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Search results for: GSK3β (Phospho-Ser9) Antibody

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#33422940   2020/12/28 To Up

Immune checkpoint inhibition in syngeneic mouse cancer models by a silicasome nanocarrier delivering a GSK3 inhibitor.

Checkpoint blocking antibodies that interfere in the PD-1/PD-L1 axis provide effective cancer immunotherapy for tumors that are immune inflamed or induced to become "hot". It has also been demonstrated that a small molecule inhibitor of the signaling hub kinase GSK3 can interfere in the PD-1/PD-L1 axis in T-cells by suppressing PD-1 expression. This provides an alternative approach to intervening in the PD-1/PD-L1 axis to provide cancer immunotherapy. In this communication, we demonstrate the remote loading of GSK3 inhibitor AZD1080 into the porous interior of mesoporous silica nanoparticles coated with a lipid bilayer (a.k.a. silicasomes). In a MC38 colon cancer model, intravenous injection (IV) of silicasome-encapsulated AZD1080 significantly improved biodistribution and drug delivery to the tumor site. The improved drug delivery was accompanied by cytotoxic MC38 tumor cell killing by perforin-releasing CD8 T-cells, exhibiting reduced PD-1 expression. IV injection of encapsulated AZD1080 also resulted in significant tumor shrinkage in other syngeneic mouse tumor models, including another colorectal tumor (CT26), as well as pancreas (KPC) and lung (LLC) cancer models. Not only was the therapeutic efficacy of encapsulated AZD1080 similar or better than anti-PD-1 antibody, but the treatment was devoid of treatment toxicity. These results provide proof-of-principal demonstration of the feasibility of using encapsulated delivery of a GSK3 inhibitor to provide cancer immunotherapy, with the possibility to be used as a monotherapy or in combination with chemotherapy or other immunomodulatory agents.
Sean D Allen, Xiangsheng Liu, Jinhong Jiang, Yu-Pei Liao, Chong Hyun Chang, Andre E Nel, Huan Meng

1524 related Products with: Immune checkpoint inhibition in syngeneic mouse cancer models by a silicasome nanocarrier delivering a GSK3 inhibitor.

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#33179111   2020/11/12 To Up

Astragaloside‑IV modulates NGF‑induced osteoblast differentiation via the GSK3β/β‑catenin signalling pathway.

Astragaloside (AST) is derived from the Chinese herb Astragalus membranaceus, and studies have demonstrated that it promotes differentiation of bone marrow‑derived mesenchymal stem cells (BMSCs). To the best of our knowledge, however, the functions of the component AST‑IV in osteogenesis have not previously been elucidated. The present study aimed to verify the effects of AST‑IV in osteogenesis. First, the proliferation and differentiation status of human BMSCs incubated with AST‑IV were analysed and compared with a control (no AST‑IV treatment). In order to determine the involvement of the glycogen synthase kinase (GSK)3β signalling pathway in AST‑IV, overexpression and inhibition of GSK3β was induced during incubation of BMSCs with AST‑IV. In order to investigate how neuronal growth factor (NGF) contributes to BMSCs differentiation, BMSCs were co‑incubated with an anti‑NGF antibody and AST IV, and then levels of osteogenesis markers were assessed. The results demonstrated for the first time that AST‑IV contributed to BMSCs differentiation. Furthermore, the GSK3β/β‑catenin signalling pathway was revealed to be involved in AST‑IV‑induced osteogenesis; moreover, AST‑IV accelerated differentiation by enhancing the expression levels of NGF. In summary, the present study demonstrated that AST‑IV promotes BMSCs differentiation, thus providing a potential target for the treatment of osteoporosis.
Nan-Yang Sun, Xiao-Lan Liu, Juan Gao, Xiao-Hui Wu, Ben Dou

1455 related Products with: Astragaloside‑IV modulates NGF‑induced osteoblast differentiation via the GSK3β/β‑catenin signalling pathway.

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#32972302   2020/10/22 To Up

TSPAN1 promotes autophagy flux and mediates cooperation between WNT-CTNNB1 signaling and autophagy via the -FAM83A-TSPAN1 axis in pancreatic cancer.

Pancreatic cancer is one of the most aggressive tumors associated with a poor clinical prognosis, weakly effective therapeutic options. Therefore, there is a strong impetus to discover new therapeutic targets in pancreatic cancer. In the present study, we first demonstrated that TSPAN1 is upregulated in pancreatic cancer and that TSPAN1 depletion decreases pancreatic cancer cell proliferation and . TSPAN1 expression was correlated with poor overall survival of pancreatic cancer patients. Moreover, we demonstrated that TSPAN1 is a novel positive regulator of macroautophagy/autophagy characterized by decreased LC3-II and SQSTM1/p62 expressions, inhibited puncta formation of GFP-LC3 and autophagic vacuoles. We also demonstrated that mutation impaired autophagy in the zebrafish model. Furthermore, we showed that TSPAN1 promoted autophagy maturation via direct binding to LC3 by two conserved LIR motifs. Mutations in the LIR motifs of TSPAN1 resulted in a loss of the ability to induce autophagy and promote pancreatic cancer proliferation. Second, we discovered two conservative TCF/LEF binding elements present in the promoter region of the gene, which was further verified through luciferase activity and ChIP assays. Furthermore, TSPAN1 was upregulated by FAM83A through the canonical WNT-CTNNB1 signaling pathway. We further demonstrated that both TSPAN1 and FAM83A are both direct targets of (microRNA 454). Additionally, we revealed the role of -FAM83A-TSPAN1 in the proliferation of pancreatic cancer cells and . Our findings suggest that components of the -FAM83A-TSPAN1 axis may be valuable prognosis markers or therapeutic targets for pancreatic cancer.: AMPK: adenosine 5'-monophosphate (AMP)-activated protein kinase; APC: APC regulator of WNT signaling pathway; ATG: autophagy related; AXIN2: axin 2; BECN1: beclin 1; CCND1: cyclin D1; CSNK1A1/CK1α: casein kinase 1 alpha 1; CTNNB1/β-catenin: catenin beta 1; DAPI: 4'6-diamino-2-phenylindole; EBSS: Earle's balanced salt solution; EdU: 5-ethynyl-20-deoxyuridine; FAM83A: family with sequence similarity 83 member A; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; GSEA: gene set enrichment analysis; GSK3B: glycogen synthase kinase 3 beta; IHC: immunohistochemical; LAMP1: lysosomal associated membrane protein 1; LIR: LC3-interacting region; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; : microRNA 454; miRNA: microRNA; MKI67: antigen identified by monoclonal antibody Ki 67; MTOR: mechanistic target of rapamycin kinase; MTT: 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide; MYC: MYC proto-oncogene, bHLH transcription factor; OS: overall survival; PDAC: pancreatic ductal adenocarcinoma; RAB7A: RAB7A, member RAS oncogene family; shRNA: short hairpin RNA; SQSTM1: sequestosome 1; TBE: TCF/LEF binding element; TCGA: The Cancer Genome Atlas; TCF/LEF: transcription factor/lymphoid enhancer binding factor; TCF4: transcription factor 4; TSPAN1: tetraspanin 1; TUNEL: terminal deoxynucleotidyl transferase mediated dUTP nick end labeling; UTR: untranslated region; WT: wild type.
Cefan Zhou, Yanyan Liang, Li Zhou, Yanan Yan, Nanxi Liu, Rui Zhang, Yuan Huang, Ming Wang, Yongfei Tang, Declan William Ali, Yefu Wang, Marek Michalak, Xing-Zhen Chen, Jingfeng Tang

2676 related Products with: TSPAN1 promotes autophagy flux and mediates cooperation between WNT-CTNNB1 signaling and autophagy via the -FAM83A-TSPAN1 axis in pancreatic cancer.



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#32692785   2020/07/21 To Up

Screening of tau protein kinase inhibitors in a tauopathy-relevant cell-based model of tau hyperphosphorylation and oligomerization.

Tauopathies are a class of neurodegenerative disorders characterized by abnormal deposition of post-translationally modified tau protein in the human brain. Tauopathies are associated with Alzheimer's disease (AD), chronic traumatic encephalopathy (CTE), and other diseases. Hyperphosphorylation increases tau tendency to aggregate and form neurofibrillary tangles (NFT), a pathological hallmark of AD. In this study, okadaic acid (OA, 100 nM), a protein phosphatase 1/2A inhibitor, was treated for 24h in mouse neuroblastoma (N2a) and differentiated rat primary neuronal cortical cell cultures (CTX) to induce tau-hyperphosphorylation and oligomerization as a cell-based tauopathy model. Following the treatments, the effectiveness of different kinase inhibitors was assessed using the tauopathy-relevant tau antibodies through tau-immunoblotting, including the sites: pSer202/pThr205 (AT8), pThr181 (AT270), pSer202 (CP13), pSer396/pSer404 (PHF-1), and pThr231 (RZ3). OA-treated samples induced tau phosphorylation and oligomerization at all tested epitopes, forming a monomeric band (46-67 kDa) and oligomeric bands (170 kDa and 240 kDa). We found that TBB (a casein kinase II inhibitor), AR and LiCl (GSK-3 inhibitors), cyclosporin A (calcineurin inhibitor), and Saracatinib (Fyn kinase inhibitor) caused robust inhibition of OA-induced monomeric and oligomeric p-tau in both N2a and CTX culture. Additionally, a cyclin-dependent kinase 5 inhibitor (Roscovitine) and a calcium chelator (EGTA) showed contrasting results between the two neuronal cultures. This study provides a comprehensive view of potential drug candidates (TBB, CsA, AR, and Saracatinib), and their efficacy against tau hyperphosphorylation and oligomerization processes. These findings warrant further experimentation, possibly including animal models of tauopathies, which may provide a putative Neurotherapy for AD, CTE, and other forms of tauopathy-induced neurodegenerative diseases.
Hamad Yadikar, Isabel Torres, Gabrielle Aiello, Milin Kurup, Zhihui Yang, Fan Lin, Firas Kobeissy, Richard Yost, Kevin K Wang

2991 related Products with: Screening of tau protein kinase inhibitors in a tauopathy-relevant cell-based model of tau hyperphosphorylation and oligomerization.

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#32098116   2020/02/21 To Up

Antigen-Based Nano-Immunotherapy Controls Parasite Persistence, Inflammatory and Oxidative Stress, and Cardiac Fibrosis, the Hallmarks of Chronic Chagas Cardiomyopathy, in A Mouse Model of Infection.

Chagas cardiomyopathy is caused by (). We identified two candidate antigens (TcG2 and TcG4) that elicit antibodies and T cell responses in naturally infected diverse hosts. In this study, we cloned and in a nanovector and evaluated whether nano-immunotherapy (referred as nano2/4) offers resistance to chronic Chagas disease. For this, C57BL/6 mice were infected with and given nano2/4 at 21 and 42 days post-infection (pi). Non-infected, infected, and infected mice treated with pcDNA3.1 expression plasmid encoding (referred as p2/4) were used as controls. All mice responded to infection with expansion and functional activation of splenic lymphocytes. Flow cytometry showed that frequency of splenic, poly-functional CD4 and CD8 T cells expressing interferon-γ, perforin, and granzyme B were increased by immunotherapy (nano2/4 > p2/4) and associated with 88%-99.7% decline in cardiac and skeletal (SK) tissue levels of parasite burden (nano2/4 > p2/4) in Chagas mice. Subsequently, nano2/4 mice exhibited a significant decline in peripheral and tissues levels of oxidative stress (e.g., 4-hydroxynonenal, protein carbonyls) and inflammatory infiltrate that otherwise were pronounced in Chagas mice. Further, nano2/4 therapy was effective in controlling the tissue infiltration of pro-fibrotic macrophages and established a balanced environment controlling the expression of collagens, metalloproteinases, and other markers of cardiomyopathy and improving the expression of (encodes β myosin heavy chain) and (encodes glycogen synthase kinase 3) required for maintaining cardiac contractility in Chagas heart. We conclude that nano2/4 enhances the systemic T cell immunity that improves the host's ability to control chronic parasite persistence and Chagas cardiomyopathy.
Nandadeva Lokugamage, Subhadip Choudhuri, Carolina Davies, Imran Hussain Chowdhury, Nisha Jain Garg

2734 related Products with: Antigen-Based Nano-Immunotherapy Controls Parasite Persistence, Inflammatory and Oxidative Stress, and Cardiac Fibrosis, the Hallmarks of Chronic Chagas Cardiomyopathy, in A Mouse Model of Infection.

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#32067159   2020/02/17 To Up

CEPO (carbamylated erythropoietin)-Fc protects hippocampal cells in culture against beta amyloid-induced apoptosis: considering Akt/GSK-3β and ERK signaling pathways.

The tissue-protective properties of erythropoietin (EPO) have been described in several neurodegenerative diseases models, but erythrocytosis following EPO treatment may lead to deleterious effects. Carbamylated erythropoietin, an EPO derivative lacking hematopoietic side effects, has shown protective properties in some studies. However, it is not known if CEPO protects primary hippocampal cells against Aβ toxicity. The present study aimed to investigate the effect of CEPO-Fc on biochemical alterations in Akt, GSK-3β, and ERK signaling and cell death induced by Aβ in isolated hippocampal cell culture. The embryonic hippocampal cells were obtained from 18-19 day rat embryos. The cells were exposed with Aβ (20 µM) in the absence or presence of CEPO-Fc (1 or 5 IU) and PI3k and ERK inhibitors. CEPO-Fc at the dose of 5 IU significantly prevented the cell loss and caspase-3 cleavage caused by Aβ. Additionally, CEPO-Fc noticeably reversed Aβ mediated decrement of Akt and GSK-3β phosphorylation. With exposure to LY294002, PI3 kinase inhibitor, Akt phosphorylation diminished and CEPO-Fc protective effects disappeared. Furthermore, while CEPO-Fc nullified Aβ-induced increment of phospho-ERK, inhibition of ERK activity by PD98059, had no effect on Aβ-mediated caspase-3 cleavage and cell toxicity. These results imply that protective effects of CEPO-Fc seem to be mainly exerted through the PI3K/Akt pathway rather than ERK signaling. This study suggested that CEPO-Fc prevents Aβ-induced cell toxicity as well as Akt/GSK-3β and ERK alterations in isolated hippocampal cells. These findings might provide a new perspective on CEPO-Fc protective properties as a prospective remedial factor for neurodegenerative diseases like AD.
Etrat Hooshmandi, Maryam Moosavi, Hermann Katinger, Shima Sardab, Rasoul Ghasemi, Nader Maghsoudi

1180 related Products with: CEPO (carbamylated erythropoietin)-Fc protects hippocampal cells in culture against beta amyloid-induced apoptosis: considering Akt/GSK-3β and ERK signaling pathways.

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#32066788   2020/02/17 To Up

Dietary AGEs involvement in colonic inflammation and cancer: insights from an in vitro enterocyte model.

The number of colon cancer cases is increasing worldwide, and type II diabetes patients have an increased risk of developing colon cancer. Diet-borne advanced glycation end-products (AGEs) may promote neoplastic transformation; however, the mechanisms involved remain elusive. The present study helped to define the relationship between dietary AGEs and cancer progression. C2BBe1 adenocarcinoma enterocytes were exposed to 200 µg/mL glycated casein (AGEs-Csn) for up to 24 h. AGEs-Csn exposure resulted in increased cell proliferation, maladaptative changes in SOD and CAT activity and moderate levels of hydrogen peroxide (HO) intracellular accumulation. AGEs-Csn activated pro-survival and proliferation signalling, such as the phosphorylation of mTOR (Ser2448) and Akt (Ser473). GSK-3β phosphorylation also increased, potentially inducing extracellular matrix remodelling and thus enabling metastasis. Moreover, AGEs-Csn induced MMP-1, -3, -7, -9 and -10 expression and activated MMP-2 and MMP-9, which are regulators of the extracellular matrix and cytokine functions. AGEs-Csn induced inflammatory responses that included extracellular IL-1β at 6 h; time-dependent increases in IL-8; RAGE and NF-κB p65 upregulation; and IκB inhibition. Co-treatment with anti-RAGE or anti-TNF-α blocking antibodies and AGEs-Csn partially counteracted these changes; however, IL-8, MMP-1 and -10 expression and MMP-9 activation were difficult to prevent. AGEs-Csn perpetuated signalling that led to cell proliferation and matrix remodelling, strengthening the link between AGEs and colorectal cancer aggressiveness.
Ovidiu I Geicu, Loredana Stanca, Sorina N Voicu, Anca Dinischiotu, Liviu Bilteanu, Andreea I Serban, Valentin Calu

2587 related Products with: Dietary AGEs involvement in colonic inflammation and cancer: insights from an in vitro enterocyte model.

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#31815045   2019/11/01 To Up

Disulfiram combined with copper induces immunosuppression via PD-L1 stabilization in hepatocellular carcinoma.

As a potential antitumor drug and chemotherapeutic sensitizer, disulfiram combined with Copper (DSF/Cu) does not exert considerable antitumor effects on an immunocompetent hepatocellular carcinoma (HCC) model. In this article, we will explore the mechanism underlying the resistance to DSF in HCC. We analyzed the antitumor effect of DSF/Cu in vivo studies. Tumor and immune cells collected from mice were analyzed by flow cytometry. Then, we analyzed the transcriptional changes in liver cancer cells after DSF/Cu treatment by transcriptional expression profiling. The expression of PD-L1 was detected by real-time PCR, Western blotting and flow cytometry. The expression of PARP1 and GSK3β was knocked down by small interfering RNAs (siRNAs). A subcutaneous Hepa1-6 tumor model was used for single-drug or combined-drug studies. Tissue chips (268 samples of liver cancer tissue) were used to analyze the relationship among PARP1, p-GSK3β and PD-L1. We found that DSF/Cu failed to inhibit HCC tumor growth in C57BL/6 mice. DSF/Cu upregulated PD-L1 expression by inhibiting PARP1 activity and enhancing GSK3β phosphorylation at Ser9 and ultimately inhibited T cell infiltration. The combination of DSF/Cu and an anti-PD-1 antibody produced an additive effect that slowed HCC growth in mice. In addition, we observed negative associations between PARP1 and p-GSK3β (Ser9) or PD-L1 expression in tumor tissue samples from HCC patients. Through in vitro and in vivo studies, we found that DSF/Cu could restrain GSK3β activity by inhibiting PARP1, leading to the upregulation of PD-L1 expression. Combination therapy with DSF/Cu and an anti-PD-1 antibody showed much better antitumor efficacy than monotherapy.
Binghai Zhou, Lei Guo, Bo Zhang, Shuang Liu, Kewei Zhang, Jiuliang Yan, Wentao Zhang, Mincheng Yu, Zheng Chen, Yongfeng Xu, Yongsheng Xiao, Jian Zhou, Jia Fan, Hui Li, Qinghai Ye

1994 related Products with: Disulfiram combined with copper induces immunosuppression via PD-L1 stabilization in hepatocellular carcinoma.



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