EUROPEAN JOURNAL OF PHARMACOLOGY
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2025
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IF 4.7
Linting Huang,Jiakai Pi,Liqin Gu,Zirou Liao,Wenya Wang
Parkinson's disease is a progressive neurodegenerative disorder with pathological hallmarks of loss of nigrostriatal dopaminergic neurons. Oxidative stress is one of the pivotal molecular pathways involved. Ferroptosis, a novel form of cell death, is closely associated with oxidative stress and presents a new potential therapeutic target for PD. Amounting reports showed that dipeptidyl peptidase-4 (DPP4) inhibitors, may hold potential for PD treatment. In this study, we found that Teneligliptin, a DPP4 inhibitor, when pretreated in SH-SY5Y cells, alleviated MPP + -induced cellular damage, including enhancing cell viability and modulating the Bax/Bcl-2 ratio. Furthermore, Teneligliptin not only inhibited the accumulation of reactive oxygen species (ROS), prevented the decline of mitochondrial membrane potential, decreased malondialdehyde (MDA) levels, restored glutathione (GSH) and superoxide dismutase (SOD) contents, but also lowered ferrous ion levels. At the same time, Teneligliptin restored antioxidant defenses by inhibiting DPP4 to enhance p62-mediated Keap1 degradation, thereby activating the Nrf2 signaling pathway. This upregulated downstream target including HO-1 and xCT, maintaining glutathione peroxidase 4 (GPX4) expression. Finally, Teneligliptin improved behavioral performance and protected dopaminergic neurons in MPTP-induced PD mouse. Taken together, our findings of Teneligliptin as a promising candidate for the treatment of PD warrant further study.
研究领域:
神经科学
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药理学
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PubMed
高影响因子
NEUROSCIENCE LETTERS
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2022
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IF 3.197
Lingjun Yang,Gang Zhou,Junming Chen,Sainan Zhang
Background Based on the previous findings on the relieving role of gelsemine in neuropathic pain, this research aims to further investigate the relevant regulatory mechanism. Methods Targets of gelsemine were predicted using SwissTargetPrediction. The peripheral neuropathic pain rat model was established by ligating spinal nerves, and then gelsemine (10 μg for one day) or dipeptidyl peptidase 4 (DPP4) oligonucleotides (5 μg/day, for 7 days) was injected into intrathecal bolus of rats. The mechanical threshold (0, 1, 2, 4 h after the last injection) was examined to evaluate the mechanical allodynia of rats. After the mechanical threshold measurement, the rats were anesthetized with isoflurane and then sacrificed by cervical dislocation. IBA1- and DPP4-positive cells in the spinal dorsal horn of rats were determined using immunohistochemistry and immunofluorescence assays. The expressions of DPP4, IL-1β and TNF-α in the spinal dorsal horn of rats were measured by Western blot and quantitative real-time PCR. Results DPP4 was one of the targets of gelsemine. Gelsemine could elevate the down-regulated mechanical threshold, and lessen the up-regulated IBA1- and DPP4-positive cells and expressions of DPP4, IL-1β and TNF-α in the spinal dorsal horn of rats with neuropathic pain. DPP4 overexpression reversed the role of gelsemine in neuropathic pain. Conclusion Gelsemine relieves neuropathic pain by down-regulating DPP4 level in rats, providing a novel drug candidate and biomarker for neuropathic pain treatment.
研究领域:
药理学
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神经科学
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疼痛管理
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PubMed
高影响因子
Frontiers in Pharmacology
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2025
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IF 4.8
Yuming Zhai,Jiamei Fu,Jianfei Yang,Yabin Zhou
Background: Myocardial infarction (MI) is characterized by high morbidity. In this study, we aimed to elucidate potential targets of Shengxian Decoction (SXD) against MI.Methods: Pairing of SXD active ingredients and MI targets was conducted using the Chinese Medicine System Pharmacological Database, Gene Expression Omnibus (GEO), and STRING databases. The effects of SXD on MI were validated in vitro. Molecular docking was verified using cellular thermal shift assay (CETSA).Results: A total of 40 active ingredients and 28 MI-related targets were obtained. Cross-analysis on 28 targets and cell death-related genes identified two crucial ferroptosis-related targets, namely, dipeptidyl peptidase 4 (DPP4) and heme oxygenase 1 (HMOX1). In cobalt chloride (CoCl2)-induced hypoxic H9c2 cells, SXD could remarkably improve cell viability and inhibit cell death. Meanwhile, SXD treatment significantly affected the ferroptosis-related markers in hypoxic H9c2 cells. Molecular docking and CETSA results showed that quercetin had good binding activity with DPP4 and HMOX1.Conclusion: Important active ingredient quercetin in SXD could exert anti-ferroptosis protective roles on MI through targeting ferroptosis-related genes (DPP4/HMOX1), thereby contributing to the protective role of SXD on MI.
研究领域:
药理学
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分子生物学
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心血管病学
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高影响因子
Cell Host & Microbe
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2026
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IF 23.2
Junxia Zhang,Changyun Liu,Yupeng Wang,Yusi Chen,Haibao Shang,Wen Zheng,Li Jin,Peng Xie,Yingjia Li,Yahan Liu,Yunxiao Zhang,Yang Wang,Wei Zhao,Han Xiao,Guisong Wang,Xin Zhang,Xiaolei Yang,Erdan Dong,Yan Zhang
Ischemia/reperfusion (I/R) injury is a key driver in cardiomyocyte loss and cardiac dysfunction in ischemic heart disease. Here, we uncover a previously unrecognized gut microbiota-mediated mechanism that contributes to myocardial I/R injury. Using murine I/R models and fecal microbiota transplantation, we demonstrate that the gut microbiota mediates cardiac damage through selective enrichment of Bacteroides acidifaciens ( B. acidifaciens ) following I/R-induced intestinal hypoxia and elevated luminal lactate levels. B. acidifaciens produces dipeptidyl peptidase 4 (BaDPP4), which degrades cardioprotective peptides (e.g., glucagon-like peptide-1 [GLP-1]) in the plasma, amplifying myocardial injury. Pharmacological inhibition of BaDPP4 with daurisoline, a microbial DPP4-specific inhibitor, mitigates cardiac dysfunction. In acute myocardial infarction patients with I/R injury, B. acidifaciens abundance and BaDPP4 levels correlate with clinical markers of cardiac damage. Together, these findings reveal a gut-heart axis whereby microbial-derived DPP4 exacerbates cardiac I/R injury and highlight the hypoxia-lactate-BaDPP4 axis as a promising target for microbiota-based cardioprotection.
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Advanced Science
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2026
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IF 14.1
Wanhao Gao,Wenzhu Hu,Du Tang,Xinxin Liu,Kun Yu,Lixia Feng,Minyu Liao,Wang Lin,Wenqiang Zhu,Sanjay Rajagopalan,Xiaoli Lan,Jixin Zhong,Dao Wen Wang,Dawei Jiang,Xiaoquan Rao
Myocarditis, primarily induced by viral infection, lacks reliable non-invasive imaging for early diagnosis. We developed a novel PET probe, 68 Ga-DOTA-linagliptin (abbreviated as 68 Ga-linagliptin), which targets dipeptidyl peptidase-4 (DPP4), to assess its potential in detecting myocarditis. Western blotting and immunostaining showed an elevated cardiac DPP4 expression in mice with Coxsackievirus B3 (CVB3) myocarditis. Single-cell sequencing analysis and cardiac flow cytometry further revealed that the elevated DPP4 expression predominantly originated from infiltrating immune cells, including T cells, dendritic cells, and B cells. Molecular docking and dynamics simulations, together with a DPP4 enzyme inhibition assay, demonstrated high-affinity and direct binding between 68 Ga-linagliptin and DPP4. 68 Ga-linagliptin showed favorable pharmacokinetics in vivo and shows significantly higher probe uptake in DPP4-overexpressing cells in vitro and in vivo. PET/CT imaging revealed pronounced 68 Ga-linagliptin accumulation within the inflamed myocardium of mice with myocarditis, with minimal uptake in control animals. The PET/CT signal distribution closely matched histologically identified inflammatory regions. Moreover, pretreatment with the unlabeled precursor drug linagliptin effectively attenuated inflammation and improved cardiac function in CVB3-infected mice. These findings indicate that 68 Ga-linagliptin enables sensitive and non-invasive visualization of cardiac inflammation and may offer combined diagnostic and therapeutic benefits for viral myocarditis.
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NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
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2026
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IF 4
Xu Jie,Huang Jian,Zou Rong,Deng Yuliang,Xie Hong,Huang Wanqiu,Zhang Zhaoqi
Thyroid cancer is a prevalent endocrine malignancy with a rising incidence and limited therapeutic options for advanced disease. Cistanches Herba , a traditional medicinal herb, contains bioactive compounds with reported antitumor potential, yet its molecular mechanisms in thyroid cancer remain unclear. Here, an integrated network pharmacology strategy was employed to identify active compounds and therapeutic targets of Cistanches Herba . Active constituents were screened using TCMSP and ETCM databases, and candidate targets were predicted via SwissTargetPrediction and SEA. Thyroid cancer–associated differentially expressed genes were retrieved from GEO and TCGA datasets, and overlapping analysis was performed to identify convergent targets. Molecular docking was applied to evaluate compound–target interactions, followed by experimental validation in thyroid cancer cell lines. Twenty-five active compounds and 739 putative targets were identified, with enrichment analyses highlighting cancer-related signaling pathways. Among the intersecting targets, DPP4 emerged as a key candidate, exhibiting significant overexpression in thyroid cancer and association with poor prognosis. Docking analysis predicted strong binding between DPP4 and quercetin, a major constituent of Cistanches Herba . Consistently, quercetin selectively suppressed thyroid cancer cell proliferation, downregulated DPP4 expression, and inhibited DPP4 enzymatic activity in a dose- and time-dependent manner. Moreover, DPP4 knockdown recapitulated the antiproliferative effects of quercetin. Collectively, these findings identify DPP4 as a functional therapeutic target for thyroid cancer and demonstrate that quercetin inhibits thyroid cancer cell proliferation through a DPP4-dependent mechanism.
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BIOMEDICINE & PHARMACOTHERAPY
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2023
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IF 7.5
Yijing Yang,Ying Wang,Ying Deng,Jing Lu,Li Xiao,Jie Li,Yasha Zhou,Fujiao Nie,Xiangdong Chen,Jun Peng,Hanyu Tan,Yuhui Qin,Qinghua Peng
Aim of the study To assess the impact of Fructus Lycii and Salvia miltiorrhiza Bunge extract (FSE) on retinitis pigmentosa (RP) and to explore the mechanisms by which FSE can prevent oxidative stress-induced photoreceptor ferroptosis in RP. Methods Hydrogen peroxide(H 2 O 2 ) was used to induce oxidative stress in 661 W cells, which were then examined using flow cytometry and enzyme linked immunosorbent assay (ELISA). Changes in mitochondria were observed by using an electron microscope to characterize the ferroptosis of the cells. The protective effect of FSE on the retina function and structure of rd10 mice was evaluated using histopathological examination, fundus photographs, and electroretinography (ERG). Protein expression levels of Tumor Protein p53 (P53), Solute Carrier Family 7 Member 11 (SLC7A11), Glutathione peroxidase 4 (GPX4), Arachidonate-12-Lipoxygenase (ALOX12), and Dipeptidyl peptidase 4 (DPP4) were evaluated by Western blot assays in Vivo and in Vitro. Results H 2 O 2 -induced 661 W cells increased oxidative stress products and P53 and ALOX12, decreasing the expression of SLC7A11, GPX4, and DPP4. GPX4 activator does not reduce reactive oxygen species (ROS) generation and has little effect on ferroptosis. Fer-1 and FSE attenuate ROS generation and inhibit ferroptosis of photoreceptors in RP via inhibited P53 expression and increased SLC7A11 and GPX4 expression. Conclusion FSE may be available in clinical therapeutics to alleviating RP and the mechanism by which inhibits ferroptosis of photoreceptors following oxidative stress via the P53/ SLC7A11 pathway.
研究领域:
眼科学
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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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JOURNAL OF BIOLOGICAL CHEMISTRY
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2024
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IF 4
Yue Huang,Yuting Zhang,Yuan Liu,Yinan Jin,Hongwei Yang
Diabetic retinopathy (DR) is a neurovascular complication of diabetes. As a crucial player in the retinal physiology, Müller cells are affected in DR, impairments of Müller cell function lead to retinal malfunctions. Therefore, searching for approaches to mitigate diabetes-induced injury in Müller cells is imperative for delaying DR. Peroxiredoxin 4 (PRDX4), an important endoplasmic reticulum (ER)-resident antioxidant, was explored in this study for its potential protective role against DR. Streptozotocin (STZ)-induced mouse model of diabetes and high glucose (HG)-induced Müller cells were utilized to assess the impact of PRDX4. Compared to wild-type mice, PRDX4 knockout exacerbated retinal neurodegeneration, reactive gliosis, cell apoptosis, endoplasmic reticulum (ER) stress, oxidative stress, and mitochondrial dysfunction in diabetic retinas. Knockdown of PRDX4 aggravated high glucose (HG)-induced reactive gliosis, apoptosis, ER stress, oxidative stress, and mitochondrial dysfunction in Müller cells. Conversely, PRDX4 overexpression in Müller cells protected against HG-induced cell damage. Mechanistically, PRDX4 promoted the degradation of DPP4, which is associated with DR in type 1 diabetics, thereby alleviating HG-stimulated Müller cell abnormalities. Our study indicated that PRDX4 is a crucial protective regulator in DR progression via destabilization of DPP4 protein and suggested enhancement of PRDX4 level may represent a promising approach for treating DR.
研究领域:
眼科学
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糖尿病学
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细胞生物学
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神经科学
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BMC BIOLOGY
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2025
·Vol. 23
·期 1
·1-17
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IF 4.5
He Yi,Zhang Yan,Liu Minghao,Li Jiaying,Li Wannan,Han Weiwei
Background Dipeptidyl peptidase-4 (DPP4) is considered a crucial enzyme in type 2 diabetes (T2D) treatment, targeted by inhibitors due to its role in cleaving glucagon-like peptide-1 (GLP-1). In this study, a novel DPP4 inhibitor screening strategy was developed, which significantly improved screening accuracy. Results In this study, a DPP4 inhibitor screening method was developed, integrating receptor-based ConPLex, ligand-based KPGT, and molecular docking to enhance screening accuracy. Using this approach, four potential drugs were identified from the FDA database, achieving a 100% hit rate. Among these, Isavuconazonium demonstrated the highest inhibitory activity (IC 50 = 6.60 µM). Furthermore, a user-friendly server, DPP4META, was established to predict IC 50 values for DPP4 inhibitors. The binding and dissociation mechanisms of these drugs with DPP4 were further examined through Gaussian accelerated Molecular Dynamics (GaMD) and ligand Gaussian accelerated Molecular Dynamics (LiGaMD), revealing strong correlations with IC 50 values. Additionally, a Python-based toolkit, pymd, was developed to facilitate protein-compound binding analysis. Conclusions Our study offers a robust approach and valuable insights for the development of DPP4 inhibitors, providing an effective means to investigate the binding and dissociation mechanisms between proteins and compounds.
研究领域:
计算生物学
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结构生物学
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药学
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生物信息学
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糖尿病研究
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人工智能辅助药物发现
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高影响因子
危险品化学品经营许可证（带存储）