Drug Design Development and Therapy
·
2025
·
IF 5.1
Yijing Zhou,Chengli Lou,Xiuqin Xu,Bo Feng,Xiaoping Fan,Xiangjing Wang
Purpose Ursolic acid (UA) improves diabetic nephropathy (DN), but its regulatory mechanism requires further verification.Methods The bioactive component-target network of UA in DN was determined using a network pharmacology approach. DN mice (STZ-diabetic C57BL/6 mice, n = 8/group, 4 weeks) were treated with UA (25 mg/kg and 100 mg/kg) and the JAK agonist RO8191 (2 mg/kg). The DN cell model (high glucose-injured NRK-52E cells) was treated with UA (10 and 50 µM) and RO8191 (2 μM) for 24 h. The molecular mechanisms by which UA acts were further verified in vivo and in vitro.Results UA treatment ameliorated the general state of the DN mouse model, as characterized by the attenuation of weight loss and downregulation of fasting blood glucose (FBG) and fasting serum insulin (FINS) levels (all P < 0.05). Renal pathological changes and impaired renal function (increased levels of Scr, BUN, and UAER) were also improved by UA treatment (all P < 0.05). In vitro, UA increased the viability of DN cells in vitro (P < 0.001). Concurrently, UA remarkably downregulated the levels of ROS, SOD, and iron and up-regulated the levels of MDA, GPX4, and SLC7A11 (all P < 0.05) in vivo and in vitro. Mechanistically, activation of the JAK2-STAT3 pathway with the agonist RO8191 significantly reduced UA’s anti-ferroptosis and anti-oxidative effects of UA.Conclusion UA protected against DN by blocking JAK2/STAT3-mediated ferroptosis.
研究领域:
药理学
·
分子生物学
·
生物信息学
·
糖尿病研究
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Anti-Cancer Agents in Medicinal Chemistry
·
2024
·Vol. 24
·期 18
·1360-1370
·
IF 2.6
Linjin Li,Chengpeng Li,Feilong Miao,Wu Chen,Xianghui Kong,Ruxian Ye,Feng Wang
Background Cisplatin is a key therapeutic agent for bladder cancer, yet the emergence of cisplatin resistance presents a significant clinical challenge. Objective This study aims to investigate the potential and mechanisms of cyclanoline (Cyc) in overcoming cisplatin resistance. Methods Cisplatin-resistant T24 and BIU-87 cell models (T24/DR and BIU-87/DR) were established by increasing gradual concentration. Western Blot (WB) assessed the phosphorylation of STAT3, JAK2, and JAK3. T24/DR and BIU-87/DR cell lines were treated with selective STAT3 phosphorylation modulators, and cell viability was evaluated by CCK-8. Cells were subjected to cisplatin, Cyc, or their combination. Immunofluorescence (IHC) examined p-STAT3 expression. Protein and mRNA levels of apoptosis-related and cell cycle-related factors were measured. Changes in proliferation, invasion, migration, apoptosis, and cell cycle were monitored. In vivo, subcutaneous tumor transplantation models in nude mice were established, assessing tumor volume and weight. Changes in bladder cancer tissues were observed through HE staining, and the p-STAT3 was assessed via WB and IHC. Results Cisplatin-resistant cell lines were successfully established, demonstrating increased phosphorylation of STAT3, JAK2, and JAK3. Cisplatin or Cyc treatment decreased p-STAT3, inhibited invasion and migration, and induced apoptosis and cell cycle arrest in the G0/G1 phase in vitro. In vivo, tumor growth was significantly suppressed, with extensive tumor cell death. IHC and WB consistently showed a substantial downregulation of STAT3 phosphorylation. These changes were more pronounced when cisplatin and Cyc were administered in combination. Conclusion Cyc reverses cisplatin resistance via JAK/STAT3 inhibition in bladder cancer, offering a potential clinical strategy to enhance cisplatin efficacy in treating bladder cancer.
研究领域:
肿瘤学
·
药理学
·
分子生物学
·
细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF IMMUNOPATHOLOGY AND PHARMACOLOGY
·
2022
·
IF 3.298
Qianqian He,Xiaoqi Sun,Muqing Zhang,Li Chu,Yang Zhao,Yongchao Wu,Jianping Zhang,Xue Han,Shengjiang Guan,Chao Ding
Baicalin (BA) is a kind of flavonoid that is isolated from Scutellaria baicalensis Georgi, which has been verified to have hepatoprotective effects in some diseases. However, the role of BA in acute hepatic injury induced by arsenic trioxide (ATO) remains unclear. The aim of this study was to investigate the protective action of BA on acute hepatic injury induced by ATO and to probe its possible mechanism. Mice were pretreated with BA (50, 100 mg/kg) by gavage. After 7 h, ATO (7.5 mg/kg) was injected intraperitoneally to induce liver injury. After 7 days of treatment, serum and hepatic specimens were collected and assayed to evaluate the hepatoprotective effect of BA. Pathological sections and the liver function index indicated that ATO caused significant liver injury. The fluorescence of reactive oxygen species and oxidative stress indicators showed that ATO also increased oxidative stress. The inflammatory markers in ATO-induced mice also increased significantly. Staining of the terminal deoxynucleotidyl transferase dUTP nick end labeling and apoptotic factor assay showed that apoptosis increased. However, with BA pretreatment, these changes were significantly weakened. In addition, BA treatment promoted the expression of proteins related to the JAK2/STAT3 signaling pathway. The results suggest that BA can ameliorate acute ATO-induced hepatic injury in mice, which is related to the inhibition of oxidative stress, thereby reducing inflammation and apoptosis. The mechanism of this protection is potentially related to the JAK2/STAT3 signaling pathway.
研究领域:
药理学
·
毒理学
·
分子生物学
·
肝病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2020
·
IF 4.545
Zhanchuan Ma,Yan Xia,Cong Hu,Miaomiao Yu,Huanfa Yi
Quercetin is a natural product that has been shown to induce tumor apoptosis and necrosis through multiple mechanisms. Tumor-induced myeloid-derived suppressor cell (MDSC) expansion negatively regulates the immune response by inhibiting T cell function through signal transducer and activator of transcription 3 (STAT3) activation, thereby facilitating tumor escape from host immune surveillance. Thus MDSC is an attractive target for cancer immunotherapy to enhance cytotoxic T cell responses. However, the effects of quercetin on MDSC are poorly understood. Here, we demonstrate that quercetin treatment enhanced mouse- and human- derived granulocytic-myeloid-derived suppressor cells (G-MDSC) survival and promoted the secretion of T cell-suppressive factors in vitro. Bioinformatics analysis further showed that quercetin was highly correlated with the estrogen receptor signaling pathway, which was confirmed by quantitative reverse transcription-polymerase chain reaction and flow cytometric analysis. These findings highlight the potential advantages and feasibility of quercetin in reinforcing the suppressive property of G-MDSC. Thus impact of G-MDSC should be taken into consideration when quercetin is applied to tumor therapy.
研究领域:
免疫学
·
肿瘤学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
Oncology Letters
·
2022
·Vol. 24
·期 5
·1-9
·
IF 3.111
Yang Chen,Li Hou
It has previously been reported that human hepatocellular carcinoma‑related protein 1 (HCRP‑1), which is a tumor suppressor gene, and epidermal growth factor receptor (EGFR) are abnormally expressed in certain solid tumors. Therefore, in the present study, the expression patterns of HCRP‑1 in oral squamous cell carcinoma (OSCC) are discussed. Moreover, the present study investigated whether HCRP‑1 regulated EGFR expression levels and its downstream effectors to further determine the regulation of tumor cell behavior. Therefore, the expression levels of HCRP‑1 in normal oral epithelial and OSCC cells were determined, and the effects of HCRP‑1 overexpression on OSCC cell proliferation, migration and invasion were assessed. Moreover, the culture medium from the different groups of OSCC cells was separately supplemented into the human umbilical vein endothelial cell (HUVEC) cultures, and the migration and angiogenesis of the HUVECs were assessed. To determine the roles of EGFR/STAT3 in the regulation of HCRP‑1, EGF and colivelin, a STAT3 agonist, were used to treat CAL‑27 cells and their effects on the cells were assessed using the aforementioned functional experiments. The results demonstrated that HCRP‑1 expression levels were downregulated in OSCC cells and that HCRP‑1 overexpression could suppress OSCC cell proliferation, migration and invasion. Moreover, the culture medium from OSCC cells overexpressing HCRP‑1 facilitated the migration and angiogenesis of HUVECs. Furthermore, HCRP‑1 was demonstrated to function in cells by regulating the EGFR/STAT3 signaling pathway. In summary, the present study indicated that HCRP‑1 alleviated the malignant phenotype and angiogenesis of OSCC cells via the downregulation of the EGFR/STAT3 signaling pathway.
研究领域:
肿瘤学
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHYTOTHERAPY RESEARCH
·
2019
·Vol. 33
·期 5
·1579-1591
·
IF 3.766
Li Wan,Qun Zhang,Sheng Wang,Yong Gao,Xiaofei Chen,Yang Zhao,Xiaoping Qian
Angiogenesis is central to a wide range of physiological and pathological processes including wound healing, macular degeneration, and cancer. Excessive or inappropriate vascular supply of tumors is one of the main targets for cancer therapy. Recently, critical and selective transcriptional factors such as yes-associated protein (YAP) that control the expression of angiogenesis factors have gained increasing attention in antiangiogenic therapy. In this study, we have identified and characterized a novel inhibitor of YAP, gambogic acid (GA), which exerted striking antiangiogenic effects both in vitro and in vivo. We demonstrated that GA remarkably inhibited a variety of vascular endothelial growth factor-induced angiogenesis processes including proliferation, migration, sprouting, and tube formation of endothelial cells in vitro. In addition, GA resulted in decreased neo-vessel formation in Matrigel plugs of mice and chick chorioallantoic membrane. More importantly, we showed that GA limited tumor growth via preventing tumor angiogenesis and vascular maturation. Further mechanistic studies illustrated that GA directly targeted YAP/STAT3 signaling axis, which is critical for the transcriptional regulation of a series of angiogenic factors. Taken together, these preclinical findings suggest that GA significantly repressed tumor angiogenesis and may serve as a promising drug candidate against cancer.
研究领域:
肿瘤学
·
药理学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
·
2023
·
IF 8.2
Wang Wei,Chen Xiao-kang,Zhou Lu,Wang Feng,He Yan-ji,Lu Bing-jun,Hu Ze-gang,Li Zhu-xin,Xia Xue-wei,Wang Wei Eric,Zeng Chun-yu,Li Liang-peng
Stimulation of adult cardiomyocyte proliferation is a promising strategy for treating myocardial infarction (MI). Earlier studies have shown increased CCL2 levels in plasma and cardiac tissue both in MI patients and mouse models. In present study we investigated the role of CCL2 in cardiac regeneration and the underlying mechanisms. MI was induced in adult mice by permanent ligation of the left anterior descending artery, we showed that the serum and cardiac CCL2 levels were significantly increased in MI mice. Intramyocardial injection of recombinant CCL2 (rCCL2, 1 μg) immediately after the surgery significantly promoted cardiomyocyte proliferation, improved survival rate and cardiac function, and diminished scar sizes in post-MI mice. Alongside these beneficial effects, we observed an increased angiogenesis and decreased cardiomyocyte apoptosis in post-MI mice. Conversely, treatment with a selective CCL2 synthesis inhibitor Bindarit (30 μM) suppressed both CCL2 expression and cardiomyocyte proliferation in P1 neonatal rat ventricle myocytes (NRVMs). We demonstrated in NRVMs that the CCL2 stimulated cardiomyocyte proliferation through STAT3 signaling: treatment with rCCL2 (100 ng/mL) significantly increased the phosphorylation levels of STAT3, whereas a STAT3 phosphorylation inhibitor Stattic (30 μM) suppressed rCCL2-induced cardiomyocyte proliferation. In conclusion, this study suggests that CCL2 promotes cardiac regeneration via activation of STAT3 signaling, underscoring its potential as a therapeutic agent for managing MI and associated heart failure.
研究领域:
心脏病学
·
分子生物学
·
再生医学
✓ 已验证
DOI
PubMed
高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
·
2019
·Vol. 176
·期 14
·2627-2641
·
IF 6.583
Zheng Xu,Chunpeng Zou,Weihui Yu,Sujing Xu,Lan Huang,Zia Khan,Jingying Wang,Guang Liang,Yi Wang
Background and Purpose Hypertension adversely affects the kidney and is the second leading cause of kidney failure. Overproduction of angiotensin II greatly contributes to the progression of hypertensive kidney disease. Angiotensin II has recently been shown to activate STAT3 in cardiovascular cells. However, the underlying mechanisms of STAT3 activation by angiotensin II and downstream functional consequences in the kidneys are not fully understood. Experimental Approach C57BL/6 mice were treated with angiotensin II by subcutaneous infusion for 1 month to develop nephropathy. Mice were treated with either adeno-associated virus expressing STAT3 shRNA or STAT3 inhibitor, S3I-201. Human archival kidney samples from five patients with hypertension and five individuals without hypertension were also examined. In vitro, STAT3 was blocked using siRNA or STAT3 inhibitor S3I-201 in the renal proximal tubular cell line, NRK52E, after exposure to angiotensin II. Key Results Angiotensin II activated STAT3 in kidney epithelial cells through engaging toll-like receptor 4 (TLR4) and JAK2, which was independent of IL-6/gp130 and angiotensin AT 1 receptors. Angiotensin II-mediated STAT3 activation increased fibrotic proteins and resulted in renal dysfunction. Both STAT3 inhibition by the low MW compound S3I-201 and TLR4 deficiency normalized renal fibrosis and dysfunction caused by Ang II in mice, without affecting hypertension. Conclusions and Implications Our study reveals a novel mechanism of STAT3 activation, induced by angiotensin II, in kidney tissues and highlights a translational significance of a STAT3 inhibitor as potential therapeutic agent for hypertensive kidney disease.
研究领域:
肾病学
·
药理学
·
分子生物学
·
心血管疾病
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Scientific Reports
·
2025
·Vol. 15
·期 1
·1-11
·
IF 3.9
Li Wenlan,Zhang Zijie,Jiang Zixiao,Barasarathi Jayanthi,Zhou Ying,Liu Sui,Lee Shiou Yih,Liu Yangyang
Psychotria rubra Herbal Tea (PRHT) is a traditional Chinese folk medicine used to treat in-flammation induced by respiratory infections. Its specific mechanisms of action, however, remain unclear. The study combined ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS), network pharmacology, and in vitro cell experiments to systematically analyze the chemical composition and validate the biological activity of PRHT. Protein-protein interaction (PPI) network analysis and molecular docking were used to identify key targets and mechanisms. PRHT was found to contain 128 active compounds, including alkaloids, amino acids and their derivatives, and flavonoids. Key targets such as STAT3, IL-6, and TP53 were identified through PPI network analysis. PRHT exhibited significant anti-inflammatory effects by modulating the STAT3/IL-6/TNF-α signaling pathway. Experimental results demonstrated that PRHT inhibited the release of inflammatory cytokines in a dose-dependent manner. Molecular docking confirmed strong interactions between PRHT components and core targets. The study reveals that PRHT exerts anti-inflammatory effects by regulating the STAT3/IL-6/TNF-α signaling pathway, contributing to inflammation balance and tis-sue repair. These findings provide scientific evidence for the development of PRHT as a functional anti-inflammatory agent and offer new insights into treatment strategies for respiratory infections.
研究领域:
中药学
·
分子生物学
·
网络药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BMC Pulmonary Medicine
·
2024
·Vol. 24
·期 1
·1-16
·
IF 2.6
Sun Lili,Liu Lihua,Liang Dongxue,Liu Linlin
Pulmonary hypertension (PH) is a chronic pulmonary vascular disease and causes massive deaths. Here, we intended to investigate the function and mechanism of SOCS5 in PH. We engineered a hypoxia-induced PH model in mice. HE staining were implemented to evaluate pathological alterations in the lung tissues. The potential mechanism of SOCS5 in regulating hypoxia-induced pulmonary artery smooth muscle cell (PASMC) function was explored in vitro. RT-qPCR and western blot revealed that the level of SOCS5 was decreased both in PH mice and hypoxia-induced HPASMCs. Functional assays were performed for confirming the role of SOCS5 in modulating the cell phenotype and JAK2/STAT3 pathway in HPASMCs. Results revealed that overexpression of SOCS5 suppressed proliferation, migration and contraction of HPASMCs and negatively regulated the JAK2/STAT3 signaling pathway in HPASMCs under hypoxia in vitro, while knockdown of SOCS5 accelerated it. As evidenced by mechanism studies, SOCS5 was targeted and regulated by miR-155-5p, hence affecting on HPASMC proliferation, migration and contraction. These outcomes indicated that the decreased level of SOCS5 in hypoxia-induced HPASMCs promoted the cell proliferation, cell migration, and cell contraction through activating JAK2/STAT3 signaling pathway. Moreover, SOCS5 was targeted by miR-155-5p. All in all, our work hinted that miR-155-5p/SOCS5/JAK2/STAT3 axis played a crucial part in PH.
研究领域:
心血管疾病
·
分子生物学
·
细胞生物学
·
病理生理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Food & Function
·
2023
·Vol. 14
·期 10
·4807-4823
·
IF 6.1
Suwen Liu,Wenhong Jiang,Chang Liu,Shuo Guo,Hao Wang,Xuedong Chang
Chinese chestnut shell is a by-product of chestnut food processing and is rich in polyphenols. This study sought to investigate the effect of chestnut shell polyphenol extract (CSP) on weight loss and lipid reduction in a 12-week high-fat diet (HFD)-induced murine obesity model. CSP (300 mg per kg body weight) was administered intragastrically daily. AG490, a JAK2 protein tyrosine kinase inhibitor, was also intraperitoneally injected. The results showed that an HFD induced leptin resistance (LR). Compared to corresponding values in the HFD group, CSP treatment improved blood lipid levels, weight, and leptin levels in obese mice (p < 0.01). Additionally, CSP treatment enhanced enzyme activity by improving total antioxidant capacity, attenuating oxidative stress, and reducing fat droplet accumulation and inflammation in the liver, epididymal, and retroperitoneal adipose tissue. CSP also activated the LEPR-JAK2/STAT3-PTP1B-SOCS-3 signal transduction pathway in hypothalamus tissue and improved LR while regulating the expression of proteins related to lipid metabolism (PPARγ, FAS, and LPL) in white adipose tissue in the retroperitoneal cavity. However, the amelioration of lipid metabolism by CSP was dependent on JAK2. Molecular docking simulation further demonstrated the strong binding affinity of procyanidin C1 (−10.3983297 kcal mol−1) and procyanidin B1 (−9.12686729 kcal mol−1) to the crystal structure of JAK2. These results suggest that CSP may be used to reduce HFD-induced obesity with potential application as a functional food additive.
研究领域:
营养学
·
药理学
·
分子生物学
·
肥胖研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Biomolecules
·
2020
·Vol. 10
·期 2
·285
·
IF 4.082
Ehexige Ehexige,Mingming Bao,Purevbat Bazarjav,Xiang Yu,Hai Xiao,Shuqin Han,Huricha Baigude
Cutaneous melanoma is the most aggressive skin cancer with notorious drug resistance. Inhibition of immune checkpoint molecules is one of the most promising approaches for cancer therapy. Herein, we show that RNAi mediated silencing of STAT3 expression in the tumor tissue robustly inhibit tumor growth in B16F10 mouse model of melanoma. We designed a peptidomimetic-based lipid nanoparticles (LNPs) for the delivery of siRNA in mouse model of melanoma. When systemically administered, the novel formulation (denote DoCh) preferentially delivered siRNA to the tumor tissue. Remarkably, sequential intravenous injections of siRNA against STAT3 induced profound silencing of STAT3 expression in tumor tissue, which resulted in significant downregulation of PD-L1, leading to significant inhibition of tumor growth through inhibition of tumor immune checkpoint. Moreover, DoCh-mediated siRNA delivery did not show noticeable damage to the major organs. Collectively, our data demonstrated that DoCh LNP is a promising tumor-targeted siRNA delivery system.Keywords:peptidomimetic lipid nanoparticle;RNAi;STAT3;PD-L1;cancer immune checkpoints
研究领域:
癌症生物学
·
分子生物学
·
纳米技术
·
免疫治疗
✓ 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）