common environmental pollutants, yet their combined toxicological effects remain poorly understood. This study demonstrates that PS-NPs act as carriers of Cu²⁺, facilitating intracellular accumulation and inducing cuproptosis, a recently identified form of regulated cell death. Using zebrafish larvae and Hep G2 cells, we showed that co-exposure to PS-NPs and Cu²⁺ disrupted copper homeostasis, promoted DLAT oligomerization, impaired mitochondrial structure and function, and activated the cuproptosis pathway. Molecular docking revealed stable binding of PS-NPs and Cu²⁺ to the key regulator FDX1, further aggravating cuproptosis. FDX1 overexpression experiments confirmed its pivotal role, as enhanced expression significantly increased DLAT aggregation and cell death. This study is the first to reveal the molecular mechanism by which PS-NPs mediate FDX1-dependent cuproptosis via a “Trojan horse” effect. These findings provide novel insights into the mechanisms of nanoplastics–heavy metal co-exposure and offer a potential molecular target for mitigating environmental toxicity.
研究领域:
环境毒理学
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细胞生物学
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纳米毒理学
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生物化学
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分子生物学
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BIOMEDICINE & PHARMACOTHERAPY
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2023
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IF 7.5
Wenchang Yang,Yaxin Wang,Yongzhou Huang,Jiaxian Yu,Tao Wang,Chengguo Li,Lei Yang,Peng Zhang,Liang Shi,Yuping Yin,Kaixiong Tao,Ruidong Li
Cuproptosis, a novel copper-induced cell death pathway, is linked to mitochondrial respiration and mediated by protein lipoylation. The discovery of cuproptosis unfolds new areas of investigation, particularly in cancers. The present study aimed to explore the role of cuproptosis in colorectal cancer progression. The genetic alterations of cuproptosis in colon cancer were evaluated using a database. MTT assays, colony formation, and flow cytometry were used to examine the effect of elesclomol-Cu and 4-Octyl itaconate (4-OI) on colorectal cancer cell and oxaliplatin-resistant cell viability. The anti-tumor effect of elesclomol with 4-OI was verified in vivo assay. The results showed that FDX1, SDHB, DLAT, and DLST genes were more highly expressed in normal tissues than those in primary tumor tissues. Patients with high expressions of these genes in tumor tissues had a better prognosis. Using MTT assay and colony formation analysis, elesclomol-Cu pulse treatment showed significant inhibition of cell viability in HCT116, LoVo, and HCT116-R cells. In addition, flow cytometry revealed elesclomol-Cu significantly promoted apoptosis. Tetrathiomolybdate, a copper chelator, markedly inhibited cuproptosis. Subsequently, we found 2-deoxy- D -glucose, a glucose metabolism inhibitor, sensitized cuproptosis. Furthermore, galactose further promoted cuproptosis. Interestingly, 4-OI significantly enhanced cuproptosis which was irrelevant to ROS production, apoptosis, necroptosis, or pyroptosis pathways. Aerobic glycolysis was inhibited by 4-OI through GAPDH, one of the key enzymes of glycolysis, sensitizing cuproptosis. Meanwhile, FDX1 knockdown weakened the ability of 4-OI to promote cuproptosis. In vivo experiments, 4-OI with elesclomol-Cu showed better anti-tumor effects. These results indicated that elesclomol-Cu rapidly halted cell growth in colorectal cancer cells and oxaliplatin-resistant cell line. Importantly, we revealed that 4-OI inhibited aerobic glycolysis by targeting GAPDH to promote cuproptosis.
研究领域:
肿瘤学
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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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高影响因子
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