Biochemical pharmacology最新文献_第5页

KAT3B-mediated succinylation of DERL3 suppresses osteogenic differentiation by promoting M1/M2 macrophage polarization. kat3b介导的DERL3琥珀酰化通过促进M1/M2巨噬细胞极化抑制成骨分化。

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2024-12-21 DOI: 10.1016/j.bcp.2024.116724

Bohan Yu, Yanan Qiao, Xi Sun, Yue Yin

{"title":"KAT3B-mediated succinylation of DERL3 suppresses osteogenic differentiation by promoting M1/M2 macrophage polarization.","authors":"Bohan Yu, Yanan Qiao, Xi Sun, Yue Yin","doi":"10.1016/j.bcp.2024.116724","DOIUrl":"10.1016/j.bcp.2024.116724","url":null,"abstract":"Periodontitis is a chronic inflammatory disease influenced by macrophage polarization. Additionally, succinylation-enriched Porphyromonas gingivalis is a pathogenic factor of periodontitis. However, the role of succinylation in the pathogenesis of periodontitis remains unclear. This study aimed to investigate the effects of a succinyltransferase KAT3B on macrophage polarization, osteogenic differentiation, and the molecular mechanism. Macrophages RAW264.7 were cocultured with MC3T3-E1-differentiated osteoblasts, and macrophage polarization and osteogenic differentiation were evaluated. iTRAQ-based proteomic analysis identified that DERL3 was highly expressed in lipopolysaccharide (LPS)-treated MC3T3-E1 cells. The TLR4/MyD88 pathway is closely related to inflammatory response. Thus, the succinylation of DERL3 and the TLR4/MyD88 pathway were assessed using immunoblotting. The results showed that KAT3B-mediated succinylation was increased in LPS-treated MC3T3-E1 cells and patients with periodontitis. Knockdown of KAT3B inhibited macrophage M1-like polarization and promoted M2-like polarization, thereby promoting osteogenic differentiation in LPS-treated osteoblasts. Mechanically, overexpression of KAT3B promoted the succinylation of DERL3 and stabilized this protein, thereby upregulating DERL3 expression. Rescue experiments showed that DERL3 reversed the promotion of osteogenic differentiation and M2/M1 macrophage polarization caused by KAT3B knockdown. Moreover, DERL3 activated the TLR4/MyD88 pathway, and inhibition of this pathway reversed macrophage polarization and osteogenesis mediated by DERL3. In vivo experiments showed that KAT3B knockdown attenuated experimental periodontitis in rats. In conclusion, silencing of KAT3B promotes osteogenic differentiation by inducing M2/M1 macrophage polarization through the succinylation DERL3, which regulates the TLR4/MyD88 pathway, thereby attenuating periodontitis. These findings suggest that KAT3B may be a promising therapeutic target for periodontitis.","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"116724"},"PeriodicalIF":5.3,"publicationDate":"2024-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142880650","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

CircDUSP16 mediates the effect of triple-negative breast cancer in pirarubicin via the miR-1224-3p/TFDP2 axis. CircDUSP16通过miR-1224-3p/TFDP2轴介导吡柔比星对三阴性乳腺癌的影响。

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2024-12-20 DOI: 10.1016/j.bcp.2024.116719

Wei Dexian, Zhang Fan, Li Min, Fan Zhimin, Ma Jiulong, Ji Jiahua, Qiao Sennan, Huang Peng, Zhang Wenqing, Fan Kaiqi, Li Lu, Zheng Wentao, Li Xiangjun, Ren Liqun

{"title":"CircDUSP16 mediates the effect of triple-negative breast cancer in pirarubicin via the miR-1224-3p/TFDP2 axis.","authors":"Wei Dexian, Zhang Fan, Li Min, Fan Zhimin, Ma Jiulong, Ji Jiahua, Qiao Sennan, Huang Peng, Zhang Wenqing, Fan Kaiqi, Li Lu, Zheng Wentao, Li Xiangjun, Ren Liqun","doi":"10.1016/j.bcp.2024.116719","DOIUrl":"10.1016/j.bcp.2024.116719","url":null,"abstract":"Triple-negative breast cancer (TNBC) is an aggressive molecular subtype of breast cancer characterized by a high recurrence rate, poor prognosis, and elevated mortality. Identifying novel molecular targets is crucial for developing more effective therapeutic strategies against TNBC. Recent studies have highlighted the role of circular RNAs (circRNAs) in the progression of TNBC. In this study, we identified and validated that circDUSP16 (hsa_circ_0003855) is significantly upregulated in TNBC cells, tissues, and plasma exosomes. Functional assays in vitro demonstrated that overexpression of circDUSP16 promoted the proliferation, migration and invasion of TNBC cells, weathers circDUSP16 knockdown exerted the opposite effect. In vivo studies confirmed that circDUSP16 knockdown can inhibit tumor growth. Using bioinformatics analysis, circDUSP16/miR-1224-3p/TFDP2 pathway was predicted and cascaded. Mechanistically, circDUSP16 was shown to promote the progression of TNBC via the miR-1224-3p/TFDP2 axis. Additionally, THP, a commonly used anthracycline chemotherapy drug, was found to downregulate circDUSP16, suggesting that its therapeutic effects on TNBC may be mediated through circDUSP16/miR-1224-3p/TFDP2 pathway. Our findings suggest that circDUSP16 is a promising biomarker and potential therapeutic target for TNBC.","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"116719"},"PeriodicalIF":5.3,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142876132","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Harnessing nuclear receptors to modulate hepatic stellate cell activation for liver fibrosis resolution. 利用核受体调节肝星状细胞活化以解决肝纤维化。

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2024-12-20 DOI: 10.1016/j.bcp.2024.116730

Yaxin Sun, Xiaoyan Yuan, Zhenhua Hu, Yuanyuan Li

{"title":"Harnessing nuclear receptors to modulate hepatic stellate cell activation for liver fibrosis resolution.","authors":"Yaxin Sun, Xiaoyan Yuan, Zhenhua Hu, Yuanyuan Li","doi":"10.1016/j.bcp.2024.116730","DOIUrl":"10.1016/j.bcp.2024.116730","url":null,"abstract":"With the recent approval of Resmetirom as the first drug targeting nuclear receptors for metabolic dysfunction-associated steatohepatitis (MASH), there is promising way to treat MASH-associated liver fibrosis. However, liver fibrosis can arise from various pathogenic factors, and effective treatments for fibrosis due to other causes remain elusive. The activation of hepatic stellate cells (HSCs) represents a central link in the pathogenesis of hepatic fibrosis. Therefore, harnessing nuclear receptors to modulate HSC activation may be an effective approach to resolving the complex liver fibrosis caused by various factors. In this comprehensive review, we systematically explore the structure and physiological functions of nuclear receptors, shedding light on their multifaceted roles in HSC activation. Recent advancements in drug development targeting nuclear receptors are discussed, providing insights into their potential as rational and effective therapeutic targets for modulating HSC activation in the context of liver fibrosis. By elucidating the intricate interplay between nuclear receptors and HSC activation, this review contributes to the discovery of new nuclear receptor targets in HSCs for resolving hepatic fibrosis.","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"116730"},"PeriodicalIF":5.3,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142876134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Protective effects of cannabinoid receptor 2 on annulus fibrosus degeneration by upregulating autophagy via AKT-mTOR-p70S6K signal pathway. 大麻素受体2通过AKT-mTOR-p70S6K信号通路上调自噬对纤维环变性的保护作用。

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2024-12-20 DOI: 10.1016/j.bcp.2024.116734

Yubo Mao, Pengfei Zhu, Jiale Wang, Chunyang Fan, Zilin Yu, Lingye Yao, Wei He, Xinyun Li, Feng Zhou, Minfeng Gan, Xiexing Wu, Dechun Geng

{"title":"Protective effects of cannabinoid receptor 2 on annulus fibrosus degeneration by upregulating autophagy via AKT-mTOR-p70S6K signal pathway.","authors":"Yubo Mao, Pengfei Zhu, Jiale Wang, Chunyang Fan, Zilin Yu, Lingye Yao, Wei He, Xinyun Li, Feng Zhou, Minfeng Gan, Xiexing Wu, Dechun Geng","doi":"10.1016/j.bcp.2024.116734","DOIUrl":"10.1016/j.bcp.2024.116734","url":null,"abstract":"As an important pathological process, annulus fibrosus (AF) degeneration contributes greatly to intervertebral disc degeneration (IVDD). Moreover, extracellular matrix (ECM) degradation and AF cell (AFC) autophagy are of utmost importance. The involvement of cannabinoid receptor type 2 (CB2) in the pathological mechanisms underlying different diseases has been demonstrated dueto its capacity toregulateautophagy. The objective of this study was to explore the impact of CB2-induced autophagy on AF degeneration and its underlying mechanism. First, the expression of CB2 in human degenerative AF tissues decreased with increasing degeneration degree, whereas its expression in rat AFCs increased in a concentration- and time-dependent manner following H2O2 intervention. Activation of CB2 increased collagen Ⅰ and Ⅱ expression while decreasing MMP3 and MMP13 expression. In addition, p62 expression decreased, whereas beclin-1 and LC3-Ⅱ/LC3-Ⅰ expression increased after JWH133 intervention. After CB2 activation, the addition of 3-MA impeded the synthesis of collagen Ⅰ and Ⅱ while preserving the elevated levels of MMP3 and MMP13. The activation of CB2 greatly suppressed the protein levels of the AKT/mTOR/p70S6K signaling pathway. In vivo, the JWH133 group exhibited elevated disk height index (DHI) and MRI signals, along with a comparatively intact structure of the intervertebral disc in contrast to the vehicle group. In general, CB2 activation could modulate apoptosis and autophagy in rat AFCs, thereby mitigating the advancement of IVDD. Moreover, the AKT/mTOR/p70S6K signaling pathway plays a role in the development of AF degeneration through the regulation of autophagy. The findings suggest that CB2 is a potentially effective therapeutic target for IVDD.","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"116734"},"PeriodicalIF":5.3,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142876138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

IL-1β stimulates a novel axis within the NFκB pathway in endothelial cells regulated by IKKα and TAK-1. IL-1β在IKKα和TAK-1调控的内皮细胞中刺激NFκB通路中的新轴。

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2024-12-20 DOI: 10.1016/j.bcp.2024.116736

Rachel Craig, Kathryn McIntosh, Ka Ho Ho, Ashley McCulloch, Christopher Riley, Christopher Lawson, Simon P Mackay, Andrew Paul, Paul Coats, Robin Plevin

{"title":"IL-1β stimulates a novel axis within the NFκB pathway in endothelial cells regulated by IKKα and TAK-1.","authors":"Rachel Craig, Kathryn McIntosh, Ka Ho Ho, Ashley McCulloch, Christopher Riley, Christopher Lawson, Simon P Mackay, Andrew Paul, Paul Coats, Robin Plevin","doi":"10.1016/j.bcp.2024.116736","DOIUrl":"10.1016/j.bcp.2024.116736","url":null,"abstract":"In this study we examined the activation of the non-canonical NFκB signalling pathway in endothelial cells. In HUVECs, LIGHT stimulated a delayed induction of serine 866/870 p100 phosphorylation linked to p52 NFκB formation. Surprisingly, the canonical ligand, IL-1β, stimulated a rapid phosphorylation or p100 which was not associated with p52 formation. Inhibition of IKKα activity, using DN-IKKα adenovirus, IKKα siRNA or a novel first-in-class selective IKKα inhibitor, SU1261, revealed IL-1β induced p100 phosphorylation to be dependent on IKKα. In contrast, IKKβ inhibition was found to be without effect. The NIK inhibitor, CW15337, did not affect IL-1β induced p100 phosphorylation however, both p100 and pIKKα/β phosphorylation was substantially reduced by inhibition of the upstream kinase TAK-1, suggesting phosphorylation of p100 is mediated by IKKα from within the canonical NEMO/IKKβ /IKKα complex. IL-1β also stimulated a rapid increase in nuclear translocation of p52, which was not affected by NIK inhibition, suggesting a source of p52 independent of p100 processing. Inhibition of TAK-1 abolished p52 and p65 nuclear translocation in response to IL-1β. SiRNA deletion or inhibition with dominant-negative virus of IKKα activity partially reduced p52 translocation, however pharmacological inhibition of IKKα was without effect. Inhibition of IKKβ abolished both p52 and p65 translocation. Taken together these results show that IL-1β stimulates a novel IKKα -dependent axis within the non-canonical NFκB pathway in endothelial cells which is NIK-independent and regulated by TAK-1. However, this pathway is not primarily responsible for the early nuclear translocation of p52, which is dependent on IKKβ. Elucidation of both these new pathways may be significant for NFκB biology within the endothelium.","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"116736"},"PeriodicalIF":5.3,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142876136","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

E3 ubiquitin ligase ITCH-mediated proteasomal degradation of WBP2 sensitizes breast cancer cells to chemotherapy through restraining AMOTL2/c-JUN axis. 瘙痒介导的WBP2蛋白酶体降解通过抑制AMOTL2/c-JUN轴使乳腺癌细胞对化疗敏感。

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2024-12-19 DOI: 10.1016/j.bcp.2024.116720

Maoshu Zhu, Weimin Zhong, Solomon Wong, Xianyang Luo, Zhicong Hong, Juli Lin, Junhua Wu, Yi Zhou, Zhongquan Qi, Shuai Chen

{"title":"E3 ubiquitin ligase ITCH-mediated proteasomal degradation of WBP2 sensitizes breast cancer cells to chemotherapy through restraining AMOTL2/c-JUN axis.","authors":"Maoshu Zhu, Weimin Zhong, Solomon Wong, Xianyang Luo, Zhicong Hong, Juli Lin, Junhua Wu, Yi Zhou, Zhongquan Qi, Shuai Chen","doi":"10.1016/j.bcp.2024.116720","DOIUrl":"10.1016/j.bcp.2024.116720","url":null,"abstract":"Our study had demonstrated that WW domain-binding protein 2 (WBP2) conferred chemoresistance in breast cancer (BC). However, the underlying mechanism remains unclear. Herein, a decreased expression of itchy E3 ubiquitin protein ligase (ITCH) was observed in drug-resistant BC tissues which negatively regulated the expression of WBP2. However, ligase-deficient ITCH C830A mutant missed this function. WBP2 upregulation-initiated the chemoresistance to doxorubicin was reversed by exogenous ITCH, which was not affected by ITCH C830A mutant. In in vivo model, exogenous ITCH obstructed WBP2-mediated chemoresistance, which was destroyed by the proteasome inhibitor (MG132). Upon RNA sequencing, the excessive activations of angiomotin-like 2 (AMOTL2) and c-JUN (Jun proto-oncogene, AP-1 transcription factor subunit) were screened in WBP2-overexpressed BC cells. Additionally, AMOTL2 and endonuclear phosphorylated c-JUN were at a high level in chemoresistant BC tumors and WBP2-overexpressed BC cells. Mechanistically, exogenous ITCH transfection prevented the activation of AMOTL2/c-JUN induced by WBP2 overexpression, which was restored by MG132-mediated inhibition on ITCH activation. The increase of multiple drug-resistant proteins caused by WBP2 upregulation were restrained by AMOTL2 knockdown or c-JUN antagonist, respectively. Our findings present how ITCH/WBP2 signaling functions to link the intricate AMOTL2/c-JUN signaling networks in chemoresistant BC cells. Targeting WBP2 combined with c-JUN inhibitors may be a potential option to overcome chemoresistance in breast cancer patients.","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"116720"},"PeriodicalIF":5.3,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871126","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Histone acetylation alteration by KAT6A inhibitor WM-1119 suppresses IgE-mediated mast cell activation and allergic inflammation via reduction in AP-1 signaling. KAT6A抑制剂WM-1119的组蛋白乙酰化改变通过减少AP-1信号传导抑制ige介导的肥大细胞活化和过敏性炎症。

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2024-12-19 DOI: 10.1016/j.bcp.2024.116732

Yu-Xin Jiao, Yan-Mei Zhou, Zi-Wen Zhou, Yong He, Shan Liu, Xue-Ting Xu, Kunmei Ji, Jia-Jie Chen

{"title":"Histone acetylation alteration by KAT6A inhibitor WM-1119 suppresses IgE-mediated mast cell activation and allergic inflammation via reduction in AP-1 signaling.","authors":"Yu-Xin Jiao, Yan-Mei Zhou, Zi-Wen Zhou, Yong He, Shan Liu, Xue-Ting Xu, Kunmei Ji, Jia-Jie Chen","doi":"10.1016/j.bcp.2024.116732","DOIUrl":"10.1016/j.bcp.2024.116732","url":null,"abstract":"Activation of immunoglobulin E (IgE)-associated mast cells (MCs) triggers the onset of pro-inflammatory signals associated with type I allergic diseases. Although histone acetylation changes have been associated with inflammatory diseases, the impact of lysine-acetyltransferase (KAT) inhibitors on IgE-mediated MCs function is unclear. Potential anti-allergic effects of the KAT6A inhibitor WM-1119 on IgE-mediated MCs activation and allergic inflammation were examined in this study. WM-1119 was observed to reduce IgE-mediated degranulation in rat basophilic leukemia-2H3 cells (RBLs) and murine bone marrow-derived mast cells (BMMCs), as demonstrated by reduced the release of β-hexosaminidase (β-hex)or histamine(HA) and decreased inflammatory cytokines. Additionally, WM-1119 attenuated allergic responses in IgE-induced passive cutaneous anaphylaxis (PCA) and active systemic anaphylaxis (ASA) mice. No WM-1119 effects on histamine-induced hypothermia in mice were observed. Mechanically, WM-1119 reduced levels of histone H3 lysine 14 acetylation (H3K14ac) and H3K27ac, while also reducing IgE-induced MAPK or NF-κB activity. Moreover, WM-1119 reduced activator protein-1 (AP-1) activity in a manner involving inhibition of c-Fos transcription and translation together with decreased AP-1 binding of its downstream promoters. KAT6A knockdown in MCs also reduced AP-1 activity by inhibiting c-Fos expression. H3K14ac enrichment in the Fos promoter was observed, indicating that H3K14ac may regulate c-Fos expression. In conclusion, KAT6A inhibition or knockdown was shown to reduce IgE-mediated MCs activation and allergic inflammation through a mechanism involving changes in c-Fos expression and downstream AP-1 activity consequent to down-regulation of histone acetylation. KAT6A inhibition may represent a new treatment strategy for suppressing MCs in treating allergic diseases.","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"116732"},"PeriodicalIF":5.3,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Proteomic and cytokine profiling of a CTRP8-RXFP1 glioma mouse model. CTRP8-RXFP1胶质瘤小鼠模型的蛋白质组学和细胞因子分析。

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2024-12-19 DOI: 10.1016/j.bcp.2024.116722

Thatchawan Thanasupawat, Yared Pages Mejia, Santhosh S Anandhan, Yaxiong Guo, Jasneet Tiwana, Adline Fernando, Aleksandra Glogowska, Talia Shafai, Simone daSilva, Nimrat Kaur, Farhana Begum, Rene Zahedi, Sabine Hombach-Klonisch, Thomas Klonisch

{"title":"Proteomic and cytokine profiling of a CTRP8-RXFP1 glioma mouse model.","authors":"Thatchawan Thanasupawat, Yared Pages Mejia, Santhosh S Anandhan, Yaxiong Guo, Jasneet Tiwana, Adline Fernando, Aleksandra Glogowska, Talia Shafai, Simone daSilva, Nimrat Kaur, Farhana Begum, Rene Zahedi, Sabine Hombach-Klonisch, Thomas Klonisch","doi":"10.1016/j.bcp.2024.116722","DOIUrl":"10.1016/j.bcp.2024.116722","url":null,"abstract":"Glioblastoma (GB) is the most prevalent and aggressive primary brain tumor with fatal outcome due to a lack of effective treatments. We previously identified C1q-tumor necrosis factor-related protein 8 (CTRP8), a new member of the adiponectin family, as a novel agonist of the relaxin family peptide receptor 1 (RXFP1) and showed that the CTRP8-RXFP1 ligand-receptor system facilitates increased invasiveness and chemoresistance in GB cells. In the present study, we have investigated the role of the CTRP8-RXFP1 signaling axis in glioma progression using an orthotopic mouse model xenografted with human U251 glioma cells stably expressing CTRP8 and RXFP1. Our results demonstrate that this in-vivo U251-CTRP8/RXFP1 glioma model promoted the formation of aggressive, highly proliferative glioma that resulted in significantly shorter survival times of xenografted mice. CTRP8/RXFP1 xenografts showed strongly elevated mitotic activity, increased expression of cathepsin B at the migrating front and promoted a pro-inflammatory tumor microenvironment characterized by a strong upregulation of cytokines, among them eotaxin-2 and-3, interleukin (IL)-6, IL-18 and others. Proteomic analysis of xenografted mouse brain identified both human and mouse proteome signatures unique to CTRP8/RXFP1 xenografts compared to U251 xenografts. In conclusion, our results suggest that co-expression of CTRP8 and RXFP1 promotes signaling pathways that generate unique tissue proteomic and inflammatory cytokine signatures which promote glioma aggressiveness. The CTRP-RXFP1 signaling pathway may represent an effective therapeutic target for the treatment of fast-progressing and currently untreatable GB.","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"116722"},"PeriodicalIF":5.3,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The complex interplay between redox dysregulation and mTOR signaling pathway in cancer: A rationale for cancer treatment. 癌症中氧化还原失调和mTOR信号通路之间的复杂相互作用：癌症治疗的基本原理。

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2024-12-19 DOI: 10.1016/j.bcp.2024.116729

Christophe Glorieux, Cinthya Enríquez, Pedro Buc Calderon

{"title":"The complex interplay between redox dysregulation and mTOR signaling pathway in cancer: A rationale for cancer treatment.","authors":"Christophe Glorieux, Cinthya Enríquez, Pedro Buc Calderon","doi":"10.1016/j.bcp.2024.116729","DOIUrl":"10.1016/j.bcp.2024.116729","url":null,"abstract":"The mechanistic target of rapamycin (mTOR) is a highly conserved serine/threonine kinase that plays a critical role in regulating cellular processes such as growth, proliferation, and metabolism in healthy cells. Dysregulation of mTOR signaling and oxidative stress have been implicated in various diseases including cancer. This review aims to provide an overview of the current understanding of mTOR and its involvement in cell survival and the regulation of cancer cell metabolism as well as its complex interplay with reactive oxygen species (ROS). On the one hand, ROS can inhibit or activate mTOR pathway in cancer cells through various mechanisms. Conversely, mTOR signaling can induce oxidative stress in tumor cells notably due to the inhibition in the expression of antioxidant enzyme genes. Since mTOR is often activated and plays crucial role in cancer cell survival, the use of mTOR inhibitors, which often induce ROS accumulation, could be an interesting approach for cancer treatment. This review will address the advantages, disadvantages, combination strategies, and limitations associated with therapeutic modulation of mTOR signaling pathway in cancer treatment.","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"116729"},"PeriodicalIF":5.3,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Brain glucose metabolism: Role of nitric oxide. 脑葡萄糖代谢：一氧化氮的作用。

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2024-12-19 DOI: 10.1016/j.bcp.2024.116728

Asghar Ghasemi, Sajad Jeddi, Khosrow Kashfi

{"title":"Brain glucose metabolism: Role of nitric oxide.","authors":"Asghar Ghasemi, Sajad Jeddi, Khosrow Kashfi","doi":"10.1016/j.bcp.2024.116728","DOIUrl":"10.1016/j.bcp.2024.116728","url":null,"abstract":"One possible reason for failure in achieving optimal glycemic control in patients with type 2 diabetes (T2D) is that less attention has been paid to the brain, a fundamental player in glucose homeostasis, that consumes about 25% of total glucose utilization. In addition, animal and human studies indicate that nitric oxide (NO) is a critical player in glucose metabolism. NO synthesis from L-arginine is lower in patients with T2D, and endothelial NO synthase (eNOS)-derived NO bioavailability is lower in T2D. NO in the nervous system plays a role in neurovascular coupling (NVC) and the hypothalamic control of glucose sensing and energy homeostasis, influencing glucose utilization. This review explores NO's role in the brain's glucose metabolism. Literature indicates that glucose metabolism is different between neurons and astrocytes. Unlike neurons, astrocytes have a higher rate of glycolysis and a greater ability for lactate production. Astrocytes produce a greater amount of NO than neurons. NO inhibits mitochondrial respiration in both neurons and astrocytes and decreases intracellular ATP. NO-induced inhibition of mitochondrial respiration in neurons is not accompanied by compensatory glycolysis because phosphofructokinase 2.3 (PFK2.3), the most potent activator of PFK1 and thus glycolysis, is subjected to ubiquitylation and proteasomal degradation by cadherin-1 (Cdh1)-activated anaphase-promoting complex/cyclosome (APC/C), which leads to a low glycolytic rate in neurons. In astrocytes, NO inhibits mitochondrial respiration, but astrocytes display compensatory glycolysis by activating the adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathway.","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"116728"},"PeriodicalIF":5.3,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0