EMBO REPORTS
·
2023
·
IF 7.7
Zhi-Jun Zhang,Han-Yu Shao,Chuan Liu,Hao-Lin Song,Xiao-Bo Wu,De-Li Cao,Meixuan Zhu,Yuan-Yuan Fu,Juan Wang,Yong-Jing Gao
A11 dopaminergic neurons regulate somatosensory transduction by projecting from the diencephalon to the spinal cord, but the function of this descending projection in itch remained elusive. Here, we report that dopaminergic projection neurons from the A11 nucleus to the spinal dorsal horn (dopaminergicA11-SDH) are activated by pruritogens. Inhibition of these neurons alleviates itch-induced scratching behaviors. Furthermore, chemogenetic inhibition of spinal dopamine receptor D1-expressing (DRD1+) neurons decreases acute or chronic itch-induced scratching. Mechanistically, spinal DRD1+ neurons are excitatory and mostly co-localize with gastrin-releasing peptide (GRP), an endogenous neuropeptide for itch. In addition, DRD1+ neurons form synapses with GRP receptor-expressing (GRPR+) neurons and activate these neurons via AMPA receptor (AMPAR). Finally, spontaneous itch and enhanced acute itch induced by activating spinal DRD1+ neurons are relieved by antagonists against AMPAR and GRPR. Thus, the descending dopaminergic pathway facilitates spinal itch transmission via activating DRD1+ neurons and releasing glutamate and GRP, which directly augments GRPR signaling. Interruption of this descending pathway may be used to treat chronic itch.
研究领域:
神经科学
·
药理学
·
疼痛研究
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产品关联
DOI
PubMed
高影响因子
Anti-Cancer Agents in Medicinal Chemistry
·
2019
·Vol. 19
·期 8
·992-1001
·
IF 2.18
Yu Ming-Jun,Yao Sen,Li Ting-Ting,Yang Rui,Yao Ri-Sheng
Background: Cancer patients treated with targeted anti-cancer drug suffer from itch or pruritus. Itch or pruritus is an unpleasant sensation that brings about a negative impact on quality of life, and serious itch may lead to dose reduction and even discontinuation. Gastrin releasing
peptide receptor (GRPR) plays a critical role in itch, inflammation and cancer, and GRPR antagonist has obvious effect on cancer, inflammation and itch. The aim of this paper is to develop a new agent with anti-cancer and anti-itch activity. Methods: A series of GRPR antagonist PD176252
analogues (3a-3l) were designed and synthesized. Both anticancer and anti-itch activities were evaluated. Anti-cancer activity was evaluated in three human cancer cell lines in vitro, the anti-itch activity in evaluated with Kunming mice by intrathecal injection of chloroquine phosphate as
a modeling medium. And the cytotoxicity on normal cells was evaluated. Results: Of the tested compounds, compound 3i showed potently anti-cancer activity to all cancer cell lines tested with IC50 values of 10.5μM (lung), 11.6μM (breast) and 12.8μM (liver) respectively and it
also showed significant inhibition of the scratching behavior. Comparing with PD17625, compound 3i and 3g gave better inhibition activities against all cancer cell lines, compound 3b, 3c and 3i showed better anti-itch activity. The compound 3i is safe for normal breast and liver normal cells,
but it has high cytotoxicity on normal lung cell. Conclusion: The synthesized compounds have dual anti-cancer and anti-itch activity, so the development of drug with dual anti-tumor and anti-itch property is possible.
研究领域:
肿瘤学
·
药理学
·
医学
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DOI
PubMed
高影响因子
Chemical & Biomedical Imaging
·
2026
·
IF 6.7
Chaoping Sun,Xiuqi Hu,Zhongsheng Zhao,Yun Gao,Mengdan Xu,Ning Wang,Qianqian Zhang,Lishu Zhao,Jianxian Ge,Jianfeng Zeng
Pretargeting is an emerging strategy for tumor imaging that offers improved specificity and reduced off-target toxicity compared to conventional direct targeting approaches. However, a major limitation lies in the rapid internalization of pretargeting molecules, which reduces the availability of binding sites for effector probes and compromises imaging performance. In this study, we present a GRPR-targeted pretargeting system designed to overcome this challenge by employing the GRPR antagonist peptide RM26, which remains on the cell surface after receptor binding and thus minimizes internalization. The system is based on a bioorthogonal inverse electron-demand Diels–Alder reaction between IBA-RM26-TCO and 99mTc-HYNIC-Tz, which is completed quantitatively within 10 min under physiological conditions, with excellent stability, as evidenced by over 93% radiochemical purity after 24 h. In vitro experiments confirmed that RM26 maintained high GRPR binding affinity with minimal internalization, facilitating robust bioorthogonal reactivity. In vivo SPECT/CT imaging in GRPR-positive U-87MG xenograft mice further demonstrated more than 2-fold higher tumor uptake and an improved tumor-to-muscle ratio compared to direct targeting. Collectively, this work establishes a GRPR antagonist peptide-based pretargeting platform that not only addresses the internalization barrier but also enhances diagnostic performance, offering a safer and more effective approach for precision tumor imaging.
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DOI
高影响因子
Biomaterials Science
·
2020
·Vol. 8
·期 23
·6764-6772
·
IF 6.183
Peifei Liu,Yuanbiao Tu,Ji Tao,Zicun Liu,Fang Wang,Yi Ma,Zhaolun Li,Zhihao Han,Yueqing Gu
Colorectal cancer (CRC) is the third most common cancer worldwide, and the prognosis of CRC is better with an earlier diagnosis. The presence of the gastrin-releasing peptide receptor (GRPR) has been documented in very high numbers on colorectal cancer cells, which makes it an ideal biomarker for the diagnosis of CRC. Bombesin (BBN) peptide analogs have been extensively investigated for the imaging of human cancers with GRPR overexpression. Recently, we have reported a novel GRPR-targeted peptide named the GB-6 peptide. The GB-6 peptide based on BBN7–14 was designed to improve in vivo metabolic stability and decrease intestinal uptake. Meanwhile, GB-6 greatly retained the original GRPR-binding affinity of BBN7–14. In this study, the GB-6 peptide was labeled with radionuclide 99mTc or fluorescent dye for colorectal cancer imaging. In vitro receptor binding was studied in Caco-2 cells, and the GRPR targeting capacity and kinetics in vivo were evaluated using Caco-2 tumor xenografted mice models. In addition, cells and mice were also subjected to the corresponding BBN7–14 conjugations for comparison. The GB-6 peptide exhibited specific GRPR binding in vitro with a high affinity similar to that of BBN7–14. Furthermore, we observed that GB-6 showed higher tumor uptake and displayed lower intestinal activity than corresponding unmodified probe BBN7–14 in Caco-2 tumor-bearing mice. Overall, our studies demonstrated that GB-6 has the potential for early detection of CRC patients, and it may also serve as a valuable tool for non-invasive monitoring of colorectal tumor growth.
研究领域:
医学成像
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肿瘤学
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分子生物学
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药学
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DOI
PubMed
高影响因子
MOLECULES
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2025
·Vol. 30
·期 11
·2400
·
IF 4.6
Ming Yuan,Huai Wang,Mingjun Yu,Sen Yao,Risheng Yao
Cisplatin (CIS) is a widely used chemotherapeutic agent that is highly effective against various cancers. However, its clinical application is frequently limited by its substantial nephrotoxic side effects. The gastrin-releasing peptide receptor (GRPR), a critical regulator in inflammatory diseases, has been identified as a promising therapeutic target. Our previous studies have demonstrated that the GRPR antagonists PD176252 and RH-1402 can mitigate CIS-induced nephrotoxicity through anti-inflammatory mechanisms. Based on these findings, we designed and synthesized a series of 2-arylpropanoic acid-L-tryptophan derivatives to enhance the therapeutic effects. Among these compounds,3mexhibited superior renal protection by significantly improving mouse renal tubular epithelial cell (mRTEC) viability from 50.2 ± 2.6% to 80.5 ± 3.9%, surpassing PD176252 (70.8 ± 1.4%) and RH-1402 (73.9 ± 3.7%). Moreover, compound3mmarkedly reduced the expression of kidney injury molecule-1 (KIM-1) and inflammatory cytokines [Tumor Necrosis Factor-α (TNF-α), Interleukin-6 (IL-6), Monocyte Chemoattractant Protein-1 (MCP-1)]. Finally, molecular docking results revealed that3mexhibited a high binding affinity for GRPR. Computational predictions using SwissADME further indicated that3mpossesses favorable drug-like properties, thereby supporting its potential as a promising candidate for mitigating CIS-induced nephrotoxicity.
研究领域:
药理学
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肿瘤学
·
毒理学
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分子生物学
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DOI
PubMed
高影响因子
Anti-Cancer Agents in Medicinal Chemistry
·
2022
·Vol. 22
·期 17
·3009-3024
·
IF 2.527
Zhu Yuting,Wang Huai,Yu Mingjun,Li Chao,Meng Xiaoming,He Meng,Yao Risheng
Background: GRPR is over-expressed in cancer cells and is a potential drug target for the treatment of cancer. PD176252, as the most representative non-peptide inhibitor of GRPR, can inhibit the growth of cancer cells, but its low selectivity to cancer cells and normal cells limits
its further application. Objective: The aim of this study was to design and synthesize novel GRPR inhibitor with stronger anti-cancer activity and higher affinity with GRPR than the lead compound PD176252. Methods: A series of 1, 3, 4-oxadiazole derivatives as PD176252 analogues
(4a-4j, 6a-6q) were synthesized and their cytotoxic activity was investigated on four cancer lines with high expression of GRPR (gastric (HGC-27), colon (HCT- 116), prostate (PC-3), and lung (A549)) and one human cell line (gastric mucosal epithelial (GES-1)) by MTT assay. Flow cytometry analysis
and Western Blot were used to determine whether the compound induced programmed apoptosis of cancer cells. Competitive binding experiment was used to verify the affinity between GRPR and the optimal compound. Results: Compound 6m exhibited significant growth inhibition on all tested cancer
cell lines, especially gastric cancer cells (HGC-27 cellular IC50 0.37 ± 0.04μM). Also, the selectivity of 6m to HGC-27 was much higher than that of PD176252. Flow cytometric analysis and Western Blot proved that 6m significantly promoted the apoptosis of HGC-
27 cells. Moreover, competitive binding experiment confirmed the close binding of 6m with GRPR, which indicated 6m with a higher affinity than lead compound PD176252. Conclusion: Our results suggested that 6m, as a novel GRPR inhibitor, had a higher affinity with GRPR and potential anti-cancer
effect than PD176252, which can be used as a template for further optimization.
研究领域:
肿瘤学
·
药理学
·
药物化学
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DOI
PubMed
高影响因子
Cell Reports
·
2025
·
IF 6.9
Kangtai Xu,Xuefei Liu,Qian Zeng,Yaqi Liu,Leyan Shan,Luyao Ji,Yifei Wu,Jiawei Wu,Yiming Chen,Yitong Li,Songqiang Huang,Changyu Jiang,Xin Hong,Chaoran Wu,Zilong Wang
Chronic itch is a devastating clinical condition, and its central mechanisms remain poorly understood. We reported that spinal cannabinoid receptor type 2 (CB 2 R) activation exerts antipruritic effects and that itch escalates in mice lacking Cnr2 in mouse models of dermatitis and psoriasis. In the spinal cord, CB 2 R is mainly expressed in microglia, and microglial ablation or inhibition attenuated chronic itch, suggesting that microglial activation contributes to chronic itch. Particularly, conditional Cnr2 deletion in microglia also exacerbated chronic itch in mice. Single-cell RNA sequencing and molecular mechanistic studies suggest that CB 2 R activation reprogrammed microglia by inducing anti-inflammatory suppressor of cytokine signaling 3 (SOCS3) and reducing itch-related p38 and signal transducer and activator of transcription 1 (STAT1) phosphorylation. Finally, CB 2 R activation suppressed neuronal excitability and synaptic transmission in gastrin-releasing peptide (GRP)/GRP receptor (GRPR) interneurons and ascending projection neurons by inhibiting microglia-derived cytokines. These findings demonstrate that microglial activation contributes to chronic itch, while CB 2 R activation in microglia alleviates chronic itch via neuro-immune interactions.
研究领域:
神经科学
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免疫学
·
药理学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Medicine
·
2024
·
IF 3.1
Zhongzhu Ai,Dongfeng Yuan,Jingyi Cai,Ruotong Dong,Wei Liu,Daonian Zhou
Background: Pruritus ani (PA), a neurofunctional dermatosis, is one of the most common complications of hemorrhoids, which seriously affects the quality of life of patients. Medical hemorrhoid gel (MHG), a product mainly composed of herbal medicine, is widely used for treatment of PA clinically. This study aim to assess the alleviating effect and mechanism of MHG on PA based on rectal epidermis-spinal cord-brain axis using animal models.Methods: A chloroquine-induced mouse itching model and a croton oil preparation-induced rat hemorrhoid model were established to evaluate anti-PA effect of MHG. Scratching behaviors of mice were recorded, and histopathology of mice skin and rat ano-rectal tissues was observed through H&E staining. Network pharmacology and western blotting were employed to explore potential mechanism of MHG.Results: The study indicated that MHG significantly alleviated chloroquine-induced skin itching and improved pathological injuries in mice skin and rat ano-rectal tissues. Network pharmacology suggested that MHG might regulate the JAK/STAT signaling pathway. Experimental findings showed that MHG significantly downregulated TRPV1 and TRPA1 in rectal tissue, c-Fos and GRPR in spinal cord tissue, and 5-HT1a protein in brain tissue, while upregulating TRPM8 protein in rectal tissue. Furthermore, MHG inhibited the activation of the JAK2/STAT3 signaling pathway in the rectal epidermis-spinal cord-brain axis.Conclusion: MHG improves PA by inhibiting the transmission of itching signals in rectal epidermis-spinal cord-brain axis via the JAK2/STAT3 signaling pathway, providing experimental evidence for its clinical application.
研究领域:
药理学
·
神经科学
·
皮肤病学
·
分子生物学
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DOI
PubMed
高影响因子
Biomaterials Science
·
2020
·Vol. 8
·期 9
·2682-2693
·
IF 6.183
Yuanbiao Tu,Ji Tao,Fang Wang,Peifei Liu,Zhihao Han,Zhaolun Li,Yi Ma,Yueqing Gu
Pancreatic cancer has a high mortality rate and efforts towards diagnosis and therapy at an early stage are particularly appealing. Recently, a small peptide, BBN7–14, has attracted much attention for its specific binding ability to gastrin releasing peptide receptor (GRPR), which is highly overexpressed in various types of cancer, including pancreatic cancer. However, its poor stability in vivo restricts its direct clinical application. Herein, by rational design and transformation of BBN7–14, a novel six-amino acid peptide, GB-6, which maintains a specific GRPR-binding feature and exhibits enhanced stability in vitro and in vivo, was designed. Competitive binding with BBN7–14 and cellular uptake related to GRPR expression levels verified the specific affinity of GB-6 to GRPR. Additionally, this novel peptide was conjugated with near-infrared dye and the radionuclide 99mTc for pancreatic cancer diagnosis in cells and in vivo. Surprisingly, despite having the same cellular affinity as BBN7–14, GB-6 showed much higher pancreatic cancer-targeting ability than BBN7–14 by both fluorescence imaging and radionuclide imaging. It was proven that this strange phenomenon was attributed to the distinct in vivo stability of GB-6 and its more favorable pharmacokinetic properties and metabolic stability relative to BBN7–14. Altogether, this novel peptide GB-6, with GRPR-targeting ability and enhanced stability, is a more promising candidate for the clinical diagnosis of pancreatic cancer.
研究领域:
肿瘤学
·
分子生物学
·
药学
·
医学影像学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）