Frontiers in Neuroscience
·
2019
·
IF 3.648
Chen Xiao,Xi Zhiyu,Liang Huaibin,Sun Yuhao,Zhong Zhihong,Wang Baofeng,Bian Liuguan,Sun Qingfang
Secondary injuries mediated by oxidative stress lead to deterioration of neurological functions after intracerebral hemorrhage (ICH). Cortical astrocytes are among the most important cells in the central nervous system (CNS), and play key roles in maintaining redox homeostasis by providing oxidative stress defense. Hemin is a product of hemoglobin degradation, which has strong toxicity and can induce reactive oxygen species (ROS). Melatonin (Mel) and its metabolites are well tolerated without toxicity, prevent tissue damage as well as effectively assist in scavenging free radicals. We evaluated the hemin neurotoxicity to astrocytes and the resistance of Mel-treated astrocytes to hemin neurotoxicity. And we found Mel induced PKCα phosphorylation (p-PKC), nuclear translocation of Nrf2 in astrocytes, and upregulation of HO-1, which contributed to the reduction of ROS accumulation and cell apoptosis. Nrf2 and HO1 protein expression upregulated by Mel were decreased after administration of PKC inhibitor, Ro 31-8220 (Ro 31). Luzindole (Luz), a melatonin receptor inhibitor, suppressed p-PKCα, HO-1, and Nrf2 expression upregulated by Mel and increased cell apoptosis rate. The upregulation of HO-1 induced by Mel was depressed by knocking down Nrf2 expression by siRNA, which also decreased the resistance of astrocytes to toxicity of hemin. Mel activates astrocytes through PKCα/Nrf2/HO-1 signaling pathway to acquire resistance to toxicity of hemin and resist from oxidative stress and apoptosis. The positive effect of Mel on PKCα/Nrf2/HO-1 signaling pathway may become a new target for neuroprotection after intracerebral hemorrhage.
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
Food & Function
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2023
·
IF 6.1
Haixia Che,Jie Yi,Xiaoting Zhao,Hong Yu,Xianyao Wang,Rui Zhang,Xin Li,Jia Fu,Qian Li
As a common plant-derived dietary flavonoid, rutin receives the widespread attention because of its good antioxidant bioactivities. Protein kinase Cα (PKCα) is a serine/threonine kinase that is involved in uncountable cellular processes, among which ferroptosis, a novel form of cell death, is triggered by lipid peroxidation and has been reported to associate with pulmonary arterial hypertension (PAH). But it is still not well appreciated how rutin inhibits ferroptosis in PAH and what function of PKCα plays in this process. In this study, we firstly observed whether rutin could prevent PAH by attenuating ferroptosis with PAH animal model and pulmonary artery smooth muscle cells (PASMCs) under hypoxia. Mitochondrial metabolomics and network pharmacology were employed to clarify the metabolic alteration and screen target proteins, results showed PKCα was a vital node in rutin regulating mitochondrial metabolism related to ferroptosis in PAH. Based on molecular docking and multispectral analysis, we found rutin could directly interact with PKCα through hydrogen bonds, which could induce static quenching, and then influence the secondary structure of PKCα. In conclusion, these findings mainly point to a novel mechanism that rutin protect PAH rat by modifying the structure, altering activity of PKCα, and then suppressing ferroptosis. This work was great helpful to reveal that the interaction behaviours between small molecules and bio-macromolecules are the critical point to develop the natural biological active ingredients and give an insight into the potential applications of flavonoid in health and disease.
研究领域:
药理学
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生物化学
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分子生物学
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心血管疾病
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PubMed
高影响因子
Stem Cell Research & Therapy
·
2023
·Vol. 14
·期 1
·1-18
·
IF 7.5
Yang Jing,Yang Na,Zhao Huifang,Qiao Yan,Li Yanqiu,Wang Chunfang,Lim Kah-Leong,Zhang Chengwu,Yang Wulin,Lu Li
Background Lipodystrophy-associated metabolic disorders caused by Seipin deficiency lead to not only severe lipodystrophy but also neurological disorders. However, the underlying mechanism of Seipin deficiency-induced neuropathy is not well elucidated, and the possible restorative strategy needs to be explored.Methods In the present study, we used Seipin knockout (KO) mice, combined with transcriptome analysis, mass spectrometry imaging, neurobehavior test, and cellular and molecular assay to investigate the systemic lipid metabolic abnormalities in lipodystrophic mice model and their effects on adult neurogenesis in the subventricular zone (SVZ) and olfactory function. After subcutaneous adipose tissue (AT) transplantation, metabolic and neurological function was measured in Seipin KO mice to clarify whether restoring lipid metabolic homeostasis would improve neurobehavior.Results It was found that Seipin KO mice presented the ectopic accumulation of lipids in the lateral ventricle, accompanied by decreased neurogenesis in adult SVZ, diminished new neuron formation in the olfactory bulb, and impaired olfactory-related memory. Transcriptome analysis showed that the differentially expressed genes (DEGs) in SVZ of adult Seipin KO mice were significantly enriched in lipid metabolism. Mass spectrometry imaging showed that the levels of glycerophospholipid and diglyceride (DG) were significantly increased. Furthermore, we found that AT transplantation rescued the abnormality of peripheral metabolism in Seipin KO mice and ameliorated the ectopic lipid accumulation, concomitant with restoration of the SVZ neurogenesis and olfactory function. Mechanistically, PKCα expression was up-regulated in SVZ tissues of Seipin KO mice, which may be a potential mediator between lipid dysregulation and neurological disorder. DG analogue (Dic8) can up-regulate PKCα and inhibit the proliferation and differentiation of neural stem cells (NSCs) in vitro, while PKCα inhibitor can block this effect.Conclusion This study demonstrates that Seipin deficiency can lead to systemic lipid disorder with concomitant SVZ neurogenesis and impaired olfactory memory. However, AT restores lipid homeostasis and neurogenesis. PKCα is a key mediator mediating Seipin KO-induced abnormal lipid metabolism and impaired neurogenesis in the SVZ, and inhibition of PKCα can restore the impaired neurogenesis. This work reveals the underlying mechanism of Seipin deficiency-induced neurological dysfunction and provides new ideas for the treatment of neurological dysfunction caused by metabolic disorders.
研究领域:
神经科学
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代谢学
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分子生物学
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移植学
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脂质组学
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DOI
PubMed
高影响因子
CHEMOSPHERE
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2019
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IF 5.108
Caihong Wang,Wenhao Huang,Jiebo Lin,Fang Fang,Xuedong Wang,Huili Wang
Triclosan (TCS) is widely used in personal care products, and its chronic exposure leads to severely toxic effects in zebrafish ( Danio rerio ). PKCα, Nrf2 and p53 are three important signaling pathways concerned with cell development. Herein, we speculated on and verified a novel TCS regulatory pathway: (1) TCS acted on GPER (G-protein-coupled estrogen receptor) to activate MAPK/ERK pathway, further resulting in the expression changes of protein kinase C (PKC) family; (2) PKC participated in Nrf2 phosphorylation; (3) The expression of miR-125b was regulated by Nrf2; and (4) The expression changes of related genes in the PKCs-Nrf2-ARE pathway showed the specificity of zebrafish tissue and organ. TCS exposure led to down-regulation of the Nrf2 and phosphorylated Nrf2(Ser40) protein in diencephalon nucleus, stratum marginale and stratum centrale areas in adult zebrafish brain. The phosphorylated Nrf2(Ser40) was mainly expressed in PGz area, while it was not the case for Nrf2. Both Nrf2 and phosphorylated Nrf2 were activated by TCS exposure; however, the changing trend of PKCs was opposite to that of Nrf2 in the liver. Both DAPI staining and Merge images demonstrated that TCS induced oxidative phosphorylation, and phosphorylated Nrf2 is translocated into the nucleus as the transcription factor to regulate gene transcription in liver and brain. Nrf2 over-expression increased accumulation of lipid droplets in yolk, brain and liver, resulting from the upregulation of pri-miR-125b1, pri-miR-125b3, but not pri-miR-125b2. These findings reveal the upstream regulation mechanism of miR-125b for TCS-induced fat-metabolism disorder from the regulatory perspective of the pri-miR-125b promoter region.
研究领域:
毒理学
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分子生物学
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水生生物学
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药理学
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PubMed
高影响因子
Acta Pharmaceutica Sinica B
·
2024
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IF 14.7
Jiaojiao Yu,Yujin Xiang,Yuzhen Gao,Shan Chang,Ren Kong,Xiaoxi Lv,Jinmei Yu,Yunjie Jin,Chenxi Li,Yiran Ma,Zhenhe Wang,Jichao Zhou,Hongyu Yuan,Shuang Shang,Fang Hua,Xiaowei Zhang,Bing Cui,Pingping Li
Protein kinase C α (PKC α ) regulates diverse biological functions of cancer cells and is a promising therapeutic target. However, clinical trials of PKC-targeted therapies have not yielded satisfactory results. Recent studies have also indicated a tumor-suppressive role of PKCs via unclear molecular mechanisms. In this study, we found that PKC α inhibition enhances CD8 + T-cell-mediated tumor evasion and abolishes antitumor activity in immunocompetent mice. We further identified PKC α as a critical regulator of programmed cell death-ligand 1 (PD-L1) and found that it enhances T-cell-dependent antitumor immunity in breast cancer by interacting with PD-L1 and suppressing PD-L1 expression. We demonstrated that PKC α -mediated PD-L1 phosphorylation promotes PD-L1 degradation through β transducin repeat-containing protein. Notably, the efficacy of PKC α inhibitors was intensified by synergizing with anti-PD-L1 mAb therapy to boost antitumor T-cell immunity in vivo . Clinical tissue array analysis revealed that PKC α expression is positively correlated with T-cell function and the interferon-gamma signature in patients with breast cancer. This study demonstrated the antitumor capability of PKC α , identified potential therapeutic strategies to avoid tumor evasion via PKC-targeted therapies, and provided a proof of concept for targeting PKC α in combination with anti-PD-L1 mAb therapy as a potential therapeutic approach against breast cancer, especially TNBC.
研究领域:
肿瘤学
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免疫学
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分子生物学
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癌症治疗
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PubMed
高影响因子
FOOD RESEARCH INTERNATIONAL
·
2026
·
IF 8.8
Qiuyu Chen,Huadi Mei,Mengyao Fang,Yiyan Cui,Ting Rong,Dun Deng,Zhimei Tian,Min Song,Zhenming Li,Zhichang Liu,Xianyong Ma,Miao Yu
Intestinal barrier dysfunction can cause gastrointestinal diseases and retardation in both human infants and young animals. Quercetin, a natural flavonoid, exhibits diverse physiological activities such as anti-inflammatory and antioxidant effects and has demonstrated potential to enhance intestinal health. However, the exact underlying mechanisms linking quercetin with the intestinal barrier integrity remains unclear. Thus, this study aimed to evaluate whether and how quercetin can ameliorate intestinal barrier dysfunction in LPS-challenged weaned piglets and TNF-α challenged IPEC-J2 cells models. The results showed that quercetin supplementation significantly reduced serum, jejunal, and ileal mucosa TNF-α and IFN-γ concentrations in the LPS-challenged piglets ( P < 0.05). Quercetin also decreased crypt depth in jejunum and ileum ( P < 0.05), while significantly increasing the villus height:crypt depth ratio in the jejunum ( P < 0.05). Meanwhile, quercetin improved intestinal barrier function, as evidenced by decreased serum endotoxin levels and diamine oxidase activity ( P < 0.05) as well as up-regulated jejunal protein expression and immunofluorescence intensity of tight junction proteins (ZO-1, occludin, and claudin-1) ( P < 0.05), ileal occludin and claudin-1 protein expression ( P < 0.05). In vitro studies further revealed that quercetin pretreatment effectively ameliorated ( P < 0.05) TNF-α-induced intestinal barrier dysfunction by suppressing the key proteins expression in PKCα-/MLCK signaling pathway in IPEC-J2 cells. These findings indicated that quercetin ameliorates intestinal barrier dysfunction by upregulating the expression of tight junction proteins, potentially through the suppression of the PKCα/MLCK signaling pathway.
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高影响因子
Theranostics
·
2023
·
IF 12.4
Chen Li,Zihui Zheng,Xiang Wu,Qiu Xie,Ping Liu,Yunfeng Hu,Mei Chen,Liming Liu,Wangxing Zhao,Linlin Chen,Jun Guo,Ying Song
Rationale: Cells migrating through interstitial matrix enables stiffening of the tumor micro-environment. To overcome the stiff resistance of extracellular matrix, aggressive cells require the extracellular mechanosensory activation and intracellular tension response. Mechanotransduction linker srGAP2 can synergistically control the mechanical-biochemical process of malignant cell migration. Methods: To mimic the tumor micro-environment containing abundant collagen fibers and moving durotaxis of triple-negative breast cancer cells, the stiff-directed matrix was established. The newly designed srGAP2 tension probe was used to real-time supervise srGAP2 tension in living cells. The phosphorylation sites responsible for srGAP2 tension were identified by phosphorylated mutagenesis. Transwell assays and Xenograft mouse model were performed to evaluate TNBC cells invasiveness in vitro and in vivo . Fluorescence staining and membrane protein isolation were used to detect protein localization. Results: The present study shows srGAP2 serves as a linker to transmit the mechanical signals among cytoskeleton and membrane. SrGAP2 exhibits tension gradients among different parts in the stiff-directionally migrating triple-negative breast cancer cells. Cells showing the polarized tension that increased in the leading edge move faster, particularly guided by the stiff interstitial matrix. The srGAP2 tension-directed cell migration results from the upstream events of PKCα-mediated phosphorylation at Ser 206 in the F-bar domain of srGAP2. In addition, Syndecan-4 (SDC4), a transmembrane mechanoreceptor protein, drives PKCα regional recruit on the area of membrane trending deformation, which requires the distinct extent of extracellular mechanics. Conclusion: SDC4-PKCα polarized distribution leads to the intracellular tension gradient of srGAP2, presenting the extra- and intracellular physiochemical integration and essential for persistent cell migration in stiff matrix and caner progression. Targeting the srGAP2-related physicochemical signaling could be developed into the therapeutic strategies of inhibiting breast cancer cell invasion and durotaxis.
研究领域:
癌症生物学
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细胞生物学
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机械生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Molecular Biosciences
·
2026
·
IF 4
Xingwei Yu,Hongao Tan,Yunqiu Gao,Dandan Qiu,Yan Zhu,Haixin Qi
Background: Given the lack of effective treatment for chronic nonbacterial prostatitis (CNP) and the anti-inflammatory property of natural bioactive compound forsythiaside A (FTA), the therapeutic potential of FTA on CNP is worthy of investigation.Methods: CNP rat models were established using complete Freundʼs adjuvant, followed by a 4-week administration of FTA at different concentrations (40 and 80 mg/kg/d). The body and prostate of rats were weighed to calculate the prostatic index. Prostate damage and inflammatory infiltration were assessed using histological analysis and immunohistochemistry staining. Levels of inflammation-related cytokines, autophagic markers as well as the protein kinase C alpha (PKCα)/NF-κB pathway in prostate tissues were detected using enzyme-linked immunosorbent assay and western blot.Results: No significant change was observed in the body weight of CNP rat models administered with or without FTA. FTA treatment reduced the prostatic index and mitigated prostate damage and inflammatory infiltration of CNP rat models. FTA treatment decreased the number of CD3-positive cells and CD45-positive cells, while downregulating interleukin 1 beta (IL-1β), IL-2, IL-6, IL-17A, monocyte chemoattractant protein-1, and tumor necrosis factor alpha in prostate tissues of CNP rat models. FTA treatment promoted Beclin-1 and LC3B II/LC3B I expressions, and inhibited PKCα and p-p65/p65 expressions in prostate tissues of CNP rat models.Conclusion: FTA alleviates inflammation and facilitates autophagy in CNP rat models by blocking the PKCα/NF-κB pathway.
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高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2023
·Vol. 24
·期 19
·14503
·
IF 5.6
Zhiye Zhao,Ye Li,Shancheng Guo,Yuxu Chen,Haiaolong Yin,Yaxian Li,Guiguang Cheng,Lei Tian
Acute hepatitis (AH) is a common liver disease with an increasing number of patients each year, requiring the development of new treatments. Hence, our work aimed to evaluate the therapeutic effect ofOryza sativaL. indica (purple rice) seed coat on concanavalin A (ConA)-induced AH and further reveal its potential mechanisms. Purple rice seed coat extract (PRE) was extracted with hydrochloric acid ethanol and analyzed through a widely targeted components method. We evaluated the effects of PRE on AH through histopathological examination, liver function, gut microbiota composition, and the intestinal barrier. The potential targets of PRE on AH were predicted by bioinformatics. Western blotting, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay (TUNEL) staining, and corresponding kits were used to investigate PRE effects on predicting targets and associated signaling pathways in AH mice. In AH model mice, PRE treatment increased transformed mouse 3T3 cell double minute 2 (MDM2) expression to inhibit apoptosis; it also markedly downregulated protein kinase C alpha (PKCα), prostaglandin-endoperoxide synthase 1 (PTGS1), and mitogen-activated protein kinase 1 (MAPK1) activity to alleviate inflammation. Thus, PRE treatment also recovered the intestinal barrier, decreased the lipopolysaccharide (LPS) levels of plasma and the liver, enhanced liver function, and improved the composition of intestinal microbiota. In general, PRE targeting MDM2, PKCα, MAPK1, and PTGS1 ameliorated ConA-induced AH by attenuating inflammation and apoptosis, restoring the intestinal barrier, enhancing the liver function, and improving the gut microbiota, which revealed that the purple rice seed coat might hold possibilities as a therapeutic option for AH.Keywords:Oryza sativaL. indica;acute hepatitis;MDM2;PKCα;PTGS1;gut microbiota
研究领域:
药理学
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肝病学
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免疫学
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生物信息学
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微生物学
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DOI
PubMed
高影响因子
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