Journal of Orthopaedic Surgery and Research
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2021
·Vol. 16
·期 1
·1-9
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IF 2.359
Zhang Hongxia,Wu Guangsheng,Feng Junjian,Lu Xiaohong,Liu Ping
Background This study aimed to investigate the effects of STOML2 and the relationship between STOML2 and PAI-1 in the development of multiple myeloma (MM). Methods Cell proliferation was tested using CCK-8 assay and cell colony formation assay. Glucose consumption, lactate production and ATP level were measured using commercial kits. The mRNA and protein expression were assessed using quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting, respectively. Results Both mRNA and protein expression of STOML2 were upregulated in MM patients compared to healthy volunteers. CCK-8 and colony formation assays demonstrated that STOML2 silencing inhibited cell proliferation in MM cells. Knockdown of STOML2 reduced glucose consumption, lactate production and ATP/ADP ratios. STOML2 silencing by shSTOML2 led to reduced PAI-1 expression. Overexpression of PAI-1 reversed the inhibitory effects of shSTOML2 on MM cell growth. Conclusion Results from this study demonstrated that STOML2 silencing inhibits cell proliferation and glycolysis through downregulation of PAI-1 expression, suggesting a new therapeutic target for MM.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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PubMed
高影响因子
Evidence-based Complementary and Alternative Medicine
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2022
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IF 2.65
Fei Kong,Meng Zhao
Myocardial ischemia/reperfusion (MI/R) injury is a common clinical problem after myocardial infarction without effective therapy. Loureirin B (LrB) is a kind of flavonoid with anti-inflammatory and antifibrotic activities. However, the effect of LrB on MI/R and its underlying mechanism remains elusive. In the present study, a mouse model of MI/R was established by coronary artery occlusion. Administration of LrB (0.5 mg/kg or 1 mg/kg) for 4 weeks effectively improved left ventricular (LV) function and reduced myocardial infarction in MI/R mice. MI/R-induced expression of IL-6, TNF-α, and IL-1β in the hearts was reduced by LrB treatment. Histological analysis showed that LrB attenuated myocardial collagen deposition. LrB downregulated fibronectin, collagen I, collagen III, and α-SMA expression. Notably, LrB inhibited the expression of profibrotic plasminogen activator inhibitor-1 (PAI-1), transforming growth factor (TGF)-β1, TGF-β1R, and p-Smad2/3. Consistently, LrB inhibited the activation of TGF-β1/Smad signaling pathway and the expression of fibrosis-related proteins in angiotensin (Ang) II-treated cardiac fibroblasts (CFs). Overexpression of PAI-1 abolished the effects of LrB on Ang II-treated CFs, suggesting that LrB may function through regulating PAI-1. These results indicated that LrB may alleviate MI/R-induced myocardial fibrosis by inhibiting PAI-1/TGF-β1/Smad signaling pathway. Thus, LrB may be a potential drug in the treatment of MI/R injury.
研究领域:
心脏病学
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药理学
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分子生物学
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病理生理学
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PubMed
高影响因子
Acta Pharmaceutica Sinica B
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2022
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IF 14.903
Jingwen Dong,Chenfei Zhu,Ying Huang,Quanhao Li,Jing Li,Zheng Wang,Yixin Wang,Zhanwei Zhou,Minjie Sun
Fibrosis is one of the key factors that lead to the immune exclusion of solid tumors. Although degradation of fiber is a promising strategy, its application was still bottlenecked by the side effects of causing metastasis, resulting in the failure of immunotherapy. Here, we developed an antimetastatic polymer (HPA) for the delivery of chemo-drug and antifibrotic siPAI-1 to form the nano-permeator. Nano-permeator shrank after protonation and deeply penetrated into the tumor core to down-regulate the expression of PAI-1 for antifibrosis, and further promoted the sustained infiltration and activation of T cells for killing tumor cells. Moreover, metastasis after fiber elimination was prevented by multivalent CXCR4 antagonistic HPA to reduce the attraction of CXCL12 secreted by distant organs. The administration of stroma-alleviated immunotherapy increased the infiltration of CD8 + T cells to 52.5% in tumor tissues, inhibiting nearly 90% metastasis by HPA in distant organs. The nano-permeator reveals the mechanism and correlation between antifibrosis and antimetastasis and was believed to be the optimizing immunotherapy for solid fibrotic tumors.
研究领域:
癌症生物学
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免疫治疗
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药学
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纳米技术
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PubMed
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MICROVASCULAR RESEARCH
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2025
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IF 2.7
Xiao Xu,Xiaohu Ge,Hongbo Ci,Maitiseyiti Abulaihaiti,JianPing Yang,YangYang Li,Feng Zhu
Background Thromboangiitis obliterans (TAO, Buerger's disease) is a chronic inflammatory disorder that affects small and medium-sized vessels in the limbs. Although the pathogenesis of TAO remains incompletely understood, elevated levels of plasminogen activator inhibitor-1 (PAI-1) have been associated with cardiovascular diseases. This study investigates the mechanism by which PAI-1 activates the NF-κB/NLRP3 inflammatory pathway in vascular endothelial cells through hypoxia-inducible factor-1α (HIF-1α), contributing to the progression of TAO. Methods Proteomic analysis was performed on plasma samples from 5 TAO patients and 5 healthy controls to identify differentially expressed proteins (DEPs). In vitro, human umbilical vein endothelial cells (HUVECs) were subjected to 1 % hypoxia to mimic TAO conditions. Interventions included PAI-1 knockdown using lentiviral vectors and treatment with the HIF-1α agonist dimethyloxalylglycine (DMOG). Cell viability was assessed using the CCK-8 assay, apoptosis was measured by flow cytometry, and inflammatory factor levels were detected by enzyme-linked immunosorbent assay (ELISA). Protein expression was analyzed by Western blotting. In vivo, a TAO rat model was established by sodium laurate injection. The severity of limb ischemia was evaluated using gross lesion grading and infrared thermography, while pathological changes were assessed by hematoxylin and eosin (H&E) staining and Masson's trichrome staining. Results Elevated levels of PAI-1, HIF-1α, and key molecules in the NLRP3/NF-κB pathway were observed in both TAO rats and hypoxic HUVECs. PAI-1 knockdown significantly improved limb ischemia and suppressed the NLRP3/NF-κB pathway in TAO rats. Compared with the DMOG intervention group, combined treatment with PAI-1 knockdown and DMOG effectively alleviated ischemic symptoms, increased body weight, and reduced the expression of HIF-1α and inflammatory pathway molecules in TAO rats. Conclusion PAI-1 promotes the progression of TAO by activating the NF-κB pathway via HIF-1α. Targeted inhibition of PAI-1 represents a potential therapeutic strategy for TAO.
研究领域:
心血管医学
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分子生物学
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炎症研究
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血管生物学
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PubMed
高影响因子
Molecular Medicine Reports
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2023
·Vol. 29
·期 1
·1-17
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IF 3.4
Yao Zhao,Mirensha Yakufu,Chong Ma,Baicai Wang,Jianhua Yang,Junping Hu
Nonalcoholic steatohepatitis (NASH) is emerging as the primary driver of liver disease‑induced fibrosis. The imperative need for noninvasive biomarkers to ascertain disease progression stage is evident. The present study elucidated the biological roles of hub genes that could potentially serve as diagnostic markers for NASH. Using an in vivo approach, C57BL/6J mice were subjected to a high‑fat and fructose diet (HFFD) for 6, 10, 14, 18 or 22 weeks. Serological biochemical indices were assessed and liver specimens were obtained to identify potential markers linked to the NASH process, employing a comprehensive strategy that combined transcriptomic and histopathological analyses. The HFFD regimen induced hyperlipidemia, obesity and insulin resistance, progressively culminating in NASH with fibrosis over time. The transcriptomic analyses indicated temporal patterns of pivotal gene sets intricately connected to NASH progression, which encompassed processes such as glucose homeostasis, inflammatory responses, reactive oxygen species‑mediated damage, lipid metabolism disruptions and the formation of fibrotic tissue. Among these genes, Serpine1 and Mmp9 demonstrated promising diagnostic potential for NASH, with their intrahepatic mRNA expression levels serving as robust indicators. Moreover, the levels of PAI‑1 (encoded by the Serpine1 gene) and MMP‑9 in the serum of mice demonstrated a parallel increase with the duration of HFFD intervention. In vitro experiments utilizing HepG2 cells further validated these findings, demonstrating a significant elevation in the protein expression levels of both PAI‑1 and MMP‑9 upon exposure to free fatty acids, in agreement with the results of the animal study. Consequently, PAI‑1 and MMP‑9 are promising noninvasive biomarkers for assessing the progression of NASH.
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JOURNAL OF ETHNOPHARMACOLOGY
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2021
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IF 4.36
Pu-Yang Gong,Yu-Jie Guo,Yu-Shan Tian,Li-Fei Gu,Jin Qi,Bo-Yang Yu
Ethnopharmacological relevance In traditional Chinese medicine (TCM) and modern pharmacodynamics , dried Rehmannia Radix (DRR) possesses prominent anti-thrombotic activity that decreases after processing by nine steaming and drying cycles to develop processed Rehmannia Radix (PRR). Due to the complexity of the DRR components, the chemical mechanism leading to efficacy changes of DRR caused by processing is still unclear. Aim of study This study aimed to trace the anti-thrombotic active compounds of DRR and different degrees of processed RR (PRR) and to evaluate the synergistic effects among different active components. Materials and methods The anti-thrombotic active chemical fraction of DRR extracts was evaluated. Targeted fractions of the processed products of RR were prepared at different processing stages. The changes in monosaccharides , oligosaccharides and secondary metabolites during processing were characterized by multidimensional high-performance liquid chromatography (HPLC). The anti-thrombotic effects of targeted fractions of different RR samples were evaluated by analyzing the length of tail thrombus (LT) and serum biochemical indicators in carrageenan-induced tail-thrombus mice. The spectrum-effect relationships were investigated by partial least squares regression (PLSR) analysis and gray correlation analysis (GRA). Finally, the active compounds were screened by spectrum-effect relationship analysis and validated in vivo , and their synergistic effects were determined by Webb's fraction multiplication method. Results Six ingredients highly associated with anti-thrombotic activities were screened out by the spectrum-effect relationship analysis, of which oligosaccharides (stachyose, sucrose and raffinose) and iridoid glycosides (catalpol, leonuride and melitoside) possessed a synergistic effect on tumor necrosis factors (TNF-α), interleukin 1β (IL-1β) and plasminogen activator inhibitor 1 (PAI-1)/tissue-type plasminogen activator (t-PA) ratio in vivo with synergistic coefficient (SC) > 1. Conclusion The main material basis of the anti-thrombotic activities of DRR is oligosaccharide components of stachyose, raffinose and sucrose, iridoid glycosides components of catalpol , leonuride and melittoside. The two kinds of components exert synergistic anti-thrombotic effects by inhibiting the expression of inflammatory factors and regulating the balance of the fibrinolysis system.
研究领域:
民族药理学
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药理动力学
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传统中药
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化学分析
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血栓研究
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生物统计学
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PubMed
高影响因子
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