Purinergic Signalling
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2020
·Vol. 16
·期 4
·585-599
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IF 3.065
Ge Huixiang,Sun Mengyun,Wei Xingyu,Zhang Mingming,Tu Hongcheng,Hao Yuanzhen,Chen Ruxin,Ye Miao,Gao Yun
Activated astrocytes play a key role in diabetic neuropathic pain and depression. We aimed to assess the protective effects of dihydromyricetin (DHM) on primary hippocampal astrocytes cultured with high glucose (HG), substance P (SP), and corticosterone (CORT). Culturing with HG + SP + CORT resulted in damage to primary hippocampal astrocytes, which simulates the clinical damage caused by comorbidity of diabetic neuropathic pain and depression. Western blot, qPCR, and immunofluorescence analyses revealed that HG + SP + CORT increased P2X 7 receptor expression in primary hippocampal astrocytes, which was reversed by DHM treatment. Further, HG + SP + CORT elevated TNF-α, IL-1β, free Ca 2+ , and ERK1/2 phosphorylation levels, which was inhibited by DHM or P2X 7 shRNA treatment. Moreover, DHM significantly reduced the P2X 7 agonist-activated currents in HEK293 cells transfected with the P2X 7 receptor. These findings suggest that DHM can protect primary hippocampal astrocytes cultured with HG + SP + CORT from P2X 7 receptor-mediated damage. Culturing cells with HG + SP + CORT might be a viable cell model for cellular injury exploration of diabetic comorbid pain and depression.
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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PubMed
高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
·
2018
·Vol. 176
·期 3
·416-435
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IF 6.81
Jingyan Li,Junying Huang,Jing Lu,Zhen Guo,Zhuoming Li,Hui Gao,Panxia Wang,Wenwei Luo,Sidong Cai,Yuehuai Hu,Kaiteng Guo,Luping Wang,Zhenzhen Li,Minghui Wang,Xiaolei Zhang,Peiqing Liu
Background and Purpose Activation of PKC-ζ is closely linked to the pathogenesis of cardiac hypertrophy. PKC-ζ can be activated by certain lipid metabolites such as phosphatidylinositol (3,4,5)-trisphosphate and ceramide. However, its endogenous negative regulators are not well defined. Here, the role of the sirtuin1-PKC-ζ signalling axis and the underlying molecular mechanisms were investigated in cardiac hypertrophy. Experimental Approach Cellular hypertrophy in cultures of cardiac myocytes, from neonatal Sprague-Dawley rats, was monitored by measuring cell surface area and the mRNA levels of hypertrophic biomarkers. Interaction between sirtuin1 and PKC-ζ was investigated by co-immunoprecipitation and confocal immunofluorescence microscopy. Sirtuin1 activation was enhanced by resveratrol treatment or Ad-sirtuin1 transfection. A model of cardiac hypertrophy in Sprague-Dawley rats was established by abdominal aortic constriction surgery or induced by isoprenaline in vivo . Key Results Overexpression of PKC-ζ led to cardiac hypertrophy and increased activity of NF-κB, ERK1/2 and ERK5, which was ameliorated by sirtuin1 overexpression. Enhancement of sirtuin1 activity suppressed acetylation of PKC-ζ, hindered its binding to phosphoinositide-dependent kinase 1 and inhibited PKC-ζ phosphorylation in cardiac hypertrophy. Consequently, the downstream pathways of PKC-ζ' were suppressed in cardiac hypertrophy. This regulation loop suggests a new role for sirtuin1 in mediation of cardiac hypertrophy. Conclusions and Implications Sirtuin1 is an endogenous negative regulator for PKC-ζ and mediates its activity via regulating the acetylation and phosphorylation in the pathogenesis of cardiac hypertrophy. Targeting the sirtuin1-PKC-ζ signalling axis may suggest a novel therapeutic approach against cardiac hypertrophy.
研究领域:
心脏病学
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分子生物学
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药理学
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PubMed
高影响因子
Oncology Letters
·
2018
·Vol. 17
·期 2
·2498-2506
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IF 1.664
Xuefeng Yang,Handong Huang,Maijian Wang,Xingbin Zheng,Ming Xie,Jie Xu
Previous studies have indicated the potential role of estrogen in the development and prognosis of colorectal cancer (CRC). Nonylpheno (NP) is an endocrine‑disrupting chemical, which may influence the development of estrogen‑dependent types of cancer. However, the molecular mechanism of NP in the development of CRCs remains unclear. In the present study, various concentrations of NP were used to treat COLO205 CRC cells, and the expression of protein kinase C ζ (PKCζ) was knocked down using PKCζ small interfering RNA. The effects of NP in various concentrations on the cell cycle and apoptosis of COLO205 cells were examined, and the change in the expression level of PKCζ was analyzed. The results indicated that NP may significantly induce proliferation of COLO205 CRC cells, and significantly reduce cell apoptosis. However, suppression of PKCζ expression may inhibit proliferation, while NP could reduce this inhibition. The results of a western blot analysis indicated that the expression level of cyclin D1 and E were significantly increased following NP treatment, and the expression of p27 was significantly decreased. The phosphorylation of PKCζ and extracellular‑signal‑regulated kinase (ERK)1/2 was significantly increased following NP treatment in a dose‑dependent manner. Overall, NP induced human CRC COLO205 cell proliferation and inhibited the apoptotic rate of COLO205 cells by increasing the activity of PKCζ and ERK1/2.
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
Environmental Science-Nano
·
2026
·
IF 5.1
Hong Yang,Peng Zhao,Xiaolei Wei,Chao Huang,Wu-Hong Lv,Yu-Chen Zhou,Zhi Luo
Copper oxide nanoparticles (CuO NPs) are widely used in industry and agriculture, leading to their persistent occurrence and accumulation in aquatic environments and posing potential environmental risks. However, the specific role and underlying mechanisms of CuO NPs on the health risks of aquatic organisms remain unclear. This study revealed that dietary exposure to high levels of CuO NPs elevated hepatic Cu content, induced oxidative stress and mitochondrial dysfunction that exacerbate hepatic lipotoxicity. Mechanistically, high dietary CuO NPs enhanced the interaction between domains 1 and 3 of the Cu chaperone for superoxide dismutase (Ccs) and mitogen-activated protein kinase kinase 1 (Mek1), which subsequently activated the phosphorylation of extracellular signal-regulated protein kinase 1/2 (Erk1T202/Y204 and Erk2T185/Y187). The activated Erk1/2 mediated CuO NPs-induced lipotoxicity by suppressing the expression of peroxisome proliferator-activated receptor α (Pparα) and promoting its phosphorylation at the S77 site. Further investigation demonstrated that Pparα phosphorylation impaired fatty acid β-oxidation by downregulating the promoter activities of long chain acyl-coA dehydrogenase (acadl) and carnitine palmitoyl transferase Ia1b (cptIa1b). For the first time, this study elucidated the novel mechanism by which CuO NPs induced metabolic disorder via the Ccs/Mek1/Erk1/2/Pparα signaling axis. These findings provide critical evidence for the toxicological and environmental risk assessment of nanoparticles, while also deepen the mechanistic understanding of nanometal exposure-induced health effects in aquatic animals within complex environments.
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Oncology Letters
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2022
·Vol. 24
·期 5
·1-12
·
IF 3.111
Haoran Jiang,Xianxin Wen,Xue Zhang,Bingyu Zhang
Concanavalin A (Con A), the first and most typical representative of the legume lectin family, has a potent anti‑liver cancer effect by inducing cell apoptosis and autophagy. However, its function in human liver cancer cell migration remains unclear. The present study investigated the effect of Con A on the viability and migration of human liver cancer cells with different metastatic abilities. It was found that Con A could reduce the viability of human liver cancer cells (HCCLM3, MHCC97L and HepG2) and human hepatocytes (MIHA). In addition, Con A could inhibit human liver cancer cell migration specifically without affecting hepatocytes. Sugar inhibition assay showed that glucose‑related sugar binding sites played an important role in the inhibition of Con A on human liver cancer cell migration. In addition, Con A could affect HCCLM3 migration by activating ERK1/2, JNK1/2/3 and p38 signaling in the MAPK pathway. Moreover, Con A could regulate fibrous actin (F‑actin) redistribution and assembly via the MAPK signaling pathway. However, Con A had no significant effect on the activation of matrix metalloproteinase (MMP)‑2 and MMP‑9 in HCCLM3 cells. In conclusion, Con A may bind to glucose‑related receptor protein, activating ERK1/2, JNK1/2/3 and p38 signaling in the MAPK pathway, further contracting cells and reducing the content of F‑actin of single cells to inhibit HCCLM3 cell migration. These results would deepen the links between human liver cancer cell migration and related glycoproteins or signaling molecules, and may provide a new perspective for Con A as a potential anticancer agent.
研究领域:
癌症生物学
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细胞生物学
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分子生物学
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药理学
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PubMed
高影响因子
International Journal of Nanomedicine
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2023
·
IF 8
Lijuan Lin,Xizhen Zhuang,Ruiqi Huang,Simin Song,Zhaojie Wang,Shilong Wang,Liming Cheng,Rongrong Zhu
Purpose In this study, we aim to explore the effects of graphene oxide (GO), a derivative of graphene, nanoparticles of four different sizes on the cellular fate of mouse neural stem cells (mNSCs).Methods GO NPs were characterized with transmission electron microscopy (TEM), scanning electron micrography (SEM), atomic force microscopy (AFM) and Raman Spectra analysis. The cytotoxic effects of the GO NPs of different sizes on the mNSCs were determined using CCK-8 assay, Annexin V-APC/ 7-AAD staining and EdU staining assays. We investigated the biological and the mechanisms of GO NPs on cells using immunofluorescence analysis and quantitative real-time PCR (qPCR).Results The average hydrodynamic sizes of the GO NPs were 417 nm, 663 nm, 1047 nm, and 4651 nm, with a thickness of approximately 22.5 nm, 17.7 nm, 22.4 nm, and 13.4 nm, respectively. GO NPs of all sizes showed low cytotoxicity at a concentration of 20 μg/mL on the mNSCs. Immunostaining demonstrated that treatment with GO NPs, especially the 663 nm ones, enhanced the self-renewal ability of mNSCs in the absence of EGF and bFGF. Under differentiation medium conditions that are free of mitogenic factors, all the GO NPs, particularly the 4651 nm ones, increased the expression level of Tuj1 and GFAP. With regards to the migration ability, we found that 417 nm GO-NP-treated mNSCs migrated over a longer distance than the control group obviously. In addition, higher expression of Rap1, Vinculin and Paxillin was observed in the GO NP-treated groups compared to the control group. mRNA-Sequence analysis and Western blotting results suggested that the 4651 nm GO NPs triggered positive neuronal differentiation through phosphorylation of ERK1/2 by the downregulating of TRPC2.Conclusion GO NPs play an important role in the applications of inducing self-renewal and differentiation of mNSC, and are promising in the future for further studies.
研究领域:
材料科学
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神经科学
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细胞生物学
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生物医学工程
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PubMed
高影响因子
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
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2023
·
IF 8.7
Liu Yang,Hao Wu,Congcong Luo,Yang Zhao,Rongbo Dai,Zhiqing Li,Xu Zhang,Ze Gong,Zeyu Cai,Yicong Shen,Fang Yu,Wei Li,Hongmei Zhao,Tao Zhang,Junming Zhu,Yi Fu,Jing Wang,Wei Kong
Background:Thoracic aortic aneurysm and dissection (TAAD) is a highly lethal vascular disease without effective drug therapy. Whether elevated serum concentrations of uric acid are involved in TAAD development remains unclear.Methods:Serum uric acid levels were detected in different TAAD mouse models and patients. The urate-lowering drug allopurinol was administered in the drinking water of TAAD mice. Adenine diet–induced mice were established to investigate the role of hyperuricemia in TAAD formation and RNA-sequencing of thoracic aortas from these mice was performed.Results:We found serum uric acid levels were elevated in various mouse TAAD models, including mice fed a β-aminopropionitrile diet, Marfan mice with fibrillin-1 haploinsufficiency (Fbn1C1041G/+), and ApoE−/− mice infused with Ang II (angiotensin II), as well as in patients with TAAD. Administration of urate-lowering drug allopurinol in the drinking water significantly alleviated TAAD formation in β-aminopropionitrile–treated mice, Fbn1C1041G/+ mice, and Ang II–infused ApoE−/− mice. Moreover, an adenine diet was used to induce hyperuricemia in mice. Intriguingly, a 4-week adenine diet feeding directly induced TAAD formation characterized by increased maximal thoracic aortic diameters and severe elastin degradation, which were ameliorated by allopurinol. Unbiased RNA-sequencing in mouse thoracic aortas suggested that FcγR (Fc gamma receptor) was upregulated upon adenine diet, but reciprocally repressed by allopurinol. Mechanistically, hyperuricemia activated FcγR-mediated ERK1/2 (extracellular signal-regulated kinase 1/2) phosphorylation to induce macrophage inflammation and TAAD development, which was abrogated by allopurinol or FcγR deficiency.Conclusions:This study uncovered an important and previously unrecognized role of hyperuricemia in mediating the pathogenesis of TAAD, and uric acid–lowering drug may represent a promising therapeutic approach for TAAD.
研究领域:
心血管疾病
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药理学
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分子生物学
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PubMed
高影响因子
Drug Design Development and Therapy
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2022
·
IF 4.319
Xin-Yu Liao,Yang Lei,Song-Feng Chen,Jing Cheng,Dan Zhao,Zhi-Feng Zhang,Xin Han,Ya Zhang,Hua-Bao Liao,Yang Zhuang,Juan Chen,Hai-Bing Zhou,Qi Wan,Ying-Ying Zou
Background: The authors have recently designed a new compound bisperoxovandium (pyridin-2-squaramide) [bpV(pis)] and verified that bpV(pis) confers neuroprotection through suppressing PTEN and activating ERK1/2, respectively. Intracerebral hemorrhage (ICH) is the second most common cause of stroke and has severe clinical outcome. In this study, we investigate the effect of bpV(pis) in ICH model both in vivo and in vitro.Materials and methods: The novel drug bpV(pis) was synthesized in the Faculty of Pharmacy, Wuhan University School of Medicine. An ICH model was generated on both SD rats and cells. bpV(pis) was injected into intracerebroventricular or culture media. Western blotting was applied to test the signal pathway. To determine the effect of bpV(pis) on PTEN inhibition and ERK1/2 activation, we measured the phosphorylation level of AKT (a direct downstream target of PTEN that negatively regulates AKT) and ERK1/2. FJC, MTT, and LDH were applied to measure the cell viability. Neurobehavioral tests were performed to measure the effect of bpV(pis).Results: The in vivo results showed that intracerebroventricular administration of bpV(pis) significantly alleviates hematoma, the damage of brain–blood barrier and brain edema. The in vitro results demonstrated that bpV(pis) treatment reduces ICH-induced neuronal injury. Western blotting results identified that bpV(pis) exerts a neuroprotective effect by significantly increasing the phosphorylation level of AKT and ERK1/2 after experimental ICH. Neurobehavioral tests indicate that bpV(pis) promotes functional recovery in ICH animals.Conclusion: This study provides first and direct evidence for a potential role of bpV(pis) in ICH therapy.
研究领域:
神经科学
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药理学
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分子生物学
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PubMed
高影响因子
JOURNAL OF PHARMACY AND PHARMACOLOGY
·
2023
·Vol. 75
·期 7
·886-897
·
IF 3.3
Du Jianhao,Zhang Fugui,Chen Min,Xiao Yifei,Zhang Li,Dong Linlin,Dong Dong,Wu Baojian
ObjectiveDelirium (acute brain syndrome) is a common and serious neuropsychiatric disorder characterized by an acute decline in cognitive function. However, there is no effective treatment clinically. Here we investigated the potential effect of jujuboside A (JuA, a natural triterpenoid saponin) on cognitive impairment in delirium.MethodsDelirium models of mice were established by injecting lipopolysaccharide (LPS) plus midazolam and implementing a jet lag protocol. Novel object recognition test and Y maze test were used to evaluate the effects of JuA on delirium-associated cognitive impairment. The mRNA and protein levels of relevant clock factors and inflammatory factors were measured by qPCR and Western blotting. Hippocampal Iba1+ intensity was determined by immunofluorescence staining.Key findingsJuA ameliorated delirium (particularly delirium-associated cognitive impairment) in mice, which was proved by the behavioural tests, including a preference for new objects, an increase of spontaneous alternation and improvement of locomotor activity. Furthermore, JuA inhibited the expression of ERK1/2, p-p65, TNFα and IL-1β in hippocampus, and repressed microglial activation in delirious mice. This was attributed to the increased expression of E4BP4 (a negative regulator of ERK1/2 cascade and microglial activation). Moreover, loss of E4bp4 in mice abrogated the effects of JuA on delirium as well as on ERK1/2 cascade and microglial activation in the hippocampus of delirious mice. Additionally, JuA treatment increased the expression of E4BP4 and decreased the expression of p-p65, TNFα and IL-1β in LPS-stimulated BV2 cells, supporting a protective effect of JuA on delirium.ConclusionsJuA protects against delirium-associated cognitive impairment through promoting hippocampal E4BP4 in mice. Our findings are of great significance to the drug development of JuA against delirium and related disorders.
研究领域:
神经科学
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药理学
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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
Frontiers in Pharmacology
·
2022
·
IF 5.988
Hong Chen,Yang Lili,Zhang Yifan,Li Yiming,Wu Huali
Epimedium brevicornum Maxim. (Epimedii Folium) is a traditional medicine widely utilized in China for sexual dysfunction and osteoporosis treatment. Recently, studies have reported that Epimedium flavonoid icariin displayed hair growth and melanogenic ability by targeting tyrosinase activity. Nevertheless, icariin hydrolysate icariside II and icaritin cause depigmentation due to their tyrosinase inhibition. These pigment functional discrepancies from Epimedium constituents arouse our great interest. Then, this study focused on the pigmentation effects of Epimedii Folium extract (EFE) on melanin synthesis and melanosome biogenesis/transfer, and further identified the bioactive constituents. First, in in vitro systemic studies, we discovered that the potent melanogenic and repigmented effects of EFE were dependent on concentration and amount of time in multi-melanocytes, normal human skin tissue, and vitiligo perilesional areas. In vivo, EFE exhibited repigmented effect on two kinds of depigmented models of N-phenylthiourea-induced zebrafish and hydroquinone-induced mice. Mechanistically, EFE strongly promoted tyrosinase activity and upregulated the protein expression of tyrosinase families which finally contribute to melanin biosynthesis by activating the MAPK/ERK1/2 signal pathway. In addition, EFE effectively increased melanosome number, accelerated melanosome maturity and cytoplasmic transport through the growth/extension of melanocyte dendrites, and induced melanosome transfer from melanocyte to keratinocyte for pigmentation. The six main flavonoid ingredients were identified among EFE. Compared to others, epimedin B (EB) was confirmed as a high-content, low-toxicity, and effective melanogenic compound in EFE. Taking all these together, this study systematically demonstrates the potential pigmentation effect of Epimedium brevicornum Maxim., and clarifies its related molecular mechanisms and melanogenesis basis. These results give additional insight into Epimedium herb pharmacology and may provide a novel therapy basis for hypopigmentation disorders.
研究领域:
药理学
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皮肤科
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中医药
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分子生物学
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PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
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2021
·
IF 10.588
Tianxin Zhao,Xiangliang Tang,Dian Li,Jinglu Zhao,Rui Zhou,Fangpeng Shu,Wei Jia,Wen Fu,Huimin Xia,Guochang Liu
Polybrominated diphenyl ethers (PBDEs) are a widely used class of brominated flame retardants . Exposure to PBDEs could induce testicular damage in mammals, but the effects and potential mechanism of action of prenatal exposure to environmentally relevant PBDEs on testicular development remain unclear. For the in vivo study, pregnant ICR mice were exposed to environmentally relevant levels of 2,2′,4,4′,5-pentabromodiphenyl ether (PBDE-99), a major component of commercial PBDE mixtures. We found that the anogenital index and testicular organ coefficient were significantly decreased, the incidence of cryptorchidism was increased, and testicular histology was disturbed in male offspring . Transcriptomic profiling showed that steroidogenesis disorders were significant in all PBDE-99 exposure groups. The testosterone levels, expressions of testosterone regulators, and the number of CYP11A1-positive and 11β-HSD1-positive Leydig cells were significantly decreased after PBDE-99 exposure. For the in vitro study, TM3 Leydig cells were exposed to PBDE-99 at gradient concentrations. Transcriptomic profiling and validation experiments showed that PBDE-99 upregulated reactive oxygen species , activated the ERK1/2 pathway, inhibited the ubiquitination degradation pathway, and finally induced Leydig cell apoptosis. Cumulatively, these findings revealed that prenatal exposure to environmentally relevant levels of PBDE-99 leads to steroidogenesis disorders by inducing the apoptosis of Leydig cells, causing testicular dysgenesis.
研究领域:
毒理学
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生殖生物学
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环境健康
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PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
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2022
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IF 6.1
Min Chen,Yifei Xiao,Fugui Zhang,Jianhao Du,Li Zhang,Yifang Li,Danyi Lu,Zhigang Wang,Baojian Wu
Delirium is a common and serious neuropsychiatric syndrome characterized with acute cognitive and attentional deficits, however, the effective therapies are lacking. Here, using mouse models of delirium, we investigated the effects of tangeretin (TAN, a natural flavonoid) on cognitive impairment by assessing object preference with novel object recognition (NOR) test and spontaneous alternation with Y maze test. We found that TAN, as a RORα/γ agonist, prevented cognitive decline in delirious mice as evidenced by a normal novel object preference and increased spontaneous alternation. This was accompanied by decreased expression of ERK1/2, TNFα and IL-1β as well as diminished microglial activation in delirious mice. The protective effect of TAN on delirium was mainly attributed to increased hippocampal E4BP4 expression (a known target of RORs and a regulator of cognition in delirium through modulating the ERK1/2 cascade and microglial activation) via activation of RORα/γ. In addition, TAN treatment modulated the expression of RORα/γ target genes (such as E4bp4 and Bmal1 ) and inhibited the expression of TNFα and IL-1β in lipopolysaccharide (LPS)-stimulated cells, supporting a beneficial effect of TAN on delirium. In conclusion, TAN is identified as a RORα/γ agonist which promotes E4BP4 expression to prevent cognitive decline in delirious mice. Our findings may have implications for drug development of TAN for prevention and treatment of various diseases associated with cognitive deficiency.
研究领域:
神经科学
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药理学
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免疫学
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分子生物学
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PubMed
高影响因子
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