Yi Wang

Wenzhou Medical University

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Guang Liang

Wenzhou Medical University

Wu Luo

Wenzhou Medical University

Gaojun Wu

Wenzhou Medical University

Guang Liang

Wenzhou Medical University

Bo Jin

Wenzhou Medical University

Leiming Jin

Wenzhou Medical University

Lijiang Huang

Wenzhou Medical University

Jiong Wang

Shaoxing People's Hospital

Weijian Huang

Guangxi University

Chunpeng Zou

Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University

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Wenzhou Medical University

283

First Affiliated Hospital of Wenzhou Medical University

Zhejiang University

Chinese Academy of Sciences

Fudan University

Chinese Academy of Medical Sciences & Peking Union Medical College

University of Chinese Academy of Sciences

Shanghai Jiao Tong University

Sun Yat-sen University

Peking University

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Discovery of alantolactone as a naturally occurring NLRP3 inhibitor to alleviate NLRP3‐driven inflammatory diseases in mice

British Journal of Pharmacology (2023)

Weifeng Li Haowen Xu Jingjing Shao Jiahao Chen Yimin Lin

Background and Purpose The NLR family pyrin domain‐containing 3 (NLRP3) inflammasome is activated in many inflammatory conditions. So far, no low MW compounds inhibiting NLRP3 have entered clinical use. Identification of naturally occurring NLRP3 inhibitors may be beneficial to the design and development of compounds targeting NLRP3. Alantolactone is a phytochemical from a traditional Chinese medicinal plant with anti‐inflammatory activity, but its precise target remains unclear. Experimental Approach A bank of phytochemicals was screened for inhibitors of NLRP3‐driven production of IL‐1β in cultures of bone‐marrow‐derived macrophages from female C57BL/6 mice. Models of gouty arthritis and acute lung injury in male C57BL/6J mice were used to determine the in vivo effects of the most potent compound. Key Results Among the 150 compounds screened in vitro, alantolactone exhibited the highest inhibitory activity against LPS + ATP‐induced production of IL‐1β in macrophages, suppressing IL‐1β secretion, caspase‐1 activation and pyroptosis. Alantolactone directly bound to the NACHT domain of NLRP3 to inhibit activation and assembly of NLRP3 inflammasomes. Molecular simulation analysis suggested that Arg335 in NLRP3 was a critical residue for alantolactone binding, leading to suppression of NLRP3–NEK7 interaction. In vivo studies confirmed significant alleviation by alantolactone of two NLRP3‐driven inflammatory conditions, acute lung injury and gouty arthritis. Conclusion and Implications The phytochemical alantolactone inhibited activity of NLRP3 inflammasomes by directly targeting the NACHT domain of NLRP3. Alantolactone shows great potential in the treatment of NLRP3‐driven diseases and could lead to the development of novel NLRP3 inhibitors.

Pyrin domain

Phytochemical

NALP3

10.1111/bph.16036

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Citations (18)

Chemogenomic Screening in a Patient‐Derived 3D Fatty Liver Disease Model Reveals the CHRM1‐TRPM8 Axis as a Novel Module for Targeted Intervention

Advanced Science (2024)

Sonia Youhanna Aurino M. Kemas Shane C. Wright Yi Zhong Britta Klumpp

Abstract Metabolic dysfunction‐associated steatohepatitis (MASH) is a leading cause of chronic liver disease with few therapeutic options. To narrow the translational gap in the development of pharmacological MASH treatments, a 3D liver model from primary human hepatocytes and non‐parenchymal cells derived from patients with histologically confirmed MASH was established. The model closely mirrors disease‐relevant endpoints, such as steatosis, inflammation and fibrosis, and multi‐omics analyses show excellent alignment with biopsy data from 306 MASH patients and 77 controls. By combining high‐content imaging with scalable biochemical assays and chemogenomic screening, multiple novel targets with anti‐steatotic, anti‐inflammatory, and anti‐fibrotic effects are identified. Among these, activation of the muscarinic M 1 receptor (CHRM1) and inhibition of the TRPM8 cation channel result in strong anti‐fibrotic effects, which are confirmed using orthogonal genetic assays. Strikingly, using biosensors based on bioluminescence resonance energy transfer, a functional interaction along a novel MASH signaling axis in which CHRM1 inhibits TRPM8 via G q/11 and phospholipase C‐mediated depletion of phosphatidylinositol 4,5‐bisphosphate can be demonstrated. Combined, this study presents the first patient‐derived 3D MASH model, identifies a novel signaling module with anti‐fibrotic effects, and highlights the potential of organotypic culture systems for phenotype‐based chemogenomic drug target identification at scale.

Steatohepatitis

Dyslipidemia

Steatosis

10.1002/advs.202407572

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A magnetic-responsive biomimetic nanosystem coated with glioma stem cell membranes effectively targets and eliminates malignant gliomas

Biomaterials Research (2024)

Song Deng Dekang Nie Yue Huang Yu Yang Qianqian Liu

Glioblastoma multiforme (GBM) is among the most challenging malignant brain tumors, making the development of new treatment strategies highly necessary. Glioma stem cells (GSCs) markedly contribute to drug resistance, radiation resistance, and tumor recurrence in GBM. The therapeutic potential of nanomaterials targeting GSCs in GBM urgently needs to be explored. A magnetic-responsive biomimetic nanosystem (FDPM), coated with glioma stem cell membranes (CMs), was designed for the targeted eradication of GSCs as well as their associated tumor cells. Identified nanobodies were extensively characterized with various assays. The application tests on nanomaterials were conducted in vitro and in vivo. The tumor-suppressive effects of the nanosystem were evaluated in vitro and in vivo. FDPM can be artificially directed under magnetic guidance while inheriting various biological functions from CM. Upon intravenous injection, FDPM was drawn to the tumor site by magnetic attraction, where it could cross the blood–brain barrier aided by CM. Its homologous targeting ability originates from active proteins on CM, enabling it to specifically target GSCs and related tumor cells. The encapsulated doxorubicin (DOX) within the nanoparticle then destroyed these tumor cells. FDPM demonstrated excellent biocompatibility and tumor-targeting efficiency, effectively targeting malignant gliomas initiated by GSCs. FDPM significantly reduced tumor cells, inhibited tumor growth, and notably extended the survival of glioma-bearing nude mice. The findings position FDPM as a promising nanoplatform to target GSCs and related tumor cells for improving the therapeutic effect of glioma.

10.34133/bmr.0123

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Kaempferol attenuates streptozotocin-induced diabetic nephropathy by downregulating TRAF6 expression: The role of TRAF6 in diabetic nephropathy

Journal of Ethnopharmacology (2020)

Wu Luo Xiaojun Chen Ye Lin Xuemei Chen Wenjing Jia

Kaempferia rhizome is a famous traditional herbal medical in tropical and subtropical areas. Kaempferol (KPF) is one of the main bioactive compounds in Kaempferia rhizome, with anti-oxidant/anti-inflammatory effects demonstrated in various disease models, including cancers, obesity and diabetes. Inflammation plays an important role in the pathogenesis of diabetic nephropathy (DN). TRAF6 functions as a signal transducer in toll-like receptor 4 and NF-κB pro-inflammatory signaling pathway. We aimed at investigate whether KPF is able to mitigate inflammatory responses by regulating TRAF6 in DN. C57BL/6 mice were injected with streptozotocin to induce type 1 DN. NRK-52E, a tubular epithelial cell line, was used for in vitro analysis. TRAF6 was knockdown using siRNA in vitro and AAV2/2-shRNA in vivo. The anti-DN and inflammatory effects of KPF or knockdown of TRAF6 were evaluated by investigating renal filtration index, pathological changes of kidney tissue. Proinflammatory cytokine levels were detected using ELISA. NF-κB pathway and protein levels of related pathways were detected through Western blot. KPF significantly reduced renal inflammation, fibrosis, and kidney dysfunction in diabetic mice. These effects were associated with a downregulation of TRAF6 in diabetic mouse kidneys, indicating the potential role of TRAF6. Knockdown of TRAF6 in mice through AAV2-shTRAF6 confirmed the importance of TRAF6 in DN. In vitro, treatment of KPF in NRK-52E cells attenuated high glucose (HG)-induced inflammatory and fibrogenic responses, associated with downregulated TRAF6 expression. The conclusion was further confirmed in NRK-52E cells by knocking down the expression and by overexpression of TRAF6. Our findings provide direct evidence that TRAF6 mediates diabetes-induced inflammation leading to renal dysfunction. We also show that KPF is a potential therapeutic agent to reduce inflammatory responses in DN. Also, TRAF6 may represent an interesting target to combat DN.

Proinflammatory cytokine

10.1016/j.jep.2020.113553

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Citations (45)

Breviscapine attenuatted contrast medium-induced nephropathy via PKC/Akt/MAPK signalling in diabetic mice.

PubMed (2016)

Wenbin Jiang Zhengwei Li Wei Zhao Hao Chen Youyang Wu

Contrast medium-induced nephropathy (CIN) remains a major cause of iatrogenic, drug-induced renal injury. Recent studies reveal that Breviscapine can ameliorate diabetic nephropathy in mice. Yet it remains unknown if Breviscapine could reduce CIN in diabetic mice. In this study, male C57/BL6J mice were randomly divided into 7 groups: control, diabetes mellitus, CIN, diabetes mellitus+CIN, diabetes mellitus+Breviscapine, CIN+Breviscapine and diabetes mellitus+CIN+Breviscapine. Model of CIN was induced by tail intravenous administration of iopromide and model of diabetes mellitus was induced by Streptozotocin intraperitoneally. Breviscapine was administered intragastrically for 4 weeks. Renal function parameters, kidney histology, markers of renal fibrosis, phosphorylation of protein kinase C/Akt/mitogen activated protein kinases were measured by western blot. We found out that diabetes mellitus aggravated CIN damage. Renal histological analysis showed Breviscapine reduced of renal fibrosis and tubular damage. Breviscapine was also shown markedly to ameliorate CIN fibrotic markers expression, reduced proteinuria and serum creatinine. Furthermore, Breviscapine decreased phosphorylation of PKCβII, Akt, JNK1/2 and p38. Therefore, Breviscapine treatment could ameliorate the development of CIN in diabetic mice, which was partly attributed to its suppression of renal fibrosis via phosphorylation of PKCβII/Akt/JNK1/2/p38 signalling.

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Curcumin analog, WZ37, promotes G2/M arrest and apoptosis of HNSCC cells through Akt/mTOR inhibition

Toxicology in Vitro (2019)

Ziheng Zhang Renyu Lin Zhoudi Liu Tao Yan Yiqun Xia

10.1016/j.tiv.2019.104754

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Correlation of vascular endothelial growth factor and microvascular damage in diabetic retinopathy

DOAJ (DOAJ: Directory of Open Access Journals) (2015)

Jiquan Wen Yi Wang Jie Yang Ruo-Xin Wu

10.3980/j.issn.1672-5123.2015.12.10

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Cell-specific IL-1R1 regulates the regional heterogeneity of microglial displacement of GABAergic synapses and motor learning ability

Cellular and Molecular Life Sciences (2024)

Yi You Dadao An Wan Yu-shan Bingqin Zheng Haibin Dai

Abstract Microglia regulate synaptic function in various ways, including the microglial displacement of the surrounding GABAergic synapses, which provides important neuroprotection from certain diseases. However, the physiological role and underlying mechanisms of microglial synaptic displacement remain unclear. In this study, we observed that microglia exhibited heterogeneity during the displacement of GABAergic synapses surrounding neuronal soma in different cortical regions under physiological conditions. Through three-dimensional reconstruction, in vitro co-culture, two-photon calcium imaging, and local field potentials recording, we found that IL-1β negatively modulated microglial synaptic displacement to coordinate regional heterogeneity in the motor cortex, which impacted the homeostasis of the neural network and improved motor learning ability. We used the Cre-Loxp system and found that IL-1R1 on glutamatergic neurons, rather than that on microglia or GABAergic neurons, mediated the negative effect of IL-1β on synaptic displacement. This study demonstrates that IL-1β is critical for the regional heterogeneity of synaptic displacement by coordinating different actions of neurons and microglia via IL-1R1, which impacts both neural network homeostasis and motor learning ability. It provides a theoretical basis for elucidating the physiological role and mechanism of microglial displacement of GABAergic synapses.

10.1007/s00018-023-05111-0

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Macrophage DCLK1 promotes obesity-induced cardiomyopathy via activating RIP2/TAK1 signaling pathway

Cell Death and Disease (2023)

Bin Yang Yunjie Zhao Wu Luo Weiwei Zhu Leiming Jin

Obesity increases the risk for cardiovascular diseases and induces cardiomyopathy. Chronic inflammation plays a significant role in obesity-induced cardiomyopathy and may provide new therapeutic targets for this disease. Doublecortin-like kinase 1 (DCLK1) is an important target for cancer therapy and the role of DCLK1 in obesity and cardiovascular diseases is unclear. Herein, we showed that DCLK1 was overexpressed in the cardiac tissue of obese mice and investigated the role of DCLK1 in obesity-induced cardiomyopathy. We generated DCLK1-deleted mice and showed that macrophage-specific DCLK1 knockout, rather than cardiomyocyte-specific DCLK1 knockout, prevented high-fat diet (HFD)-induced heart dysfunction, cardiac hypertrophy, and fibrosis. RNA sequencing analysis showed that DCLK1 deficiency exerted cardioprotective effects by suppressing RIP2/TAK1 activation and inflammatory responses in macrophages. Upon HFD/palmitate (PA) challenge, macrophage DCLK1 mediates RIP2/TAK1 phosphorylation and subsequent inflammatory cytokine release, which further promotes hypertrophy in cardiomyocytes and fibrogenesis in fibroblasts. Finally, a pharmacological inhibitor of DCLK1 significantly protects hearts in HFD-fed mice. Our study demonstrates a novel role and a pro-inflammatory mechanism of macrophage DCLK1 in obesity-induced cardiomyopathy and identifies DCLK1 as a new therapeutic target for the treatment of this disease. Upon HFD/PA challenge, DCLK1 induces RIP2/TAK1-mediated inflammatory response in macrophages, which subsequently promotes cardiac hypertrophy and fibrosis. Macrophage-specific DCLK1 deletion or pharmacological inhibition of DCLK1 protects hearts in HFD-fed mice.

Knockout mouse

Cardiac Fibrosis

10.1038/s41419-023-05960-4

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Curcumin analogue C66 attenuates obesity-induced renal injury by inhibiting chronic inflammation

Biomedicine & Pharmacotherapy (2021)

Ye Lin Xueting Hu Xiang Hu Sihui Yin Jianqiang Chen

Obesity has been recognized as a major risk factor for the development of chronic kidney disease, which is accompanied by increased renal inflammation, fibrosis, and apoptosis. C66 is a curcumin derivative that exerts anti-inflammatory effects by inhibiting the JNK pathway and prevents diabetic nephropathy. The present study investigates the possible protective effect of C66 on high-fat diet (HFD)-induced obesity-related glomerulopathy. Mice were fed with HFD for 8 weeks while some were treated with C66 every 2 days for 11 weeks. The HFD-fed mice developed renal dysfunction, as well as elevated triglyceride and cholesterol. Kidneys of the HFD-fed mice showed marked glomerular injuries, apoptosis, and inflammation with markedly increased cytokine production. Interestingly, treating HFD-fed mice with C66 remarkably reversed these pathological changes via inhibiting inflammation and NF-κB/JNK activation. In cultured mesangial cells, Palmitic Acid was able to activate the pro-fibrotic mechanisms, apoptosis, inflammatory response, and NF-κB and JNK signaling pathways, all of which could be attenuated by C66 treatment. In all, we demonstrated that curcumin analogue C66 attenuates obesity-induced renal injury by inhibiting chronic inflammation and apoptosis via targeting NF-κB and JNK. Our data suggest that C66 can be potentially used to prevent obesity-associated renal diseases warranting future investigations.

10.1016/j.biopha.2021.111418

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Citations (23)