INTERNATIONAL IMMUNOPHARMACOLOGY
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2025
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IF 4.7
Rihong Luo,Yuhan Kang,He Ma,Zhenqiang Zhang,Christian Hölscher,Li Hao,Zijuan Zhang
To date, no therapeutic drugs available on the market can effectively reverse the progression of Alzheimer's disease (AD). Although Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) and Cholecystokinin (CCK) RAs have shown some promise in AD research, little is known about the neuroprotective effects of a novel dual CCK/GLP-1 RA in AD. This study sought to examine the effects of the novel dual CCK/GLP-1 RA on cognitive performance in an AD mouse model and to explore the associated mechanisms. Our findings indicate that dual CCK/GLP-1 RA improved cognitive deficits, reduced amyloid-beta (Aβ) accumulation, and alleviated mitochondrial damage in 5 × FAD mice by inducing mitophagy. In an in vitro model of AD cells induced by Aβ, CCK/GLP-1 RA could exert neuroprotective effects by regulating PINK1/Parkin-mediated mitophagy. These data reveal for the first time that the new CCK/GLP-1 RA modulates mitophagy via PINK1/Parkin pathway and enhances cognitive function in the 5 × FAD animal model. Moreover, the performance of the CCK/GLP-1 RA in certain indicators was superior to that of GLP-1 analogue liraglutide, suggesting that it may represent a more promising therapeutic option for AD.
研究领域:
神经科学
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
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2024
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IF 4.2
Lanxin Li,Yang Zhang,Zhengqian Chen,Can Xu,Zhongqiu Xu,Haitao Pei,Wei Wang,Ruyong Yao,Cui Hao
Parkinson's disease (PD) is a common age-related neurodegenerative disorder, which may be largely due to the mitochondrial dysfunction and impaired mitophagy. Thus, it is of great importance to seek novel therapeutic strategies for PD targeting mitochondrial function and mitophagy. Cytarabine is a marine-derived antimetabolite used in the treatment of acute leukemia, which is also used in the study of the nervous system. In this study, we found that cytarabine pretreatment significantly inhibited the apoptosis and necrosis in the ROT-induced SH-SY5Y cell PD model and reduced the oxidative stress, as evidenced by the reduced MDA levels and the increased levels of SOD, GSH, and total antioxidant capacity. Cytarabine can also enhance mitochondrial vitality, improve mitochondrial respiratory function, and preserve mitochondrial morphology. Cytarabine also enhanced the expression of the mitophagy-related proteins PINK1, Parkin, VDAC1, and DJ-1, and its actions can be reversed by treatment with AMPK inhibitor - Compound C (CC), suggesting that AMPK activation may be involved in cytarabine-enhanced mitophagy. Furthermore, cytarabine can also ameliorate the motor symptoms in the MPTP-induced PD-like mice model, and attenuate the neuropathy in the substantia nigra (SN) of PD mice, while Compound C antagonized cytarabine's beneficial effects. In summary, marine-derived compound cytarabine could resist neurological damage both in vitro and in vivo by activating AMPK to increase PINK1/Parkin-induced mitophagy, serving as a promising disease modulator for treating neurodegenerative disease.
研究领域:
神经科学
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药理学
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细胞生物学
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神经退行性疾病
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Yang Zhang,Deguo Xing,Yi Liu,Shiyu Sha,Yueying Xiao,Zhonghao Liu,Qingfeng Yin,Zengxin Gao,Wenguang Liu
Intervertebral disc degeneration (IVDD) is a chronic degenerative disease with a complex pathophysiological mechanism. Increasing evidence suggests that the NOD-like receptor thermal protein domain associated protein 3 (NLRP3)-mediated pyroptosis of nucleus pulposus cells (NPCs) plays a crucial role in the pathological progression of IVDD. Pyroptosis is a novel form of programmed cell death characterized by the formation of plasma membrane pores by gasdermin family proteins, leading to cell swelling, membrane rupture, and the release of inflammatory cytokines, which trigger an inflammatory response. The close relationship between pyroptosis and mitophagy has been previously described in various diseases, but the crosstalk between pyroptosis and mitophagy in IVDD remains unexplored. Cellular repressor of E1A-stimulated genes 1 (CREG1) is a secreted glycoprotein involved in cell differentiation and homeostasis regulation and has been shown to promote lysosomal biogenesis and function. However, the potential role and underlying mechanisms of CREG1 in the progression of IVDD have not yet been reported. In this study, we first observed that CREG1 is downregulated following IVDD and that pyroptosis occurs. Furthermore, CREG1 knockdown inhibited NPC proliferation and exacerbated apoptosis and degeneration. Moreover, we confirmed that CREG1 knockdown induced NLRP3 activation while also leading to mitophagy inhibition and mitochondrial dysfunction in NPCs. CREG1 overexpression ameliorated LPS-induced mitophagy inhibition and mitochondrial dysfunction by promoting PINK1/Parkin-mediated mitophagy, thereby suppressing NLRP3 inflammasome activation. However, these protective effects were reversed by pretreatment with the mitophagy inhibitor cyclosporin A (CsA). In a rat model of IVDD, imaging and histological assessments revealed that CREG1 overexpression effectively alleviated the progression of IVDD. Additionally, CREG1 overexpression reduced the expression of NLRP3, caspase-1, and IL-1β while increasing the expression of collagen II, PINK1 and LC3, delaying the course of IVDD. Overall, this study highlights the importance of the interplay between CREG1-mediated regulation of mitophagy and pyroptosis in the pathogenesis of IVDD, identifying CREG1 as a promising therapeutic target for IVDD treatment.
研究领域:
骨科
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细胞生物学
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分子生物学
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病理生理学
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
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2024
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IF 5.3
Jia Xi Ye,Jia Ying Wu,Liang Ai,Min Zhu,Yun Li,Dong Yin,Qihui Huang
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the significant involvement of amyloid-beta (Aβ) peptide in its pathogenesis. Geniposide, derived from the versatile medicinal of Gardenia jasminoides , is one of the active compounds studied extensively. The objective was to explore the impact of geniposide on Aβ 25-35 -induced damage in HT22 cells, specifically focusing on its modulation of PINK1/Parkin-mediated mitophagy. In our investigation, geniposide exhibited remarkable restorative effects by enhancing cell viability and preserving the mitochondrial membrane potential. Moreover, it effectively reduced and mitigated the oxidative stress and apoptosis rates induced by Aβ 25-35 . Notably, geniposide exhibited the capacity to enhance autophagic flux, upregulate LC3II and Beclin-1 expression, and downregulate the expression of p62. Furthermore, geniposide positively influenced the expression of PINK1 and Parkin proteins, with molecular docking substantiating a strong interaction between geniposide and PINK1/Parkin proteins. Intriguingly, the beneficial outcomes of geniposide on alleviating the pronounced apoptosis rates, the overproduction of reactive oxygen species, and diminished the PINK1 and Parkin expression induced by Aβ 25-35 were compromised by the mitophagy inhibitor cyclosporine A (CsA). Collectively, these findings suggested that geniposide potentially shields HT22 cells against neurodegenerative damage triggered by Aβ 25-35 through the activation of mitophagy. The insights contribute valuable references to the defensive consequences against neurological damage of geniposide, thereby highlighting its potential as a therapeutic intervention in AD.
研究领域:
神经科学
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药理学
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细胞生物学
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分子生物学
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神经退行性疾病
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DOI
PubMed
高影响因子
International Journal of Nanomedicine
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2021
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IF 6.4
Xiaodi Gong,Xin Pu,Jing Wang,Linlin Yang,Yunxia Cui,Lijuan Li,Xiao Sun,Jichang Liu,Jingfeng Bai,Yudong Wang
Purpose Iron-based nanomaterials have recently been developed as excellent and potent Fenton reagents to reactive oxygen species (ROS) during chemodynamic therapy (CDT). The performance of the materials, however, can be impaired by the intrinsic antioxidant defense mechanism in organisms, such as autophagy. Methods The nanoscale metal-organic frameworks (nMOFs), nMIL-100 (Fe), were exploited and characterized. Also, the Fenton-like catalytic characteristics, anti-endometrial cancer (EC) effects and potential mechanisms of nMIL-100 (Fe) nanoparticles were investigated in vitro. Results The synthesized nMIL-100 (Fe) nanocatalyst catalyzed hydroxyl radicals (·OH) production in the presence of hydrogen peroxide (H 2 O 2 ) and simultaneously depleted intracellular glutathione (GSH). Combining with H 2 O 2 , nMIL-100 (Fe) nanoparticles exhibited enhanced cytotoxicity for EC cells, especially for progesterone treatment-insensitive KLE cells, probably due to relatively lower expression of the catalase gene. The accumulated ·OH initiated PTEN induced putative kinase 1 (PINK1)/E3 ubiquitin-protein ligase Parkin-mediated cytoprotective mitophagy in turn to partially rescue ·OH-induced cell apoptosis. Furthermore, both pretreatments of EC cells with siRNA-mediated Parkin knockdown and Mdivi-1 (a mitophagy inhibitor) addition were sufficient to ensure nMIL-100 (Fe) synergizing with H 2 O 2 -induced oxidative damages. Conclusion These results suggest that the degree of mitophagy should be taken into consideration to optimize therapeutic efficiency when developing ROS based-CDT for EC cancer therapies. Therefore, a nMIL-100 (Fe)-guided, elevated ROS and overwhelmed mitophagy-mediated therapeutic strategy may have greater promise for EC therapy compared with current treatment modalities.
研究领域:
纳米技术
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癌症研究
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细胞生物学
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治疗学
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肿瘤学
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
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2025
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IF 8.3
Lu Bocheng,Chen Yongfu,Cai Junjie,Li Ziqi,Guo Lina,Qu Tingli,Tang Li,Zheng Qian
Objective Guzhi Zengsheng Zhitong Decoction (GZZD) is a classic traditional Chinese medicine (TCM) prescription for treating knee osteoarthritis (OA), and has been widely used in clinical practice in China. Given that Forkhead box protein O 1 (FoxO1) has been identified as a potential therapeutic target for OA treatment, this study investigates the chondroprotective effects of GZZD through FoxO1-mediated mitochondrial regulation, bridging traditional medicine with contemporary molecular insights. Methods The therapeutic effects of GZZD on OA and its chondroprotective mechanisms were evaluated both in vivo and in vitro . A rat model of knee OA was established by intra-articular injection of monosodium iodoacetate (MIA), while an in vitro OA model was induced by IL-1β stimulation in chondrocytes. Histological staining, immunohistochemistry, and Western blot analyses were performed to assess cartilage protection. Serum ingredients of GZZD were identified using LC-MS/MS, and the core pathways involved in GZZD-mediated chondroprotection were explored through transcriptomics and network pharmacology. Key protein expression was examined, and molecular biology techniques were applied to validate the role of FoxO1 and its downstream pathways in regulating chondrocyte autophagy, apoptosis, and mitochondrial dysfunction. Additionally, molecular docking and molecular dynamics simulations were conducted to analyze interactions between bioactive compounds and FoxO1. Results GZZD significantly ameliorated MIA-induced knee joint damage, reduced cartilage degradation and subchondral bone destruction, and decreased OARSI scores. Treatment with GZZD markedly decreased serum levels of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) while enhancing protective autophagy in chondrocytes. Furthermore, GZZD inhibited chondrocyte apoptosis and mitochondrial dysfunction, accompanied by the upregulation of the cartilage matrix protein COL2A1 and the anti-apoptotic protein BCL2, along with downregulation of catabolic factors (MMP13, IL-1β). Mechanistically, GZZD activated the FoxO1/PINK1/Parkin pathway, restoring mitochondrial homeostasis and mitigating mitochondrial-dependent apoptosis, ultimately protecting chondrocytes from OA-related damage. Conclusion For the first time, this study demonstrates that the traditional Chinese medicine formula GZZD alleviates osteoarthritis by activating the FoxO1/PINK1/Parkin pathway, thereby restoring mitochondrial function and protecting chondrocytes from injury. These findings not only establish GZZD as a promising complementary therapy for OA but also provide a scientific foundation for developing FoxO1-targeted therapeutics.
研究领域:
中医中药
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分子生物学
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药理学
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风湿病学
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线粒体生物学
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系统生物学
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计算生物学
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产品关联
DOI
PubMed
高影响因子
Food & Function
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2023
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IF 6.1
Dekun Cheng,Zhangtie Wang,Xin Guo,Yiwen Guo,Yu Zhang,Yuanhui Zhao,Ruijie Liu,Ming Chang
Dietary nutritional support for special populations is an effective and feasible method to improve quality of life of patients and reduce medical pressure. The effects of ATSO on chemotherapy population were evaluated by a zebrafish model of demyelination. The results showed that 100 μg/mL ATSO reversed tail morphology damage, axon degeneration, touch response delay, ROS level upregulation and the expression of myelin basic protein decrease in chemotherapy-induced zebrafish. In addition, the expression of myelin markers (including sox10, krox20, pmp22) in oxaliplatin-induced cells was markedly reversed by ATSO and its active components (gondoic acid, erucic acid, nervonic acid). ATSO and its active components could reverse demyelination by ameliorating mitochondrial dysfunction. Conversely, linoleic acid and linolenic acid promoted demyelination by exacerbating mitochondrial dysfunction. Moreover, the Pink1/Parkin pathway was recognized as the main reason for ATSO and its active components to improve mitochondrial function by activating mitophagy and restoring autophagic flow. Taken together, this study demonstrated that ATSO and its active components could be further developed as novel functional food ingredients to antagonize demyelination.
研究领域:
神经科学
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药理学
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营养学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
PHYTOMEDICINE
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2024
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IF 6.7
Jia-Yi Dou,Mei-Jie Zhou,Mei-Yan Xuan,Jia Guo,Sai-Hu Liu,Li-Hua Lian,Zhen-Yu Cui,Ji-Xing Nan,Yan-Ling Wu
Background Astilbin (ATB), a natural dihydroflavonol compound, exists in many plants, processed and functional foods. ATB has multiple pharmacological effects, such as antioxidant, lipid-lowering, and hepatoprotective. However, its anti-hepatic fibrosis and mechanisms remain unclearly elucidated. Purpose This study explored the effect of ATB against the hepatic fibrosis and its regulation of hepatic microenvironment by regulating hepatic stellate cells-macrophage crosstalk. Method Thioacetamide (TAA) was intraperitoneal injected to establish hepatic fibrosis mice, and treated with ATB or curcumin by gavage, respectively. Hepatic stellate cells (HSCs) were stimulated with TGF-β or conditioned medium (CM) from LPS-induced THP-1, then cultured with ATB, PXR agonist or antagonist. Results In TAA-induced mice, ATB improved histopathological changes, serum transaminases increase; alleviated extracellular matrix (ECM) deposition, epithelial-mesenchymal transformation (EMT), inflammatory infiltration, PTEN induced kinase 1 (PINK1)/Parkin-mediated mitophagy and activated pregnane X receptor (PXR) expression. In vitro , ATB significantly reduced ECM, inflammatory cytokines release, mitophagy, EMT, and activated PXR expression. ATB could increase PXR and decrease PINK1/Parkin, functioning as a PXR agonist. PXR deficiency in LX-2 could degrade the regulation of ATB on ECM, inflammation, EMT, and mitophagy. CM from LPS-induced THP-1 activated LX-2 and resulted in PXR decreasing, while ATB could regulate the crosstalk between HSCs and macrophages. Deficiency of PXR, whether in LX-2 or in macrophages, all weakened the inhibitory effect of ATB on α-SMA, EMT, inflammatory cytokines, and PINK1/Parkin signaling. Conclusion ATB ameliorated hepatic fibrosis by inhibiting HSCs activation, inflammation and EMT through PXR-mediated PINK1/Parkin signaling. Especially, ATB targeted the hepatic microenvironment between hepatic stellate cells and macrophages, which might be a promising strategy for the treatment of hepatic fibrosis.
研究领域:
药理学
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肝病学
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细胞生物学
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免疫学
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产品关联
DOI
PubMed
高影响因子
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
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2023
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IF 3.9
Qingqing Du,Xiaoyun Wu,Kai Ma,Weiwei Liu,Panwen Liu,Toshihiko Hayashi,Kazunori Mizuno,Shunji Hattori,Hitomi Fujisaki,Takashi Ikejima
Type 2 diabetes (T2DM) is induced by the abundance of glucose and lipids , which causes glucolipotoxicity to the pancreatic β-cells. Silibinin is a natural flavonoid possessing the regulatory activity on insulin production and therapeutic activity in diabetic mice; however, its effect on glucolipotoxicity is not fully explained. This in vitro study investigates the effects of silibinin on palmitic acid (PA) and high glucose (HG)-induced cell loss and ferroptosis of rat insulinoma INS-1 cells. In the cells treated with PA and HG, expressions of glucose transporter 4 (Glut4) and carnitine acyltransferase I (CPT1) for β-oxidation of fatty acids are reduced. Mitochondria are the metabolic organelles for glucose and fatty acids. The mitochondrial membrane potential (MMP) and ATP production were decreased, while the ROS level was elevated in the cells treated with PA and HG, indicating an induction of mitochondrial disorder . Cell loss was partially rescued by ferroptosis inhibition, suggesting an involvement of ferroptosis in the cells treated with PA and HG. More importantly, the increases in total iron, lipid ROS, MDA and COX-2, and the decrease in ferroptosis inhibitory molecules GSH, GPX4 and FSP1 appeared in the cells treated with PA and HG, confirming the occurrence of ferroptosis. Moreover, PINK1/parkin-mediated mitophagy , a vital process for selective elimination of damaged mitochondria, was blocked. Interestingly, silibinin rescued the mitochondria, restricted the ferroptosis and restored the mitophagy. By using the pharmacological stimulator and inhibitor of mitophagy, and si-RNA transfection to silence PINK1 expression, silibinin's protective effect against ferroptosis caused by PA and HG treatment was found to depend on mitophagy. Collectively, our current study reveals the new mechanisms for the protection of silibinin against the injury of INS-1 cells treated with PA and HG, elucidates the participation of ferroptosis in glucolipotoxicity, highlighting the involvement of mitophagy in defense against ferroptotic cell death.
研究领域:
糖尿病
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细胞生物学
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药理学
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生物化学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
MOLECULES
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2025
·Vol. 30
·期 9
·1952
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IF 4.6
Guangyu Shi,Yikao Hu,Xiaolin Bai,Xun Liao
The aim of this study was to identify peptides fromLumbricus terrestriswith neuroprotective effects. Two peptides (GYSFTTTAER and AVFPSIVGR) isolated from earthworms improved cell viability of the SH-SY5Y human neuroblastoma cell line treated with 1-methyl-4-phenyl-1,2,3-tetrahydropyridinehydrochloride (MPP+), a commonly used model of Parkinson’s disease (PD). Both peptides increased the mitochondrial membrane potential and upregulated the mRNAs of mitophagy regulators PINK1 and Parkin in the MPP+-damaged cells. The in vitro assay and molecular docking indicated that both peptides exhibited moderate PINK1 agonistic activity. Furthermore, GYSFTTTAER and AVFPSIVGR extended the lifespan, improved locomotor behavior, and raised the ATP and dopamine levels at all ages inPINK1B9mutant flies, a PD model characterized by loss-of-function of PINK1. These findings suggest that earthworm-derived peptides possess anti-neurodegenerative properties and hold potential for the development of health products and therapeutic agents for PD.
研究领域:
生物化学
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神经科学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Reproductive Sciences
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2025
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IF 2.5
Ma Qianwen,Wu Lifei,Wu Jianfei,Ni Binfei,Wang Jiajia,Song Shiyan
Objective To investigate the mechanism in the progression of decreased ovarian reserve (DOR). Methods Three-month-old female SD rats were employed and randomly divided into the model group and the normal group. The model group was intraperitoneally injected with 4-vinylcyclohexene diepoxide (VCD). Thereafter, blood sample from the abdominal aorta was taken, and rats were sacrificed, and ovarian tissues were obtained by laparotomy. Results HE staining results revealed that the model group exhibited significantly reduced ovarian volume, increased follicular atresia, and decreased quantities of growing follicles and corpus luteum, thereby indicating degraded reserve function of ovarian. TEM images revealed that prominent autophagic vacuoles could be observed in the model group, accompanied by the mitochondria shrinkage and generation of the autophagosome. The expression of Pink1, Parkin, BNIP3L and LC3II genes in ovaries of the model group was significantly higher than those of the normal group ( P < 0.05). In addition, the protein expression of Pink1, Parkin, BNIP3L and LC3II in ovaries of the model group were higher than those of the normal group ( P < 0.05). The expression of Fe 2+ and GSH in oocytes of the model group was higher than those of the normal group ( P < 0.05). The expression of FTH1 and GPX4 in oocytes of the model group was significantly higher than those of the normal group ( P < 0.05). Conclusions Mitochondrial autophagy and ferroptosis may participate in the progression of decreased ovarian reserve (DOR).
研究领域:
生殖生物学
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细胞生物学
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医学
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产品关联
DOI
PubMed
高影响因子
Autophagy
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2026
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IF 18.6
Zhangjie Wang,Chaoyi Li,Ruiqiu Zhu,Minghao Duan,Zhenyu Kuang,Xin Li,Weifang Cui,Chaojun Duan,Chunfang Zhang
Lactylation is an emerging post-translational modification that is well established for its involvement in epigenetic regulation. However, its functional significance and regulatory mechanisms in non-small cell lung cancer (NSCLC) remain poorly understood. In this study, integrated proteomic and lactylomic analyses of clinical NSCLC specimens and matched adjacent normal tissues showed that USP7 (ubiquitin specific peptidase 7) was upregulated and USP7 K1084 lactylation was increased in NSCLC. Knockout of USP7 or inhibition of USP7 lactylation impaired cellular mitophagy, resulting in mitochondrial damage and attenuated NSCLC tumorigenicity. We identified CREBBP/CBP (CREB binding lysine acetyltransferase) as the key lactyltransferase responsible for USP7 K1084 lactylation. USP7 lactylation induced its localization to mitochondria and increased its interaction with PINK1 (PTEN induced kinase 1), promoting PINK1 deubiquitination and stabilization. Pharmacological inhibition of CREBBP reduced USP7 lactylation levels and promoted PINK1 ubiquitination and degradation, exerting antitumor effects in vitro and in vivo. Analysis of NSCLC clinical specimens showed that the protein levels of USP7, CREBBP, and PINK1 were positively correlated, and their high expression was associated with poor patient prognosis. Collectively, our findings establish the CREBBP-USP7-PINK1 axis as a promising therapeutic target for NSCLC treatment.Abbreviations: CHX: cycloheximide; CREBBP/CBP: CREB binding lysine acetyltransferase; DUB: deubiquitinating enzyme; IHC: immunohistochemistry; IP: immunoprecipitation; KO: knockout; LDHA: lactate dehydrogenase A; MS: mass spectrometry; NALA: L-sodium lactate; NSCLC: non-small cell lung cancer; OCR: oxygen consumption rate; PBS: phosphate-buffered saline; PINK1: PTEN induced kinase 1; PLA: proximity ligation assay; ROS: reactive oxygen species; shRNA: short hairpin RNA; TEM: transmission electron microscopy; TUBE: tandem ubiquitin binding entity; UPS: ubiquitin-proteasome system; USP7: ubiquitin specific peptidase 7; WT: wild type.
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DOI
高影响因子
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