JOURNAL OF HYPERTENSION
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2025
·Vol. 43
·期 5
·827
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IF 4.1
Tang Liang-Liang,Xu Xin-Yu,Zhang Mei,Qin Qi,Xue Rong,Jiang Shuai,Yang Xu,Liang Chen,Wang Qiu-Shi,Yu Chang-Jiang,Zhang Zhi-Ren
Background and purpose: Ponatinib, a tyrosine kinase inhibitor (TKI) leads to hypertension; however, the mechanisms remain elusive. We aimed to investigate whether lysine acetyltransferase 7 (KAT7), a key regulator of cellular senescence that is closely associated with cardiovascular diseases, involves in ponatinib-induced hypertension. Methods and results: After administering ponatinib to Sprague–Dawley (SD) rats for 8 days, we measured blood pressure, vasodilation, and endothelial function using tail-cuff plethysmography, isometric myography, and the Total NO Assay kit, respectively. The results indicated that ponatinib increased blood pressure, impaired endothelium-dependent relaxation (EDR), and caused injury to endothelial cells in SD rats. Furthermore, PCR and Western blot experiments demonstrated an upregulation of KAT7 expression in rat mesenteric artery endothelial cells (MAECs) following ponatinib treatment. To further study the role of KAT7 in ponatinib-induced hypertension, we divided the SD rats into four groups: control, ponatinib, WM-3835 (a KAT7 inhibitor), and ponatinib plus WM-3835. Notably, WM-3835 administration significantly improved ponatinib-induced hypertension and EDR dysfunction in SD rats. Mechanistically, over-expression of KAT7 (OE-KAT7) in MAECs led to cellular senescence and inflammation, phenomena that were also observed in the mesenteric arteries of ponatinib-treated rats and in MAECs exposed to ponatinib. However, WM-3835 mitigated these detrimental effects in both in vivo and in vitro experiments. Additionally, both OE-KAT7 and ponatinib treatment induced H3K14 acetylation (H3K14ac), with OE-KAT7 also elevating the recruitment of the H3K14ac to the p21 promoter. Moreover, BAY 11-7085, a nuclear factor (NF)-κB inhibitor, potently alleviated the accumulation of IL-6 and IL-8, as well as endothelial cell senescence induced by ponatinib and KAT7 overexpression. Conclusion: Our data indicate that ponatinib-induced elevation of KAT7 led to endothelial cells senescence and inflammatory responses through H3K14 acetylation and NF-κB signaling pathway, subsequently caused vasotoxicity and hypertension.
研究领域:
心血管药理学
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分子生物学
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病理生理学
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Qingqi Zhou,Xun Li,Decai Hou
Background Osteoarthritis (OA) is an age-related progressive joint disease characterized by loss of cartilage and subsequent inflammation. Perillaldehyde is a compound extracted from Perilla , which has multiple pharmacological activities including anti-inflammatory, and anti-apoptosis. However, it still remains unknown whether and how perillaldehyde could regulate chondrocyte apoptosis and inflammation in OA. Methods The interleukin-1beta (IL-1β)-treated chondrocytes and destabilized medial meniscus (DMM) -induced rats were used as in vitro and in vivo models of OA. Cell viability, proliferation, and apoptosis were investigated by cell counting kit-8 (CCK-8), 5-ethynyl-2′-deoxyuridine (EdU) and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assays. The mitochondrial membrane potential was analyzed by 5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolylcarbocyanine iodide (JC-1) staining. Light chain 3 (LC3) location, and expression of NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) and apoptosis-associated speck-like protein (ASC) were detected by immunofluorescence staining. Relative protein levels were measured via western blotting. Tumor necrosis factor-alpha (TNF-α), IL-6 and IL-8 levels were measured by enzyme-linked immunosorbent assay (ELISA). The cartilage injury in rats was investigated via hematoxylin-eosin (HE) staining. Results Perillaldehyde attenuated IL-1β-induced inhibition of viability (from 44.45 % to 92.72 %, p < 0.05) and proliferative potential of chondrocytes ( p < 0.05). Perillaldehyde mitigated mitophagy-associated apoptosis of chondrocytes by enhancing mitophagy ( p < 0.05) and reducing cell apoptosis (from 32.36 % to 8.00 %, p < 0.05). Perillaldehyde attenuated NLRP3-mediated inflammation through reducing NLRP3, ASC, TNF-α, IL-6 and IL-8 levels ( p < 0.05). ALOX5 expression was upregulated in OA (fold change: 2.61, p < 0.05), and decreased by perillaldehyde treatment (fold change: 1.34, p < 0.05). Perillaldehyde inhibits p65 nuclear factor kappa B (NF-κB) signaling activation (fold change: 3.19 to 1.33, p < 0.05) by regulating ALOX5 expression. ALOX5 overexpression reversed the effects of perillaldehyde on mitophagy-associated apoptosis and NLRP3-mediated inflammation ( p < 0.05), and these roles were mitigated due to NF-κB inactivation ( p < 0.05). Perillaldehyde attenuated cartilage injury in OA rats ( p < 0.05). Conclusion Perillaldehyde attenuated IL-1β-induced mitophagy-associated apoptosis and NLRP3-mediated inflammation through decreasing ALOX5 and inactivating NF-κB signaling, indicating the potentially protective potential of perillaldehyde in osteoarthritis.
研究领域:
医学
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药理学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF HYDROGEN ENERGY
·
2019
·
IF 4.084
Ying Li,Hui Su,Jianpeng Fu,Xiaoqiang Du
In recent years, the exploration of efficient and stable noble-metal-free electrocatalysts is becoming increasingly important, used mainly for oxygen evolution reaction (OER) and hydrogen evolution reaction (HER). In this work, a new ultrathin porous Cu 1-x Ni x S/NF nanosheets array was constructed on the 3D nickel skeleton by two-step method: hydrothermal method and vulcanization method. Through these two processes, Cu 1-x Ni x S/NF has a larger specific surface area than that of foamed nickel (NF) and Cu 1-x Ni x O/NF. The Cu 1-x Ni x S/NF materials show excellent catalytic activity by accelerating the electron transfer rate and increase the amount of H 2 and O 2 produced. The lower overpotential was obtained only 350 mV at 20 mA cm −2 for OER, not only that, but also the same phenomenon is pointed out in HER, optimal Cu 1-x Ni x S/NF presents low overpotentials of 189 mV to reach a current density of 10 mA cm −2 in 1.0 M KOH for HER. Both OER and HER shows a lower Tafel slope: 51.2 mV dec −1 and 127.2 mV dec −1 , subsequently, the overall water splitting activity of Cu 1-x Ni x S/NF was investigated, and the low cell voltage was 1.64 V (current density 10 mA cm −2 ). It can be stable for 14 h during the overall water splitting reaction. These results fully demonstrate that Cu 1-x Ni x S/NF non-precious metal materials can be invoked become one of the effective catalysts for overall water splitting, providing a richer resource for energy storage.
研究领域:
材料科学
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能源化学
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DOI
高影响因子
CELLULAR ONCOLOGY
·
2021
·Vol. 44
·期 3
·557-568
·
IF 6.73
Wang Wanyue,Li Xin,Xu Ye,Guo Weikang,Yu Hui,Zhang Lu,Wang Yaoxian,Chen Xiuwei
Purpose Cervical cancer remains a major cause of cancer-related death in women, especially in developing countries. Previously, we found that the acetylation levels of chloride intracellular channel 1 (CLIC1) at lysine 131 were increased in cervical cancer tissues using a label-free proteomics approach. The aim of this study was to further determine the role of CLIC1 expression and its acetylation in cervical cancer. Methods CLIC1 expression and its implications for the prognosis of cervical cancer were analyzed using primary patient samples and cells, and the Gene Expression Profiling Interactive Analysis (GEPIA) database (gepia.cancer-pku.cn). The effect of CLIC1 on cervical cancer cells was evaluated using Cell Counting Kit (CCK)-8, flow cytometry, scratch wound healing, transwell, Western blotting and co-immunoprecipitation (Co-IP) assays. In vivo tumor growth was assessed using mouse xenograft models. Results We found that CLIC1 expression was increased in cervical cancer tissues and cells and that patients with a high CLIC1 expression tended to have a shorter overall survival time. Knockdown of CLIC1 significantly reduced in vitro cervical cancer cell proliferation, migration and invasion, and in vivo tumorigenesis. At the molecular level, we found that nuclear factor kappa B (NF-κB) activity was positively regulated by CLIC1. Pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-κB, attenuated the tumor-promoting effect of CLIC1. Moreover, we found that CLIC1 acetylation at K131 was upregulated in cervical cancer cells, which stabilized CLIC1 by inhibiting its ubiquitynation. Substitution of K131 inhibited CLIC1 ubiquitynation and promoted in vitro cervical cancer cell proliferation, migration and invasion, and in vivo tumor growth. In addition, we found that acetyltransferase HAT1 was responsible for CLIC1 acetylation at K131. Conclusion Our data indicate that CLIC1 acts as a tumor promoter in cervical cancer, suggesting a potential treatment strategy for cervical cancer by regulating CLIC1 expression and/or acetylation.
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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DOI
PubMed
高影响因子
FASEB JOURNAL
·
2020
·Vol. 34
·期 6
·8671-8685
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IF 4.966
Jie Cai,Diming Wang,Shulin Liang,Jinrong Peng,Fengqi Zhao,Jianxin Liu
During lactation, an improper glucose supply often threatens mammary gland (MG) health. However, information is limited on the metabolic trajectories and molecules that regulate lactating MGs with an excessive glucose supply. Based on the network analysis of transcriptome and microRNAs, we found that the oversupply of glucose-induced severe glucose metabolic disorders in MGs of lactating goats, shifting lactose synthesis to acute fermentative glycolysis which caused increased flux of glucose metabolism into lactate. Moreover, NF-κB2 played a key role in regulating glycolysis, exhibiting a metabolic shift when MGs had an excessive supply of glucose. In primary mammary epithelial cells, fermentative glycolysis, and intracellular concentration of reactive oxygen species (ROS) were reduced by ganoderic acid A through blocking NF-κB2, while activation of NF-κB2 with phorbol myristate acetate (PMA) upregulated fermentative glycolysis and increased cellular ROS accumulation under excessive glucose. Thus, we established an NF-κB2-targeting method to reform the metabolic shift toward glycolysis caused by glucose oversupply by integrating NF-κB2 blockade and intracellular ROS scavenging.
研究领域:
动物生理学
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分子生物学
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营养学
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DOI
PubMed
高影响因子
Archives of Medical Science
·
2020
·
IF 2.807
Ning Xu,Lili Wang,Shiping Fu,Bin Jiang
Introduction Osteosarcoma is the most common primary malignancy of the bone. The existing adjuvant chemotherapy regimens, while improving the overall survival, have been limited by the significant systemic toxicity. Substantial clinical and research efforts are being invested to develop novel pharmaceutical agents. Resveratrol (Res) has been suggested to have a chemopreventive effect. However, the mechanism of Res in osteosarcoma remains to be elucidated. Material and methods The MG-63 osteosarcoma cell culture model was used to investigate the chemotherapeutic effect of Res. MTT assay, wound healing assay, and Transwell migration assay were used to document the effect of Res on cell proliferation, migration, and invasion, respectively. Apoptosis in MG-63 cells was quantified with the TUNEL assay. Western blotting analysis was used to examine the molecular changes following Res treatment. Data processing and analysis were conducted using GraphPad Prism 5.0. P < 0.05 was considered statistically significant. Results Our data suggested that Res blocks cell proliferation, migration, and invasion, and activates apoptotic cell death in osteosarcoma MG-63 cells. We found that Res potentially down-regulates nuclear factor κB (NF-κB) and Akt intracellular signaling transduction. Moreover, the combination of Res and pyrrolidine dithiocarbamate (PDTC), an NF-κB inhibitor, resulted in synergistic growth inhibition of osteosarcoma. Conclusions Our in vitro preclinical study in the MG-63 cell line model supports the translation of Res to the clinical management of patients with osteosarcoma.
研究领域:
肿瘤学
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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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产品关联
DOI
PubMed
高影响因子
IMMUNOPHARMACOLOGY AND IMMUNOTOXICOLOGY
·
2022
·
IF 3.712
Haihua Zhang,Wuying Lang,Sufen Li,Chao Xu,Xiumin Wang,Yunyu Li,Zhiqiang Zhang,Tonglei Wu,Minshan Feng
Objective Corynoline is an active substance extracted from Corydalis bungeana Turcz and exerts a therapeutic effect in multiple diseases by alleviating inflammatory response. The present study sought to elucidate the role of corynoline in ulcerative colitis (UC).Methods The experimental colitis models were induced in BALB/c mice via receiving a drinking water supplemented with 3.5% (I) dextran sulfate sodium (DSS) ad libitum for 7 days.Results Corynoline administration inhibited body weight loss, colon shortening, disease activity index and colonic pathomorphological changes in DSS-treated mice. Besides, corynoline down-regulated the levels of pro-inflammatory interleukin (IL)-1β, IL-6 and tumor necrosis factor Alpha (TNF-α), as well as decreased myeloperoxidase (MPO) activity in the colon of DSS-treated mice. In addition, severe oxidative stress in the colonic tissues of DSS-treated was mitigated by corynoline treatment. However, these beneficial effects were reversed by a specific nuclear factor E2-related factor 2 (Nrf2) inhibitor ML385 intervention. Further evidence confirmed that corynoline promoted Nrf2 nuclear migration and heme oxygenase-1 gene expression in the colonic tissues of UC mice. Besides, corynoline treatment restrained colonic nuclear factor-kappa B (NF-κB) activation as proved by the decrease in phosphorylation and nuclear translocation of NF-κB.Conclusions Corynoline ameliorates DSS-induced mouse colitis, which may provide a promising therapeutic strategy for UC treatment.
研究领域:
药理学
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免疫学
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胃肠病学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF PERIODONTAL RESEARCH
·
2024
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IF 3.4
Siying Xia,Rui Jing,Mingyan Shi,Yanan Yang,Meiting Feng,Li Deng,Lijun Luo
Background and Objective Periodontitis is intimately associated with the development of various systemic diseases, among which type 2 diabetes mellitus (T2DM) has a bidirectional relationship with the pathogenesis of periodontitis. The objective of the present work was to investigate the role of berberine (BBR) in periodontitis with T2DM and related mechanisms. Methods The mRNA expression of macrophage polarization-related factors in the microenvironment of periodontal inflammation was detected using real-time quantitative PCR (RT-qPCR). The experimental periodontitis model was constructed in wild-type (WT) and T2DM ( db/db ) mice, which were administered BBR after 7 days of modeling. Alveolar bone loss (ABL) in each group of mice was measured utilizing micro-computed tomography images. RT-qPCR was performed to analyze the levels of macrophage polarization-related factors in mouse gingiva. Lastly, using western blotting and RT-qPCR, the signaling pathway of BBR affecting macrophage polarization in the microenvironment of periodontitis was explored. Results BBR inhibited M1 polarization and stimulated M2 polarization in the periodontitis microenvironment. BBR decreased ABL in the WT and T2DM periodontitis models. And BBR reduced the production of proinflammatory cytokines and increased anti-inflammatory cytokine expression in the gingiva of WT and T2DM model mice. Ultimately, BBR mediates its anti-inflammatory effects on periodontitis through inhibition of the NF-κB pathway. Conclusions BBR had a therapeutic effect on T2DM-associated periodontitis via inhibiting the NF-κB pathway to affect macrophage polarization, which may have implications for the new pharmacological treatment of T2DM-associated periodontitis.
研究领域:
药理学
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牙医学
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免疫学
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分子生物学
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DOI
PubMed
高影响因子
PULMONARY PHARMACOLOGY & THERAPEUTICS
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2021
·
IF 3.41
Bo Zou,Yue Fu,Chaofan Cao,Dianzhu Pan,Wei Wang,Lingfei Kong
Allergic asthma is a common airway inflammatory disorder with increasing morbidity and mortality worldwide. Gentiopicroside (GPS) is a secoiridoid glycoside compound that exhibits anti-inflammatory property. However, the effect of GPS on allergic asthma has not been reported yet. In this study, we investigated the role of GPS in a mouse model of ovalbumin (OVA)-induced allergic asthma and explored its potential mechanism. Mice were sensitized with OVA and gavaged with 20, 40, or 80 mg/kg GPS. Administration of GPS decreased lung wet-to-dry weight ratio. Histological analysis of H&E and PAS staining showed that GPS treatment alleviated inflammatory cell infiltration and goblet cell hyperplasia in lung tissue of OVA-sensitized mice. Moreover, GPS inhibited the recruitment of inflammatory cells including total cells, macrophages, eosinophils , lymphocytes and neutrophils and the secretion of T helper type 2 (Th2) cytokines (interleukin (IL)-4, IL-5 and IL-13) in bronchoalveolar lavage fluid (BALF) of OVA-sensitized mice in a dose dependent manner. The levels of OVA-specific immunoglobulin E (IgE) and pro-inflammatory tumor necrosis factor (TNF)-α were also attenuated by GPS treatment. Interestingly, GPS upregulated the expression of silent information regulator 1 (SIRT1) while downregulated the expression of acetyl-nuclear factor kappa B (NF-κB) p65 in lung tissue of OVA-sensitized mice. Furthermore, treatment with an SIRT1 inhibitor (EX-527) partially abolished the inhibitory effect of GPS on OVA-induced airway inflammation, suggesting that the anti-inflammation of GPS might be achieved through regulating SIRT1/NF-κB p65 signaling pathway . These findings indicate that GPS might be a novel drug candidate in the treatment of allergic asthma.
研究领域:
免疫学
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药理学
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呼吸医学
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DOI
PubMed
高影响因子
INFLAMMATION
·
2020
·Vol. 44
·期 2
·746-757
·
IF 3.212
Gao Yang,Kang Kai,Liu Yan-song,Li Na-na,Han Qiu-yuan,Liu Hai-tao,Kong Wei-lan,Zhang Xing,Huang Rui,Yang Zhen-yu,Qi Zhi-dong,Zheng Jun-bo,Li Ming,Wang Hong-liang,Li Jia-yu,Liu Rui-jin,Wang Si-cong,Zhang Wei-hua,Zhao Ming-yan,Yu Kai-jiang
This study aimed to investigate the effect of splenectomy on dexmedetomidine-activated cholinergic anti-inflammatory pathway-mediated alleviation of LPS-induced AKI. A mouse model of septic kidney injury was established in C57BL/6 mice. A total of 30 C57BL/6 mice were randomly divided into the control group, LPS group, dexmedetomidine + LPS group, splenectomy group, splenectomy + LPS group, and splenectomy + dexmedetomidine + LPS group. The pathological effects in kidney tissues in each group were analyzed by HE staining. Apoptosis in each group was examined by the TUNEL method. Cr and Cys-C levels in each group were measured by ELISA. The expression levels of IL-6, NF-κB p65, Caspase-3, the antiapoptotic protein Bcl-2, the proapoptotic protein Bax, and α7nAChR in each group were measured by qRT-PCR and Western blotting. Dexmedetomidine alone reduced apoptosis in kidney tissue; however, apoptosis was increased after splenectomy in mice treated with dexmedetomidine. Splenectomy reduced the production of proinflammatory cytokines in circulation and had a protective effect on the kidney. Splenectomy inhibited dexmedetomidine-mediated activation of the α7nAChR pathway. Dexmedetomidine effectively alleviated LPS-induced kidney injury, and splenectomy inhibited the anti-inflammatory, antiapoptotic, and renoprotective effects of dexmedetomidine. The kidney-spleen axis is mediated by the α7nAChR-NF-κB signaling pathway and is involved in the development of AKI.
研究领域:
肾病学
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免疫学
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药理学
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产品关联
DOI
PubMed
高影响因子
Cancer Management and Research
·
2020
·
IF 2.886
Weixu Luo,Yuanshan Han,Pan Meng,Qin Yang,Hongqing Zhao,Jia Ling,Yuhong Wang
Background Breast cancer is one of the most common cancer with high risk in females all over the world. It is usually complicated with depression, which can further accelerate the development and progression of breast tumors. We aim to identify a new drug and identify its functional mechanism in the regulation of hippocampal microglia (MG) in breast cancer complicated with depression (BCCD). Methods The activation model of MG was established by treatments from corticosterone (CORT) or lipopolysaccharides (LPS). The inhibitory effects of resatorvid on MG were investigated by CCK-8, ROS, immunofluorescence, TUNEL, scratch test, ELISA, RT-qPCR and Western blot. BCCD animal model was established using 4T1 inflammatory breast cancer cells and CORT treatment in vitro. Open field experiment (OFE), tail suspension test (TST), ELISA, RT-qPCR and Western blot experiments were utilized to examine the effects of resatorvid on the animal model in vivo. Results The cell viability and migration ability of the BCCD model group were suppressed. The expressions of inflammatory factors, ROS, and the apoptotic rate of the BCCD model group were up-regulated, in contrast to the control group. The expressions related to the TLR4/NF-κB/NLRP3 signaling in the BCCD model group were also elevated. Resatorvid reversed the above changes, which showed good therapeutic effects in depression-related behavioral changes, tumor treatment, and blood–brain barrier function. Conclusion In summary, resatorvid inhibited the activation of hippocampal MG in BCCD by regulating TLR4/NF-κB/NLRP3 signaling pathway.
研究领域:
肿瘤学
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神经科学
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药理学
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
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2022
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IF 5.988
Lei Jin,Xiang Peng,Zeng Shengmei,Chen Le,Zhang Lei,Yuan Zhiyi,Zhang Jun,Wang Tingting,Yu Ruihong,Zhang Wanping,Ibrahim Issa Issoufou,Ma Limei,Yu Chao
Tetramethylpyrazine (TMP), a Chinese traditional herbal extraction widely used in treating cardiovascular diseases, could attenuate vascular endothelial injuries, but the underlying mechanism remains incomprehensive. Vascular glycocalyx coating on the endothelium would be damaged and caused endothelial dysfunction in the inflammatory microenvironment, which was the initial factor of morbidity of many vascular diseases, such as atherosclerosis (AS). Here, we thoroughly investigated the molecular mechanism of TMP on vascular endothelial glycocalyx in the LPS-induced inflammatory model both in vitro and in vivo. Results showed that pretreatment with TMP significantly inhibited glycocalyx degradation and monocytes adhesion to the endothelial process. Moreover, TMP pretreatment inhibited the expression of HPSE1 (a major degrading enzyme of endothelial glycocalyx), Toll-like receptor 4 (TLR4), and the translocation of nuclear factor kappa B p65 (NF-κB p65). We were utilized withTLR4 siRNA, NF-κB inhibitor, and HPSE1 overexpression analysis confirmed TMP’s protection on endothelial glycocalyx injury, which further contributed to the monocyte-endothelial adhesion process. It was indicated that TMP might suppress glycocalyx degradation through TLR4/NF-κB/HPSE1 signaling pathway. Taken together, our results enriched the occurrence molecular mechanism of glycocalyx shedding and molecular regulation mechanism of TMP in protecting integrity of the glycocalyx structure during inflammation. As TMP is currently used in clinical applications, it may be considered a novel strategy against atherosclerosis through its ability to protect endothelial glycocalyx.
研究领域:
心血管疾病
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分子生物学
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药理学
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炎症研究
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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）