BIOMEDICINE & PHARMACOTHERAPY
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2020
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IF 4.545
Gaojun Wu,Zhengxian Wang,Peiren Shan,Shanjun Huang,Shuang Lin,Weijian Huang,Zhouqing Huang
Background Myocardial remodeling caused by angiotensin II (Ang II) is essential for the pathological process of heart failure. Netrin-1, which is an axonal guidance cue, has been shown to be involved in the inflammatory response, tumorigenesis, and angiogenesis in non-neuronal tissues. However, the role of Netrin-1 in cardiac remodeling has not been fully elucidated. Methods The rat cardiomyocyte cell line H9c2 and primary neonatal rat cardiomyocytes were treated with Ang II. Cells were transfected with siRNA to silence Netrin-1 expression. Real-time polymerase chain reaction and Western blot analysis were used to detect the markers for fibrosis, apoptosis, and hypertrophy in cardiomyocytes. An Annexin V-EGFP/PI cell apoptosis detection kit was used to measure the level of apoptosis caused by angiotensin II. Results We found that Netrin-1 expression was upregulated in the H9c2 cells and the neonatal rat cardiomyocytes stimulated by Ang II. The increased Netrin-1 expression was decreased by valsartan to block AT1R. Importantly, the application of Netrin-1 siRNA significantly alleviated the degrees of myocardial hypertrophy, fibrosis (reflected by Myhc, collagen I, and TGF-β) and apoptosis (reflected by the level of Caspase 3, Bax, and Bcl-2) induced by Ang II. In addition, the silencing of Netrin-1 substantially decreased the phosphorylation of PKCα, JNK, and P38. We treated H9c2 cells with LY317615, SP600125, and SB203580, inhibitors of PKCα, JNK, and P38, respectively, thereby resulting in a substantial decrease in hypertrophy, fibrosis, and apoptosis. Conclusions Ang II produces cardiac hypertrophy, fibrosis, and apoptosis through the upregulation of Netrin-1 and the activation of the AT1R/PKCα/MAPK (JNK, P38) pathway. Suppression of Netrin-1 can relieve Ang II-induced cardiac remodeling via inhibition of the PKCα/MAPK (JNK and P38) signaling pathway. Thus, Netrin-1 may be a novel therapeutic target for Ang II-mediated cardiac remodeling.
研究领域:
心脏病学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
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2025
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IF 8.2
Jingyi Chen,Xuan Wang,Xuemei Yuan,Haiting Zou,Jiaye Li,Guopu Chen,Qian Tan
Fibroblast dysfunction is a key factor in the prolonged healing of diabetic wounds. Netrin-1 was found to be able to ameliorate high-glucose-induced fibroblast dysfunction. In this study, we developed a biomimetic dual-network hydrogel loaded with Netrin-1 to promote diabetic wound healing. The hydrogel was composed of natural ingredients, sodium alginate (SA) and glycyrrhizic acid (GA). In addition, with the octopus’s suction cup structure on the surface, this hydrogel exhibited strong adhesion properties and provided protective and sustained release of Netrin-1. The released could promote autophagy by activating the AMPK-mTOR pathway under sustained hyperglycemic conditions, thereby reversing fibroblast dysfunction and restoring cell migration and collagen synthesis. The resultant SA/GA@Netrin-1 hydrogel not only possessed potent antioxidant and antimicrobial effects but also enhanced collagen deposition in diabetic rat wounds, attenuated the inflammatory response, promoted autophagy, and significantly accelerated wound closure. These findings suggest that the SA/GA@Netrin-1 hydrogel provided an innovative solution for chronic diabetic wound management and has the potential to be applied to other refractory wound therapies.
研究领域:
生物材料学
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伤口修复与再生医学
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分子生物学
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糖尿病并发症
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药理学
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转化医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EUROPEAN SPINE JOURNAL
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2026
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IF 3.2
Wang Min,Gao Feng,Xu Zixuan,Xue Kaiyang,Yu Yang,Wang Fuwei,Zou Jing,Huang Guofu
Purpose Lumbar intervertebral disc degeneration (IVDD) is characterized by abnormal innervation and neurogenic inflammation, contributing to chronic discogenic pain. Electroacupuncture (EA) alleviates IVDD-related pain, yet its underlying mechanisms remain incompletely understood. This study aimed to investigate the role of the axonal guidance factor Netrin-1 in EA-mediated inhibition of myelinated nerve fiber ingrowth into degenerative intervertebral discs and to elucidate the downstream signaling pathways involved. Methods A rabbit axial compression IVDD model was established. Animals were divided into sham, model, EA, model+OV-Netrin-1, EA+sh-Netrin-1, EA+μ-opioid antagonist (β-FNA), and EA+δ-opioid antagonist (NTI) groups. Tarlov scoring, MRI, HE, AB-PAS, immunohistochemistry, TEM, Western blot, RT-qPCR, Co-IP, ELISA and flow cytometry were used to evaluate disc histology, nerve ingrowth, Netrin-1 expression in annulus fibrosus (AF) and dorsal root ganglion (DRG), endogenous opioid peptides, receptor interactions, cAMP/cGMP levels and intracellular calcium concentration. Results EA improved Tarlov scores, restored disc structure and reduced pathological nerve ingrowth in degenerative discs. EA downregulated Netrin-1 in AF but upregulated Netrin-1 in L2 DRG. DRG Netrin-1 overexpression mimicked EA’s anti-neoinnervation effect, whereas Netrin-1 knockdown abolished EA efficacy. EA elevated spinal POMC/M-ENK; blocking μ/δ opioid receptors reversed EA-mediated Netrin-1 upregulation in DRG. Mechanistically, EA promoted UNC5B-DCC complex formation, reduced cAMP, increased cGMP and lowered intracellular Ca 2+ via Netrin-1 receptors to inhibit myelinated axon sprouting. Conclusion EA upregulates DRG Netrin-1 by activating endogenous opioid peptide signaling. Netrin-1 subsequently modulates UNC5B/DCC downstream cAMP-cGMP-calcium pathways to suppress abnormal myelinated nerve fiber ingrowth, thereby alleviating discogenic pain and delaying IVDD progression.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACTA HISTOCHEMICA
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2025
·Vol. 128
·期 1
·152300
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IF 2.4
Ting Xu,Kairan Yang,Yuhu Feng,Yun-Cheng Wu,Lin-Yuan Zhang,Zuisu Yang,Falei Yuan,Haiyan Lyu
The study of oligodendrocyte precursor cells (OPCs) in both physiological and pathological contexts is challenging due to their capacity for self-renewal. This research aimed to examine the effects of OPC depletion on neurons. Tamoxifen-inducible Sox10/iCreER T2 ; netrin-1 flox/flox (NTN-1 cKO) mice were used to inactivate NTN-1 in Sox10 + oligodendroglia at varying tamoxifen doses. The impact of Necrostatin-1s (Nec-1s) and cytarabine on neuronal degeneration was evaluated, along with a comparison of the effects of tamoxifen dissolved in different plant oils on lineage tracing in Sox10/iCreER T2 ; tdTomato mice, as well as on neuronal degeneration in NTN-1 cKO mice. Our findings showed that administering 3 mg of tamoxifen per NTN-1 cKO mouse triggered necroptosis and apoptosis in Sox10 + cells. Notably, a higher dose of 6 mg of tamoxifen resulted in the degeneration of cortical neurons, which was accompanied by astrogliosis, amyloidosis, and a reduction in microglia. Immunostaining and RNAscope analysis indicated that it was Cre recombinase, rather than Cre mRNA, that was transferred to neurons. Nec-1s and cytarabine successfully prevented cortical neuron degeneration, though through distinct mechanisms. Furthermore, administering tamoxifen dissolved in vitamin E-rich wheat germ oil reduced Cre transfer in both Sox10/iCreER T2 ; tdTomato mice and NTN-1 cKO mice, significantly preventing cortical neurons from being labeled with tdTomato and protecting them from degeneration. These results suggest that, under pathological conditions, Cre recombinase can transfer from oligodendroglia to neurons, a process triggered by neuronal stress. This highlights the need for careful consideration in using Cre-loxP lineage tracing and gene-editing methods involving oligodendrocyte lineage cells and neurons.
✓ 已验证
DOI
PubMed
高影响因子
EXPERIMENTAL ANIMALS
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2024
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IF 2.2
Jingzhi WANG,Zhongyu HUANG,Yiwen LI,Qian LI,Xi LI,Li CHEN
At present, there lacks a definitive pharmaceutical intervention or therapeutic approach for diabetes-associated cognitive impairment. Herein, we delved into the impact of electroacupuncture on cognitive function in high-fat diet/streptozocin (HFD/STZ)-induced T2DM mice and underlying mechanisms. Hippocampal insulin resistance was determined by western blot analysis. Cognitive function was evaluated by Morris water maze test. The morphology of the hippocampal neurons was observed through hematoxylin & eosin staining and Nissl staining. Synaptic plasticity was assessed by western blot analysis. Immunofluorescence, immunohistochemistry, western blot and real-time PCR were employed to detect the levels of ferroptosis markers, autophagy markers, and netrin-1. Electroacupuncture treatment exhibited ameliorative outcomes on spatial learning, memory function, hippocampal insulin resistance, neuronal damage, and synaptic plasticity in T2DM mice. Furthermore, it effectively suppressed neuronal ferroptosis within the hippocampus by upregulating GPX4 and SLC7A11 expression, and reducing 4-HNE expression. Meanwhile, electroacupuncture intervention increased the levels of Beclin1 and LC3II/LC3I, as well as decreased the levels of p62 and phosphorylated-mTOR in the hippocampus of T2DM mice, suggesting that electroacupuncture facilitated autophagy activation by inhibiting mTOR activity. 3-MA-mediated autophagy inhibition undermined the beneficial effects of electroacupuncture on neuronal ferroptosis and cognitive deficits in T2DM mice. Additionally, the beneficial effects of electroacupuncture on autophagy and ferroptosis was achieved by upregulation of netrin-1 in the hippocampus. Our study revealed that that electroacupuncture therapy inhibited neuronal ferroptosis via the activation of autophagy, thereby ameliorating cognitive deficits in T2DM mice.
研究领域:
神经科学
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糖尿病学
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认知科学
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药理学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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