BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2026
·
IF 2.5
Ming Li,Dong Ren,Haowei Hou,Jian Lu,Guowei Ren,Shuangquan Yao,Lindan Geng,Pengcheng Wang
Objective To investigate the role of endothelin receptor B (Ednrb/ETB) in tranexamic acid (TXA)-induced post-traumatic osteoarthritis (PTOA) and to elucidate the underlying molecular mechanisms. Methods Adult rats were assigned to four groups: control + TXA (T), cartilage scratch + TXA (CT), subchondral fracture + TXA (ST), and combined cartilage-subchondral fracture + TXA (CST). RNA sequencing combined with Venn analysis was used to identify candidate genes, including Ednrb . Molecular docking was performed to evaluate the binding affinity between TXA and ETB. Rats were subsequently regrouped for histological, immunohistochemical, and biochemical analyses of cartilage. ATDC5 chondrocytes were transfected with si-Ednrb-1/2 and co-treated with TXA to assess cell viability and pathway activation. Results RNA sequencing identified Ednrb as a core upregulated gene in the CT and CST groups. Molecular docking demonstrated strong binding between TXA and ETB (binding energy: –5.1 kcal/mol). In the rat PTOA model, TXA significantly increased OARSI scores in the NCT and NCST groups (P < 0.0001), upregulating the expression of ETB, matrix metalloproteinase 13 (MMP13), RXFP1, endothelin-1 (ET-1), phosphorylated nuclear factor-kappa B, and phosphorylated AKT, as well as the inflammatory mediators interleukin-1 beta, tumor necrosis factor alpha, and interleukin-6. In ATDC5 cells, Ednrb knockdown significantly increased cell viability, reduced apoptosis, and downregulated ETB, MMP13, and pathway-related signaling molecules, thereby attenuating inflammatory responses. TXA treatment significantly reversed these protective effects. Conclusion Ednrb functions as a key mediator in TXA-induced PTOA progression. The binding of TXA to ETB activates the relaxin and ET-1/ETB pathways, thereby promoting cartilage degradation and inflammation. Targeting Ednrb may represent a promising therapeutic strategy for preventing TXA-associated PTOA.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ENVIRONMENTAL TOXICOLOGY
·
2022
·Vol. 38
·期 1
·136-145
·
IF 4.109
Dandan Wang,Peng Li,Lixiang Liu,Peng Liu,Zheng Zhou,Meihui Jin,Baoxiang Li,Fan Li,Yao Chen,Hongmei Shen
Iodine excess (IE) can cause thyroid dysfunction, thyroid diseases can adversely affect cardiovascular function. Accordingly, this study was to explore the direct and indirect effects of IE on endothelial function. Nthy-ori 3-1 and HUVECs cells were treated with potassium iodide (KI). CCK-8, LDH leakage, Elisa, RT-PCR and Western blotting were used to detect relevant indicators. Results showed that a certain level of KI can directly and indirectly reduce the viability of HUVECs and increase cytotoxicity. KI decreased the expression of ET-1 and VWF in HUVECs, inhibited the secretion of ET-1 in culture medium, and increased the expression of IL-6 and TNFα in HUVECs or Nthy-ori 3-1 cells alone. In the co-culture system, KI decreased the expression of ET-1 and THBD and increased the expression of TNFα and IL-6. Collectively, IE can directly and indirectly inhibit endothelial function of endothelial cells, which may be related to its induced inflammatory response.
研究领域:
内分泌学
·
心血管科学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ENVIRONMENTAL TOXICOLOGY
·
2023
·
IF 4.5
Yujing Wang,Min Xiao,Feng Cai,Yang Li,Tianli Shi,Xiaoyan Zhou,Shuhong Tian,Denggao Huang
Vascular calcification (VC) is a common complication of chronic kidney disease (CKD). VC is a gene-regulated process similar to osteogenic differentiation. There are still no convincing schemes to prevent and reduce the development of VC. It has been reported that hypoxia-inducing factor 1α (HIF-1α) and endothelin-1(ET-1) are related to VC. In this study, we found that the expression of ET-1 and HIF-1α was enhanced after VC, the interaction between HIF-1α and ET-1 was confirmed by CO-IP and luciferase experiments. We found that ET-1 was an upregulated differential gene of calcified vascular smooth muscle cells (VSMCs) through gene sequencing. However, hypoxia-inducing factor 2α (HIF-2α) and HIF-1α have antagonistic effects on each other. HIF-1α is a pro-inflammatory cytokine, and HIF-2α can improve inflammation and fibrosis. Roxadustat, as a selective PHD3 inhibitor, preferentially activates HIF-2α. It is still unclear whether roxadustat improves VC in CKD by regulating the expression of HIF-2α/HIF-1α. Alizarin red staining and western blot as well as immunohistochemical results showed that roxadustat could significantly reduce the degree of vascular and VSMCs calcification in CKD rats. Serum HIF-1α and ET-1 were significantly decreased after roxadustat treatment. In addition, western blot results showed that roxadustat could decrease the expression of HIF-1α and ET-1 in vascular tissues and calcified VSMC, but HIF-2α expression significantly increased. Interestingly, our study confirmed that activation of HIF-1α or inhibition of HIF-2α reversed the ameliorating effect of roxadustat on VC, proving that the effect mediated by roxadustat is HIF-2α/HIF-1α dependent. We have demonstrated for the first time that roxadustat improves VC in CKD rats by regulating HIF-2α/HIF-1α, thus providing a new idea for the application of roxadustat in VC of CKD.
研究领域:
药理学
·
肾病学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Evidence-based Complementary and Alternative Medicine
·
2022
·
IF 2.65
Ying-Ying Wu,Yi-Lin Huang,Bin Dai,Jian-Wei Liu,Xu Han
Background/Aim. Abnormal proliferation and migration of vascular smooth muscle cells is one of the main causes of atherosclerosis (AS). Therefore, the suppression of abnormal proliferation and migration of smooth muscle cells are the important means for the prevention and inhibition of AS. The clinical effects of Guanxinping (GXP) tablets and preliminary clinical research on the topic have proved that GXP can effectively treat coronary heart disease, but its underlying mechanism remains unclear. This study aimed to confirm the inhibitory effect of GXP on the abnormal proliferation of mouse aortic vascular smooth muscle (MOVAS) cells and to explore the underlying mechanism. Methods. MOVAS cells were divided into two major groups: physiological and pathological groups. In the physiological group, MOVAS cells were directly stimulated with GXP, whereas in the pathological group, the cells were stimulated by endothelin-1 (ET-1) before intervention by GXP. At the same time, atorvastatin calcium, which effectively inhibits the abnormal proliferation of MOVAS cells, was used in the negative control group. CCK8 assay, scratch test, ELISA, Western blotting, and immunofluorescence staining were performed to observe the proliferation and migration of MOVAS cells and the expression levels of related factors after drug intervention in each group. Results. In the physiological group, GXP had no significant effect on the proliferation and migration of MOVAS cells and the related factors. In the pathological group, a high dose of GXP reduced the abnormal proliferation and migration of MOVAS cells. Further, it reduced the expression levels of PI3K; inhibited the phosphorylation of Akt (protein kinase B); upregulated IκB-α levels; prevented nuclear factor kappa B (NF-κB) from entering the nucleus; downregulated the expression of interleukin 6 (IL6), IL-1β, and iNOS; and upregulated the ratio of apoptosis-related factor Bax/Bcl-2. There was no significant difference between the high-dose GXP group and the atorvastatin calcium group (negative control group). Conclusion. Our findings revealed that GXP was able to inhibit the proliferation and migration of MOVAS cells by regulating the PI3K/Akt/NF-κB pathway.
研究领域:
心脏病学
·
药理学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
Food Bioscience
·
2025
·
IF 5.9
Wenyun Xiong,Yan Zhang,Lixia Guo,Shuai Zhao,Di Zhang,Zihuan Wu,Shengbao Cai
The novel peptide LADW has umami taste characteristic, while its health benefits and gastrointestinal stability have not been investigated. This study used in vitro and in silico experiments to investigate the effects and mechanisms of this peptide on angiotensin I-converting enzyme (ACE1) and vascular function, and its gastrointestinal stability was also evaluated by a simulated digestion. Results demonstrated that LADW exhibited a good inhibitory effect against ACE1, with an IC 50 value of 28.02 ± 1.52 μM. Kinetics, isothermal titration calorimetry, and thermal shift assay revealed that LADW competitively binds ACE1, with multi-site, entropy-driven interactions and slight conformational modulation. Molecular docking and molecular dynamics simulations showed that the LADW effectively bound to the active site of ACE1 mainly through hydrogen bonding and hydrophobic interactions, stabilized the conformation of ACE1, and reduced the fluctuation of the most active amino acid residues, such as Glu411, Ala354 and Glu384. Meanwhile, the LADW promoted the nitric oxide (NO) release and inhibited the endothelin-1 (ET-1) secretion. Further analysis showed that the LADW formed strong interactions with several key proteins in the regulation of NO and ET-1 release, namely endothelial nitric oxide synthase, endothelin-converting enzyme-1 and Furin. In addition, the LADW showed a good gastrointestinal stability after a simulated gastrointestinal digestion in vitro with a retention rate of 48.37 ± 3.00 %. The findings of this study may contribute to the elucidation of the potential benefits of the peptide LADW in reducing blood pressure and safeguarding the cardiovascular system, thereby offering a foundation for further research.
研究领域:
生物化学
·
药理学
·
心血管研究
·
计算生物学
·
营养科学
✓ 已验证
产品关联
DOI
高影响因子
Bioengineered
·
2021
·
IF 3.269
Yunxin Zhang,Jianlong Liu,Wei Jia,Xuan Tian,Peng Jiang,Zhiyuan Cheng,Jinyong Li
This study is aimed at identifying the roles of AGE/RAGE and ET-1 in deep vein thrombosis (DVT). Advanced glycation end products (AGEs) in glycated human serum albumin (M-HSA) were detected by ELISA. The viability of HUVECs was examined by CCK-8 assay. Flow cytometry was performed to detect cell apoptosis, followed by ELISA for the detection of inflammatory cytokine level and oxidative stress level in HUVECs. Immunofluorescence was performed to detect ET-1 and eNOS expression. The expression of specific proteins was assayed by western blot. As a result, decreased HUVEC viability was observed after stimulation with M-HSA, whereas RAGE inhibitor improved it. Cell apoptosis showed the opposite trend. Additionally, M-HSA-induced inflammatory cytokine release and oxidative stress of HUVECs were both alleviated by RAGE inhibitor. RAGE inhibitor also increased the levels of NO and eNOS while decreasing the level of ET-1 in M-HSA-stimulated HUVECs. Furthermore, decreased protein expression of Bax, cleaved-caspase3, RAGE, p65, ET-1 and iNOS was observed after treatment with RAGE inhibitor, in addition to increased protein expression of Bcl-2 and eNOS. In conclusion, blocking AGE/RAGE pathway downregulates ET-1, thereby mitigating HUVEC damage in DVT.
研究领域:
心血管疾病
·
分子生物学
·
细胞生物学
·
血栓形成
✓ 已验证
DOI
PubMed
高影响因子
Journal of Functional Foods
·
2024
·
IF 3.8
Xiaotian Xu,Xinhui Li,Xingshu Wei,Xiaoqun Duan,Yuhui Wang
Passion fruit peel fermentation extract (PFPFE) increased gastrointestinal transport power and fecal moisture content, protected the structural integrity of colon tissue, and reduced inflammatory infiltration. PFPFE also increased secretion of the ET-1, GAS, MTL, and SP, and decreased secretion of the inhibitory SS and VIP. In addition, PFPFE alleviated perirectal redness and hemorrhage in hemorrhoid mice, and downregulated levels of the serum inflammatory factors tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β). In this study, we also analyzed the main active components and core targets of PFPFE for alleviating constipation and hemorrhoids through network pharmacology, and predicted its mechanism of action. Finally, we carried out Western blot experiments to verify that PFPFE and its active component kae alleviates constipation and hemorrhoids in mice by downregulating ESR1 and PI3K/Akt pathways. These results provide a scientific basis for the development of PFPFE as a functional food for alleviating constipation and hemorrhoids.
研究领域:
药理学
·
胃肠病学
·
分子生物学
✓ 已验证
DOI
高影响因子
Acta Pharmaceutica Sinica B
·
2024
·
IF 14.7
Makhloufi Zoulikha,Jiahui Zou,Pei Yang,Jun Wu,Wei Wu,Kun Hao,Wei He
Endothelial dysfunction is thought to be one of the early triggers of vascular remodeling during pulmonary hypertension (PH) with complex predisposing mechanisms, mainly via an unbalanced generation of vasoactive factors, increased expression of growth factors, prothrombotic elements, and inflammatory markers. Conventional treatment regimens are restricted to a single therapeutic pathway, which usually leads to limited clinical outcomes. Combination therapies targeting multiple cells and several signaling pathways are increasingly adopted in PH treatment. Herein, inspired by the cocrystal pleomorphism theory, we prepared rod-shaped nanococrystals of the endothelin-1 (ET-1) receptor antagonist (bosentan, BST) and the anti-inflammatory drug (andrographolide, AG) for targeting the pulmonary endothelium and alleviating PH. The 525 nm-sized co-delivery system displayed a rod-like morphology, preferentially accumulated in the pulmonary endothelium and alleviated pulmonary artery (PA) remodeling. A three-week treatment with the preparation significantly alleviated the monocrotaline (MCT)- or Sugen 5416/hypoxia (SuHx)-induced PH by reducing the pulmonary artery pressure, increasing the survival rate, improving the hemodynamics, and inhibiting vascular remodeling. Mechanistically, the nanococrystals collaboratively repaired endothelial dysfunction by suppressing the pathways of ET-1/NF- κ B/ICAM-1/TNF- α /IL-6. In conclusion, the cocrystal-based strategy offers a promising approach for constructing co-delivery systems. The developed rod-shaped nanococrystals effectively target the pulmonary endothelium and relieve experimental PH.
研究领域:
药理学
·
纳米技术
·
肺医学
·
心血管研究
·
治疗学
✓ 已验证
DOI
PubMed
高影响因子
MEDICAL SCIENCE MONITOR
·
2020
·
IF 1.918
Zhigang Xu,Zheng-Qin Zuo,Baibujiafu Gaowa,Yuan-Yun Gu,Chen Hui,Yong-Le Shen,Hou-Ping Xu
Background Laminaria japonica polysaccharide (LJP), a fucose enriched sulfated polysaccharide has been demonstrated to have excellent anticoagulant and antithrombotic activities. However, the antithrombotic effect of low molecular weight polysaccharide from enzymatically modified of LJP (LMWEP) remains unknown. Material/Methods LMWEP was prepared by fucoidanase enzymatic hydrolysis, and the antithrombotic and anticoagulant activities, and the underlying mechanism were investigated thoroughly. Rats were randomly divided into 6 groups (8 rats in each group): the blank control group, the blank control group treated with LMWEP (20 mg/kg), the model group, the model group treated with heparin (2 mg/kg), the model group treated with LJP (20 mg/kg), and the model group treated with LMWEP (20 mg/kg). After 7 days of intravenous administration, blood was collected for biochemical parameters examinations. Results LMWEP increased the activated partial thromboplastin time (APTT), thrombin time (TT), prothrombin time (PT), 6-keto prostaglandin F1α (6-Keto-PGF1α), and endothelial nitric oxide synthase (eNOS). In addition, LMWEP decreased fibrinogen (FIB), endothelin-1 (ET-1), thromboxane B2 (TXB2), erythrocyte sedimentation rate (ESR), and hematocrit (HCT). Conclusions LMWEP, an enzymatically modified fragment with a molecular weight of 25.8 kDa, is a potential antithrombotic candidate for treatment of thrombosis related diseases.
研究领域:
药理学
·
生物化学
·
血栓研究
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）