FITOTERAPIA
·
2023
·
IF 3.4
Bike Zhang,Dan Su,Yonggui Song,Huizhen Li,Changlian Chen,Liangliang Liao,Hongjie Zhang,Jian Luo,Ming Yang,Genhua Zhu,Zhifu Ai
Phytochemical investigation of the volatile oil of Yueju (YJVO) and its constituent herbs induced the detection of 52 compounds in YJVO, mainly monoterpenes and sesquiterpenes as well as a small amount of aromatic and aliphatic compounds. 5 of these compounds were found only in the YJVO instead of the volatile oil of its constituent herbs. The anti-depressant effect of YJVO was proved by behavioral tests in chronic unpredictable mild stress (CUMS) mice. An acute oral toxicity evaluation determined the LD 50 of YJVO was 5.780 mL/kg. Doppler ultrasound and laser speckle imaging have detected that the YJVO could improve depression-related cerebral blood flow. In addition, related neurotransmitters and proteins were analyzed through targeted metabolomics and immunofluorescence. The potential antidepressant mechanisms of YJVO related to significantly decreasing Glu in CUMS mice by up-regulating the ERK/AKT-mediated expression of GLT-1.
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Journal of Applied Biomedicine
·
2023
·Vol. 21
·期 4
·193-199
·
IF 1.3
Hongji Wang,Lisha Chen,Juping Xing,Xiangchao Shi,Changshui Xu
Naringin inhibits inflammation and oxidative stress, the P2 purinoreceptor X4 receptor (P2X4R) is associated with glial cell activation and inflammation, the purpose of this study is to investigate the effects of naringin on P2X4 receptor expression on satellite glial cells (SGCs) and its possible mechanisms. ATP promoted the SGC activation and upregulated P2X4R expression; naringin inhibited SGC activation, decreased expression of P2X4R, P38 MAPK/ERK, and NF-κB, and reduced levels of Ca2+, TNF-α, and IL-1β in SGCs in an ATP-containing environment. These findings suggest that naringin attenuates the ATP-induced SGC activation and reduces P2X4R expression via the Ca2+-P38 MAPK/ERK-NF-κB pathway.
研究领域:
神经科学
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药理学
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细胞生物学
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炎症研究
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JOURNAL OF THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM
·
2025
·
IF 4.1
Lu-an Weng,Luojun Zheng,Dengke Meng,Xin Zhang,Diwen Shou
BackgroundIncreasing evidence suggests that herbal-derived exosome-like nanoparticles (ELNs) can easily cross biological barriers such as the blood-brain barrier (BBB). However, current understanding of ELNs application in ischemic stroke therapy is still in its infancy.MethodWe extracted nanoparticles (TGD-NPs) from Tianma Gouteng decoction (TGD) and characterized their morphology and main active compounds. Subsequently, the potential and functional mechanism of TGD-NPs in maintaining the integrity of the BBB were evaluated in middle cerebral artery occlusion (MCAO)-induced ischemic stroke model and oxygen-glucose deprivation/reperfusion (OGD/R)-stimulated cell model.ResultWe successfully extracted NPs, which retains the main bioactive compounds of TGD: baicalin, emodin, gastrodin, and stachydrine. Functional studies indicated that in mouse MCAO model, TGD-NPs intervention was more effective than TGD preparations in maintaining the integrity of the BBB, reducing the infarct area, and improving the neurological function. Meanwhile, TGD-NPs treatment attenuated the decrease in cell viability caused by OGD/R, and it significantly enhanced expression of tight junction proteins (Occludin and ZO-1). Mechanistic exploration revealed that TGD-NPs markedly upregulated lncRNA OIP5-AS1 expression, and its beneficial effect was attributed to the activation of the S1PR1-ERK1/2-MEK1/2 signaling axis.ConclusionTGD-NPs are positive in maintaining BBB integrity and neurological function after ischemic stroke.
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ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH
·
2023
·Vol. 30
·期 32
·79423-79436
·
IF 5.8
Zhang Jingni,Wang Hongjuan,Chen Huan,Liu Yong,Wang An,Hou Hongwei,Hu Qingyuan
Long-term use of alcohol and cigarettes is associated with millions of deaths each year, directly or indirectly. The carcinogen acetaldehyde is both a metabolite of alcohol and the most abundant carbonyl compound in cigarette smoke, and co-exposure of them is usual and primarily leads to liver and lung injury, respectively. However, few studies have explored the synchronic risk of acetaldehyde on the liver and lung. Here, we investigated the toxic effects and related mechanisms of acetaldehyde based on normal hepatocytes and lung cells. The results showed that acetaldehyde caused significant dose-dependent increases of cytotoxicity, ROS level, DNA adduct level, DNA single/double-strand breakage, and chromosomal damage in BEAS-2B cells and HHSteCs, with similar effects at the same doses. The gene and protein expression and phosphorylation of p38MAPK, ERK, PI3K, and AKT, key proteins of MAPK/ERK and PI3K/AKT pathways regulating cell survival and tumorigenesis, were significantly upregulated on BEAS-2B cells, while only protein expression and phosphorylation of ERK were upregulated significantly, the other three decreased in HHSteCs. When either the inhibitor of the four key proteins was co-treated with acetaldehyde, cell viabilities were almost unchanged in BEAS-2B cells and HHSteCs. Thus, acetaldehyde could synchronically induce similar toxic effects in BEAS-2B cells and HHSteCs, and MAPK/ERK and PI3K/AKT pathways seem to be involved in different regulatory mechanisms.
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JOURNAL OF MEDICINAL CHEMISTRY
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2023
·
IF 7.3
Xiao-Meng Liu,Zhe Li,Xin-Ru Xie,Jia-Qian Wang,Xin Qiao,Xin Qiao,Cheng-Zhi Xie,Jing-Yuan Xu
Exploring multi-targeting chemotherapeutants with advantages over single-targeting agents and drug combinations is of great significance in drug discovery. Herein, we employed phytogenic evodiamine (EVO) and conventional Pt(II) drugs to design and synthesize multi-target EVO–Pt(IV) anticancer prodrugs (4–14). Among them, compound 10 exhibited a 118-fold enhancement in the IC50 value compared to cisplatin and low toxicity to normal cells. Further studies proved that 10 significantly enhanced intracellular Pt accumulation and DNA damage, perturbed mitochondrial membrane potential, inhibited cell migration and invasion, upregulated reactive oxygen species levels, and induced apoptosis and autophagic cell death. Molecular docking assay revealed that 10 fits perfectly into the extracellular signal-regulated protein kinase (ERK)-1 pocket, which was verified to produce profound ERK suppression. Most strikingly, compound 10 exhibited superior in vivo antitumor efficiency and effectively attenuated systemic toxicity. Our results emphasize that functionalizing platinum drugs with the multi-target EVO could generate synergistically excellent anticancer activity with low toxicity and decreased resistance, which may represent a brand-new cancer therapy modality.
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INTERNATIONAL IMMUNOPHARMACOLOGY
·
2023
·
IF 5.6
Pingchuan Wang,Tianming Li,Changping Niu,Siyu Sun,Dongyan Liu
Reactive oxygen species (ROS) damage to the intestinal barrier is a side effect of prolonged hyperoxia therapy in neonates, which impairs growth and development of the intestine and promotes intestinal diseases. However, the research on clinical prevention and treatment is lacking. Therefore, we investigated the molecular mechanisms of the neonate intestinal response against hyperoxia-derived ROS to find targets for intestinal barrier damage prevention. Human intestinal epithelial cells were incubated under hyperoxia (85% oxygen) to build an in vitro model. ROS and the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway were inhibited to detect the MAPK/ERK pathway, nuclear factor erythroid factor 2-related factor 2 (Nrf2), hypoxia-inducible factor-1α (Hif-1α), and interleukin-17D (IL-17D) expression. Nrf2 was inhibited to detect Hif-1α and IL-17D expression. Hif-1α was inhibited to detect Nrf2, IL-17D, and tight junction proteins expression and apoptosis. Cells were treated with human recombinant IL-17D to detect TNF-α, IL-1β, IL-10, and tight junction proteins expression. ROS, Nrf2, Hif-1α, and IL-17D were upregulated and the MAPK/ERK pathway was activated under hyperoxia. But ROS inhibition downregulated the MAPK/ERK pathway, Nrf2, Hif-1α, and IL-17D. MAPK/ERK pathway inhibition downregulated Nrf2, Hif-1α, and IL-17D. Nrf2 inhibition downregulated Hif-1α and IL-17D. Hif-1α inhibition downregulated Nrf2, IL-17D, tight junction proteins, and exacerbated apoptosis. The recombinant IL-17D downregulated TNF-α, IL-1β, but upregulated IL-10 and tight junction proteins. We concluded that Hyperoxia-generated ROS activated the MAPK/ERK pathway to regulate Nrf2, Hif-1α, and IL-17D expression. Nrf2 and Hif-1α were interdependent and promoted IL-17D. Importantly, Hif-1α and IL-17D expression protected the intestinal epithelial barrier.
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INTERNATIONAL JOURNAL OF ONCOLOGY
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2022
·Vol. 60
·期 5
·1-14
·
IF 5.884
Hang Sun,Youjie Li,Xiao Wang,Xue Zhou,Simin Rong,Dongmin Liang,Guangbin Sun,Huizhen Cao,Hongfang Sun,Ranran Wang,Yunfei Yan,Shuyang Xie,Yunxiao Sun
Chronic myeloid leukemia (CML) is a hematological disease, and imatinib (IM) resistance represents a major problem for its clinical treatment. In the present study, the role of tribbles pseudokinase 2 (TRIB2) in IM resistance of CML and the possible mechanism were investigated. It was found that TRIB2 was highly expressed in IM‑resistant patients with CML through the Oncomine database and this conclusion was confirmed using reverse transcription‑quantitative PCR and western blot experiments. Knockdown of TRIB2 was found to increase the drug sensitivity of KG cells to IM using Cell‑Counting Kit‑8 (CCK‑8) assays, and the low‑expression TRIB2 mice were further found to be more sensitive to the IM and have a higher survival rate in leukemia model mice. Moreover, using western blot and luciferase experiments, it was found that TRIB2 could regulate c‑Fos through the ERK signaling pathway, and c‑Fos suppressed the transcriptional activity and the expression of miR‑33a‑5p. Further investigation identified that the binding site for c‑Fos to function on miR‑33a‑5p was the ‑958‑965 region. Finally, CCK‑8 assays and western blot experiments demonstrated that miR‑33a‑5p could inhibit the proliferation of KG cells and reduce IM resistance by suppressing the expression of HMGA2. In conclusion, it was demonstrated that TRIB2 regulates miR‑33a‑5p to reverse IM resistance in CML, which may help identify novel targets and therapeutic strategies for the clinical treatment of IM resistance.
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Cell Death Discovery
·
2022
·Vol. 8
·期 1
·1-11
·
IF 7.109
Zhang Fangbin,Guo Changqing,Cao Xinguang,Yan Yan,Zhang Jinping,Lv Shuai
Cancer cell-derived extracellular vesicles (EVs) have extensive application in the formation of their environment, including metastasis. This study explored the ability of gastric cancer (GC) cell-derived EVs-mediated microRNA-129-5p/E2F transcription factor 7/mitogen-activated protein kinase/extracellular regulated protein kinase (miR-129-5p/E2F7/MAPK/ERK) axis to affect the peritoneal metastasis of GC by delivering lncRNA small nucleolar RNA host gene 12 (SNHG12). EV-derived lncRNA and SNHG12/miR-129-5p/E2F7 network were determined by bioinformatics analysis. The regulatory relationship among SNHG12, miR-129-5p, and E2F7 was verified using a combination of dual-luciferase reporter gene, RNA immunoprecipitation, and RNA pull-down assays. The SNHG12, miR-129-5p, and E2F7 expression was measured by RT-qPCR. After GC cell-derived EVs were isolated and co-cultured with human peritoneal mesothelial cells (HPMCs), the uptake of EVs by HPMCs was observed under laser scanning confocal microscopy. Cell viability and apoptosis were examined using cell counting kit-8 and flow cytometry, respectively. Western blot analysis was performed to measure the mesothelial–mesenchymal transition (MMT)-related protein expression. The pathological and morphological characteristics of metastatic tumors in nude mice were observed by hematoxylin–eosin staining. A high SNHG12 expression was correlated with the poor prognosis of patients with GC. GC-derived EVs led to increased HPMC apoptosis and MMT by transferring SNHG12, whereas the knockdown of SNHG12 annulled the aforementioned results. SNHG12 sponged miR-129-5p to boost E2F7 expression and activate the MAPK/ERK signaling, thus inducing HPMC apoptosis and MMT. In vivo experiments further verified that EVs derived from GC cells promoted peritoneal metastasis in nude mice. GC cell-derived EVs elevated the E2F7 expression and activated the MAPK/ERK signaling to promote peritoneal metastasis through the delivery of SNHG12.
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NEUROSCIENCE LETTERS
·
2022
·
IF 3.197
Tianyi Yang,Guang Yue,Yu Ge,Yue Zhang,Peng Xu,Youmei Wang,Bo Li,Bin Di
Nitrous oxide (N 2 O) has a long history of abuse, but its abuse mechanism has not been clear yet. This research aimed at the possibility of mesolimbic dopaminergic system (MLDS) involved in the rewarding effect of N 2 O. In this work, the rewarding behavior of N 2 O in mice was evaluated using a typical gas-administered conditioned place preference (CPP) procedure. SCH 23390, a Dopamine D1 receptor (D1R) antagonist, and Haloperidol, a Dopamine D2 receptor (D2R) antagonist were administered during CPP to evaluate the role of dopamine receptors in the N 2 O-induced CPP. The accompanying changes in phosphorylation of extracellular signal-regulated kinase (ERK) in MLDS related brain regions, including the ventral tegmental area (VTA), caudate putamen (CPu), prefrontal cortex (PFC), and nucleus accumbens (NAc) were measured to assess the neural plasticity changes in the CPP mice by Western blot analysis. Results revealed that 60% N 2 O induced CPP in the gas-administered mice and promoted the ERK phosphorylation (p-ERK) in the NAc and CPu during the test session of the CPP test. Pretreatment of SCH 23390 (0.5 mg/kg) inhibited the acquisition of N 2 O-induced CPP and the enhanced p-ERK in NAc. It suggested that Dopamine D1 receptor may play an important role in the acquisition of N 2 O-induced CPP and the accompanied ERK activation in the NAc, which provide insight into the molecular mechanism in the rewarding properties of nitrous oxide.
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JOURNAL OF BIOLOGICAL INORGANIC CHEMISTRY
·
2021
·Vol. 26
·期 7
·793-808
·
IF 3.358
Chen Jincan,Deng Yuanyuan,Wang Jie,Chen Suxiang,Peng Fa,He Xuerong,Liu Meijun,Luo Hui,Zhang Jingjing,Chen Lanmei
Abstract Two new cyclometalated Ru(II)-β-carboline complexes, [Ru(dmb) 2 (Cl-Ph-βC)](PF 6 ) (dmb = 4,4′-dimethyl-2,2′-bipyridine; Cl-Ph-βC = Cl-phenyl-9H-pyrido[3,4-b]indole; RuβC-3 ) and [Ru(bpy) 2 (Cl-Ph-βC)](PF 6 ) (bpy = 2,2′-bipyridine; RuβC-4 ) were synthesized and characterized. The Ru(II) complexes display high cytotoxicity against HeLa cells, the stabilized human cervical cancer cell, with IC 50 values of 3.2 ± 0.4 μM ( RuβC-3 ) and 4.1 ± 0.6 μM ( RuβC-4 ), which were considerably lower than that of non-cyclometalated Ru(II)-β-carboline complex [Ru(bpy) 2 (1-Py-βC)] (PF 6 ) 2 (61.2 ± 3.9 μM) by 19- and 15-folds, respectively. The mechanism studies indicated that both Ru(II) complexes could significantly inhibit HeLa cell migration and invasion, and effectively induce G0/G1 cell cycle arrest. The new Ru(II) complexes could also trigger apoptosis through activating caspase-3 and poly (ADP-ribose) polymerase (PARP), increasing the Bax/Bcl-2 ratio, enhancing reactive oxygen species (ROS) generation, decreasing mitochondrial membrane potential (MMP), and inducing cytochrome c release from mitochondria. Further research revealed that RuβC-3 could deactivate the ERK/Akt signaling pathway thus inhibiting HeLa cell invasion and migration, and inducing apoptosis. In addition, RuβC-3 -induced apoptosis in HeLa cells was closely associated with the increase of intracellular ROS levels, which may act as upstream factors to regulate ERK and Akt pathways. More importantly, RuβC-3 exhibited low toxicity on both normal BEAS-2B cells in vitro and zebrafish embryos in vivo. Consequently, the developed Ru(II) complexes have great potential on developing novel low-toxic anticancer drugs. Graphic Abstract
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CHEMICAL ENGINEERING JOURNAL
·
2024
·
IF 13.3
Xinmin Zheng,Xiang Li,Guolin Shi,Yidan Zhou,Jinxiao Yan,Hao Zhang,Xiru Liu,Jiangong Zhang,Yu Liu,Liangliang Dai,Hui Yang
The low targeting of immunity regulators & chemotherapy drugs and immune tolerance in the tumor microenvironment significantly hindered the chemo-immunotherapy effect. In this work, an MMP-2/GSH-responsive nanobomb loading Resiquimod (R848) and prodrug Cisplatin (Pt) with hierarchical drug delivery and tumor associated macrophages (TAMs) polarization traits was designed for improved chemo-immunotherapy. The Pt-carrying dendrimers penetrate the depth of tumor tissues under MMP-2 and activate the cytotoxicity of Pt prodrug in response to GSH, causing effective tumor damage and enhancing immunogenicity. Meanwhile, R848 is effectively uptake by TAMs, which were re-educated and then greatly relieved immune resistance. In vitro and in vivo results collectively revealed that the nanosystem could not only overcome the barrier of tumor penetration and the heterogeneity action sites of drugs but also re-educate TAMs and suppress immune evasion via activating extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) signal pathway regulated by heparin binding EGF like growth factor ( Hbegf ) gene. The gene silencing or knockout in vitro and in vivo demonstrated that Hbegf could regulate the re-education of TAMs and the progression of tumors.
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RSC Advances
·
2020
·Vol. 10
·期 32
·18927-18935
·
IF 3.119
Xia Jiang,Genyun Tang,Jie Yang,Jiacheng Ding,Hongwei Lin,Xiaoliang Xiang
In the present study, a novel series of acylhydrazone compounds (A0–A10) with the structure of 1,2,4-triazole have been designed and synthesized. In addition, all the synthesized compounds have been evaluated for neuritogenic activity in mouse neuroblastoma (Neuro-2a) cells. Notably, we found that one of these 11 acylhydrazone compounds, compound A5 (2-(4-amino-5-(pyridin-4-yl)-4H-1,2,4-triazol-3-ylthio)-N′-(2-hydroxybenzylidene)-acetohydrazide) displays excellent neuritogenic activity. Moreover, our present study revealed that compound A5 had the ability to induce neurite outgrowth through the PI3K/Akt and MEK-ERK signaling pathway in Neuro-2a cells. These findings suggest that compound A5 might exert neuritogenic effects and thus may be useful for the treatment of neural repair and regeneration.
研究领域:
药理学
·
神经生物学
·
有机化学
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