Journal articles on the topic 'AMPK-WNT Pathway'
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Karadeniz, Fatih, Jung Hwan Oh, Hyun Jin Jo, Jiho Yang, Hyunjung Lee, Youngwan Seo, and Chang-Suk Kong. "Dracunculin Inhibits Adipogenesis in Human Bone Marrow-Derived Mesenchymal Stromal Cells by Activating AMPK and Wnt/β-Catenin Signaling." International Journal of Molecular Sciences 23, no. 2 (January 7, 2022): 653. http://dx.doi.org/10.3390/ijms23020653.
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Increased bone marrow adiposity is widely observed in patients with obesity and osteoporosis and reported to have deleterious effects on bone formation. Dracunculin (DCC) is a coumarin isolated from Artemisia spp. but, until now, has not been studied for its bioactive potential except antitrypanosomal activity. In this context, current study has reported the anti-adipogenic effect of DCC in human bone marrow-derived mesenchymal stromal cells (hBM-MSCs). DCC dose-dependently inhibited the lipid accumulation and expression of adipogenic transcription factors peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer binding protein α (C/EBPα) in hBM-MSCs induced to undergo adipogenesis. To elucidate its action mechanism, the effect of DCC on Wnt/β-catenin and AMPK pathways was examined. Results showed that DCC treatment activated Wnt/β-catenin signaling pathway via AMPK evidenced by increased levels of AMPK phosphorylation and Wnt10b expression after DCC treatment. In addition, DCC treated adipo-induced hBM-MSCs exhibited significantly increased nuclear levels of β-catenin compared with diminished nuclear PPARγ levels. In conclusion, DCC was shown to be able to hinder adipogenesis by activating the β-catenin via AMPK, providing potential utilization of DCC as a nutraceutical against bone marrow adiposity.
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Conza, Domenico, Paola Mirra, Gaetano Calì, Luigi Insabato, Francesca Fiory, Francesco Beguinot, and Luca Ulianich. "Metformin Dysregulates the Unfolded Protein Response and the WNT/β-Catenin Pathway in Endometrial Cancer Cells through an AMPK-Independent Mechanism." Cells 10, no. 5 (April 30, 2021): 1067. http://dx.doi.org/10.3390/cells10051067.
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Multiple lines of evidence suggest that metformin, an antidiabetic drug, exerts anti-tumorigenic effects in different types of cancer. Metformin has been reported to affect cancer cells’ metabolism and proliferation mainly through the activation of AMP-activated protein kinase (AMPK). Here, we show that metformin inhibits, indeed, endometrial cancer cells’ growth and induces apoptosis. More importantly, we report that metformin affects two important pro-survival pathways, such as the Unfolded Protein Response (UPR), following endoplasmic reticulum stress, and the WNT/β-catenin pathway. GRP78, a key protein in the pro-survival arm of the UPR, was indeed downregulated, while GADD153/CHOP, a transcription factor that mediates the pro-apoptotic response of the UPR, was upregulated at both the mRNA and protein level. Furthermore, metformin dramatically inhibited β-catenin mRNA and protein expression. This was paralleled by a reduction in β-catenin transcriptional activity, since metformin inhibited the activity of a TCF/LEF-luciferase promoter. Intriguingly, compound C, a well-known inhibitor of AMPK, was unable to prevent all these effects, suggesting that metformin might inhibit endometrial cancer cells’ growth and survival through the modulation of specific branches of the UPR and the inhibition of the Wnt/β-catenin pathway in an AMPK-independent manner. Our findings may provide new insights on the mechanisms of action of metformin and refine the use of this drug in the treatment of endometrial cancer.
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Fan, Cuihong, Zhaojia Wu, David M. L. Cooper, Adam Magnus, Kim Harrison, B. Frank Eames, Rajni Chibbar, et al. "Activation of Focal Adhesion Kinase Restores Simulated Microgravity-Induced Inhibition of Osteoblast Differentiation via Wnt/Β-Catenin Pathway." International Journal of Molecular Sciences 23, no. 10 (May 17, 2022): 5593. http://dx.doi.org/10.3390/ijms23105593.
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Simulated microgravity (SMG) inhibits osteoblast differentiation (OBD) and induces bone loss via the inhibition of the Wnt/β-catenin pathway. However, the mechanism by which SMG alters the Wnt/β-catenin pathway is unknown. We previously demonstrated that SMG altered the focal adhesion kinase (FAK)-regulated mTORC1, AMPK and ERK1/2 pathways, leading to the inhibition of tumor cell proliferation/metastasis and promoting cell apoptosis. To examine whether FAK similarly mediates SMG-dependent changes to Wnt/β-catenin in osteoblasts, we characterized mouse MC3T3-E1 cells cultured under clinostat-modeled SMG (µg) conditions. Compared to cells cultured under ground (1 g) conditions, SMG reduces focal adhesions, alters cytoskeleton structures, and down-regulates FAK, Wnt/β-catenin and Wnt/β-catenin-regulated molecules. Consequently, protein-2 (BMP2), type-1 collagen (COL1), alkaline-phosphatase activity and matrix mineralization are all inhibited. In the mouse hindlimb unloading (HU) model, SMG-affected tibial trabecular bone loss is significantly reduced, according to histological and micro-computed tomography analyses. Interestingly, the FAK activator, cytotoxic necrotizing factor-1 (CNF1), significantly suppresses all of the SMG-induced alterations in MC3T3-E1 cells and the HU model. Therefore, our data demonstrate the critical role of FAK in the SMG-induced inhibition of OBD and bone loss via the Wnt/β-catenin pathway, offering FAK signaling as a new therapeutic target not only for astronauts at risk of OBD inhibition and bone loss, but also osteoporotic patients.
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Zhao, Jun-Xing, Wan-Fu Yue, Mei-Jun Zhu, and Min Du. "AMP-activated Protein Kinase Regulates β-Catenin Transcription via Histone Deacetylase 5." Journal of Biological Chemistry 286, no. 18 (March 17, 2011): 16426–34. http://dx.doi.org/10.1074/jbc.m110.199372.
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AMP-activated protein kinase (AMPK) is a key regulator of energy metabolism; it is inhibited under obese conditions and is activated by exercise and by many anti-diabetic drugs. Emerging evidence also suggests that AMPK regulates cell differentiation, but the underlying mechanisms are unclear. We hypothesized that AMPK regulates cell differentiation via altering β-catenin expression, which involves phosphorylation of class IIa histone deacetylase 5 (HDAC5). In both C3H10T1/2 cells and mouse embryonic fibroblasts (MEFs), AMPK activity was positively correlated with β-catenin content. Chemical inhibition of HDAC5 increased β-catenin mRNA expression. HDAC5 overexpression reduced and HDAC5 knockdown increased H3K9 acetylation and cellular β-catenin content. HDAC5 formed a complex with myocyte enhancer factor-2 to down-regulate β-catenin mRNA expression. AMPK phosphorylated HDAC5, which promoted HDAC5 exportation from the nucleus; mutation of two phosphorylation sites in HDAC5, Ser-259 and -498, abolished the regulatory role of AMPK on β-catenin expression. In conclusion, AMPK promotes β-catenin expression through phosphorylation of HDAC5, which reduces HDAC5 interaction with the β-catenin promoter via myocyte enhancer factor-2. Thus, the data indicate that AMPK regulates cell differentiation and development via cross-talk with the wingless and Int (Wnt)/β-catenin signaling pathway.
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Chu, Cheng-Wei, Huey-Jiun Ko, Chia-Hua Chou, Tai-Shan Cheng, Hui-Wen Cheng, Yu-Hsin Liang, Yun-Ling Lai, et al. "Thioridazine Enhances P62-Mediated Autophagy and Apoptosis Through Wnt/β-Catenin Signaling Pathway in Glioma Cells." International Journal of Molecular Sciences 20, no. 3 (January 22, 2019): 473. http://dx.doi.org/10.3390/ijms20030473.
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Thioridazine (THD) is a common phenothiazine antipsychotic drug reported to suppress growth in several types of cancer cells. We previously showed that THD acts as an antiglioblastoma and anticancer stem-like cell agent. However, the signaling pathway underlying autophagy and apoptosis induction remains unclear. THD treatment significantly induced autophagy with upregulated AMPK activity and engendered cell death with increased sub-G1 in glioblastoma multiform (GBM) cell lines. Notably, through whole gene expression screening with THD treatment, frizzled (Fzd) proteins, a family of G-protein-coupled receptors, were found, suggesting the participation of Wnt/β-catenin signaling. After THD treatment, Fzd-1 and GSK3β-S9 phosphorylation (inactivated form) was reduced to promote β-catenin degradation, which attenuated P62 inhibition. The autophagy marker LC3-II markedly increased when P62 was released from β-catenin inhibition. Additionally, the P62-dependent caspase-8 activation that induced P53-independent apoptosis was confirmed by inhibiting T-cell factor/β-catenin and autophagy flux. Moreover, treatment with THD combined with temozolomide (TMZ) engendered increased LC3-II expression and caspase-3 activity, indicating promising drug synergism. In conclusion, THD induces autophagy in GBM cells by not only upregulating AMPK activity, but also enhancing P62-mediated autophagy and apoptosis through Wnt/β-catenin signaling. Therefore, THD is a potential alternative therapeutic agent for drug repositioning in GBM.
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Dai, Haoran, Qingquan Liu, and Baoli Liu. "Research Progress on Mechanism of Podocyte Depletion in Diabetic Nephropathy." Journal of Diabetes Research 2017 (2017): 1–10. http://dx.doi.org/10.1155/2017/2615286.
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Diabetic nephropathy (DN) together with glomerular hyperfiltration has been implicated in the development of diabetic microangiopathy in the initial stage of diabetic diseases. Increased amounts of urinary protein in DN may be associated with functional and morphological alterations of podocyte, mainly including podocyte hypertrophy, epithelial-mesenchymal transdifferentiation (EMT), podocyte detachment, and podocyte apoptosis. Accumulating studies have revealed that disruption in multiple renal signaling pathways had been critical in the progression of these pathological damages, such as adenosine monophosphate-activated kinase signaling pathways (AMPK), wnt/β-catenin signaling pathways, endoplasmic reticulum stress-related signaling pathways, mammalian target of rapamycin (mTOR)/autophagy pathway, and Rho GTPases. In this review, we highlight new molecular insights underlying podocyte injury in the progression of DN, which offer new therapeutic targets to develop important renoprotective treatments for DN over the next decade.
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Alqurashi, Roaya S., Audrey S. Yee, Taylor Malone, Sumaiah Alrubiaan, Mary W. Tam, Kai Wang, Rozena R. Nandedwalla, et al. "A Warburg-like metabolic program coordinates Wnt, AMPK, and mTOR signaling pathways in epileptogenesis." PLOS ONE 16, no. 8 (August 6, 2021): e0252282. http://dx.doi.org/10.1371/journal.pone.0252282.
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Epilepsy is a complex neurological condition characterized by repeated spontaneous seizures and can be induced by initiating seizures known as status epilepticus (SE). Elaborating the critical molecular mechanisms following SE are central to understanding the establishment of chronic seizures. Here, we identify a transient program of molecular and metabolic signaling in the early epileptogenic period, centered on day five following SE in the pre-clinical kainate or pilocarpine models of temporal lobe epilepsy. Our work now elaborates a new molecular mechanism centered around Wnt signaling and a growing network comprised of metabolic reprogramming and mTOR activation. Biochemical, metabolomic, confocal microscopy and mouse genetics experiments all demonstrate coordinated activation of Wnt signaling, predominantly in neurons, and the ensuing induction of an overall aerobic glycolysis (Warburg-like phenomenon) and an altered TCA cycle in early epileptogenesis. A centerpiece of the mechanism is the regulation of pyruvate dehydrogenase (PDH) through its kinase and Wnt target genes PDK4. Intriguingly, PDH is a central gene in certain genetic epilepsies, underscoring the relevance of our elaborated mechanisms. While sharing some features with cancers, the Warburg-like metabolism in early epileptogenesis is uniquely split between neurons and astrocytes to achieve an overall novel metabolic reprogramming. This split Warburg metabolic reprogramming triggers an inhibition of AMPK and subsequent activation of mTOR, which is a signature event of epileptogenesis. Interrogation of the mechanism with the metabolic inhibitor 2-deoxyglucose surprisingly demonstrated that Wnt signaling and the resulting metabolic reprogramming lies upstream of mTOR activation in epileptogenesis. To augment the pre-clinical pilocarpine and kainate models, aspects of the proposed mechanisms were also investigated and correlated in a genetic model of constitutive Wnt signaling (deletion of the transcriptional repressor and Wnt pathway inhibitor HBP1). The results from the HBP1-/- mice provide a genetic evidence that Wnt signaling may set the threshold of acquired seizure susceptibility with a similar molecular framework. Using biochemistry and genetics, this paper outlines a new molecular framework of early epileptogenesis and advances a potential molecular platform for refining therapeutic strategies in attenuating recurrent seizures.
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Cai, Jiping, Xiaochen Tian, Jing Ren, Shuai Lu, and Jianli Guo. "Synergistic Effect of Sesamin and γ-Tocotrienol on Promoting Osteoblast Differentiation via AMPK Signaling." Natural Product Communications 17, no. 3 (March 2022): 1934578X2210748. http://dx.doi.org/10.1177/1934578x221074844.
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Background: Sesamin is a rich phytochemical found in sesame seed oil that can promote osteoblast differentiation of rat BMSCs and improve rat bone structure by regulating Wnt/-Catenin pathway. Combined sesamin and γ-Tocotrienol (γ-T3) have been clarified to inhibit the proliferation of breast cancer cells, but their role in osteoporosis has not been explored. This paper aimed to discuss the synergistic effect of sesamin and γ-T3 in osteoporosis and disclose the underlying mechanism. Materials and methods: CCK-8 assay was to appraise the proliferation of hBMSCs after treated with sesamin and γ-T3. Moreover, the proteins in AMPK signaling in osteoblasts pretreated with AMPK inhibitor compound C (CC) were detected after the induction of sesamin and γ-T3. Then, CCK-8, ALP assay and ARS staining were used to analyze whether the proliferation and osteoblast differentiation of hBMSCs was via APMK pathway. RT-qPCR and western blot were conducted to quantify the levels of markers in osteoblasts. Results: It was determined that 5 g/mL sesamin and 1 μM γ-T3 exerted obvious influences on the viability of hBMSCs. Moreover, the co-treatment of sesamin and γ-T3 elevated the protein levels of related factors in AMPK pathway, which was reversed by CC. Furthermore, The proliferation and osteoblast differentiation exhibited remarkable increments upon exposure to both sesamin and γ-T3, whereas CC abolished these effects. Conclusion: In conclusion, the present study presented the first line of evidence to verify the synergystic effects of sesamin and γ-T3 on alleviating osteoporosis, and revealed their effects were realized by modulating the AMPK pathway. This paper has indicated the great potential of combined sesamin and γ-T3 in osteoporosis treatment.
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Yu, Jinpu, and Wenwen Zhang. "532 SOCS3 deficiency blocked autophagy-dependent myeloid differentiation of early-stage myeloid-derived suppressor cells via the miR-155/C/EBPß/Wnt axis." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A568. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0532.
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BackgroundEarly-stage myeloid-derived suppressor cells (eMDSCs) are a newly defined subset of myeloid-derived suppressor cells (MDSCs) that accumulate densely in tumors and potently promote tumor growth and metastasis by suppressing antitumor immune responses in vitro and in vivo. We previously identified a subset of eMDSCs in human breast cancer with a characteristic phenotype of Lin-HLA-DR-CD33+. We also found that SOCS3 deficiency and sustained activation of the JAK/STAT signaling pathway are critical molecular events coordinating the differentiation of eMDSCs, although the distinct molecular regulation has not been fully elucidated.MethodsHerein, we genetically constructed conditional SOCS3 knockout mice with SOCS3 deficiency specifically in the myeloid linage (SOCS3MyeKO). We analyzed the number of eMDSCs in SOCS3MyeKO mice (eMDSCsSOCS3KO). To explore which pathways participated in dysfunctional eMDSC differentiation, we performed whole-genome RNA sequencing and miRNA microarray on CD11b+Gr-1+ cells, eMDSCsfl/fl and eMDSCsSOCS3KO to screen the potential regulatory ceRNA network in eMDSCsSOCS3KO. CD11b+Gr-1+ cells isolated from SOCS3fl/fl mouse spleens were used as mature myeloid cell controls. Furthermore, we applied a specific miR-155 antagonist and the autophagy agonist rapamycin to suppress tumor growth and eMDSC infiltration.ResultsThe transcriptome results and corresponding intervention experiment revealed that the differentiation block in eMDSCsSOCS3KO was caused by SOCS3 deficiency-mediated limited autophagy activation in an AMPK-independent manner. The results of miRNA microarray and RNA sequencing demonstrated that miR-155 overexpression and Wnt/ß-catenin pathway activation were involved in the SOCS3 knockout-mediated myeloid differentiation block and autophagy repression. Further experiments revealed that miR-155 was induced by activation of the STAT3/NK-?B pathway upon SOCS3 deficiency, which consequently activated the Wnt/ß-catenin pathway via targeting C/EBPß. Furthermore, applying a specific miR-155 antagonist or the autophagy agonist rapamycin efficiently suppressed tumor growth and eMDSC infiltration in vivo.ConclusionsOverall, these findings indicated that SOCS3 deficiency blocked autophagy-dependent myeloid differentiation of e-MDSCs via the miR-155/C/EBPß/Wnt axis, and thus targeted therapy against this pathway could be a potential therapeutic target in breast cancer.
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Hicks, Chindo, Jitsuda Sitthi-Amorn, Jessica Douglas, Ritika Ramani, Lucio Miele, Vani Vijayakumar, Cynthia Karlson, James Chipeta, and Gail Megason. "Molecular Analysis of Central Nervous System Disease Spectrum in Childhood Acute Lymphoblastic Leukemia." Clinical Medicine Insights: Oncology 10 (January 2016): CMO.S18180. http://dx.doi.org/10.4137/cmo.s18180.
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Treatment of the central nervous system (CNS) is an essential therapeutic component in childhood acute lymphoblastic leukemia (ALL). The goal of this study was to identify molecular signatures distinguishing patients with CNS disease from those without the disease in pediatric patients with ALL. We analyzed gene expression data from 207 pediatric patients with ALL. Patients without CNS were classified as CNS1, while those with mild and advanced CNS disease were classified as CNS2 and CNS3, respectively. We compared gene expression levels among the three disease classes. We identified gene signatures distinguishing the three disease classes. Pathway analysis revealed molecular networks and biological pathways dysregulated in response to CNS disease involvement. The identified pathways included the ILK, WNT, B-cell receptor, AMPK, ERK5, and JAK signaling pathways. The results demonstrate that transcription profiling could be used to stratify patients to guide therapeutic decision-making in pediatric ALL.
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Cui, Jianzhou, Han-Ming Shen, and Lina Hsiu Kim Lim. "The Role of Autophagy in Liver Cancer: Crosstalk in Signaling Pathways and Potential Therapeutic Targets." Pharmaceuticals 13, no. 12 (November 28, 2020): 432. http://dx.doi.org/10.3390/ph13120432.
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Autophagy is an evolutionarily conserved lysosomal-dependent pathway for degrading cytoplasmic proteins, macromolecules, and organelles. Autophagy-related genes (Atgs) are the core molecular machinery in the control of autophagy, and several major functional groups of Atgs coordinate the entire autophagic process. Autophagy plays a dual role in liver cancer development via several critical signaling pathways, including the PI3K-AKT-mTOR, AMPK-mTOR, EGF, MAPK, Wnt/β-catenin, p53, and NF-κB pathways. Here, we review the signaling pathways involved in the cross-talk between autophagy and hepatocellular carcinoma (HCC) and analyze the status of the development of novel HCC therapy by targeting the core molecular machinery of autophagy as well as the key signaling pathways. The induction or the inhibition of autophagy by the modulation of signaling pathways can confer therapeutic benefits to patients. Understanding the molecular mechanisms underlying the cross-link of autophagy and HCC may extend to translational studies that may ultimately lead to novel therapy and regimen formation in HCC treatment.
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Vernousfaderani, Eisa Kaveh, Negin Akhtari, Sara Rezaei, Yasaman Rezaee, Saba Shiranirad, Melika Mashhadi, Ali Hashemi, Hamed Parsa Khankandi, and Sahar Behzad. "Resveratrol and Colorectal Cancer: A Molecular Approach to Clinical Researches." Current Topics in Medicinal Chemistry 21, no. 29 (December 22, 2021): 2634–46. http://dx.doi.org/10.2174/1568026621666211105093658.
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Phytochemicals are the most valuable and comprehensive structures, which may have a broad range of protective benefits, from reducing inflammation and speeding healing to preventing infection and fighting cancer. Resveratrol (RSV) is a natural phenolic compound from the oligomeric stilbenoids group, which is usually found in daily human diet, such as grape, peanut, berries and grains. It exhibits anti-inflammatory, neuroprotective, antioxidant, and cancer prevention and treatment effects. RSV is thought to have an impressive outcome in colorectal cancer (CRC) treatment through the vital molecules and cancer signaling pathways, including SIRT1, P53, P21, AMPK, ROS, BMP7, COX-2, NO, caspases, Wnt, TNFs, NF-κB, EMT, and pentose phosphate pathway. Therefore, this paper reviews the current researches on the pharmacological effects and pharmacokinetics of resveratrol and its drug delivery system, as well as clinical studies involving CRC.
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Lee, Ji-Won, Jung-Yul Cha, Ki-Ho Park, Yoon-Goo Kang, and Su-Jung Kim. "Effect of flapless osteoperforation-assisted tooth movement on atrophic alveolar ridge: Histomorphometric and gene-enrichment analysis." Angle Orthodontist 88, no. 1 (October 10, 2017): 82–90. http://dx.doi.org/10.2319/061217-388.1.
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ABSTRACT Objective: To investigate the effect of flapless osteoperforation on the tissue response of the atrophic alveolar ridge affected by orthodontic tooth movement (OTM). Materials and Methods: An atrophic alveolar ridge model was established in the mandibular quadrants of eight beagle dogs. As a split-mouth design, the quadrants were randomly divided into group C (OTM only) and group OP (OTM with flapless osteoperforation). The rate of OTM for 10 weeks was compared between groups, and micro-CT-based histomorphometric analysis and RNA-sequencing-based gene-enrichment analysis were performed targeting the atrophic ridge. Results: Group OP displayed more rapid tooth movement with lower bone mineral density and higher trabecular fraction in the atrophic ridge than did group C, showing no intergroup difference of total ridge volume. As contributing biological functional pathways in group OP, the genes related to osteoclast differentiation and TNF signaling pathway were up-regulated and those associated with Wnt signaling pathway and AMPK signaling pathway were down-regulated. Conclusions: Flapless osteoperforation facilitated the rate of OTM toward the atrophic ridge, maintaining low bone density, whereas it did not increase the volume of the atrophic ridge.
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Guo, Hongfang, Rajwali Khan, Sayed Haidar Abbas Raza, Syed Muhammad Suhail, Hamayun Khan, Sher Bahadar Khan, Ayman Hassan Abd El-Aziz, and Linsen Zan. "RNA-Seq Reveals Function of Bta-miR-149-5p in the Regulation of Bovine Adipocyte Differentiation." Animals 11, no. 5 (April 22, 2021): 1207. http://dx.doi.org/10.3390/ani11051207.
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Intramuscular fat is a real challenge for the experts of animal science to improve meat quality traits. Research on the mechanism of adipogenesis provides invaluable information for the improvement of meat quality traits. This study investigated the effect of bta-miR-149-5p and its underlying mechanism on lipid metabolism in bovine adipocytes. Bovine adipocytes were differentiated and transfected with bta-miR-149-5p mimics or its negative control (NC). A total of 115 DEGs including 72 upregulated and 43 downregulated genes were identified in bovine adipocytes. The unigenes and GO term biological processes were the most annotated unigene contributor parts at 80.08%, followed by cellular component at 13.4% and molecular function at 6.7%. The KEGG pathways regulated by the DEGs were PI3K-Akt signaling pathway, calcium signaling pathway, pathways in cancer, MAPK signaling pathway, lipid metabolism/metabolic pathway, PPAR signaling pathway, AMPK signaling pathway, TGF-beta signaling pathway, cAMP signaling pathway, cholesterol metabolism, Wnt signaling pathway, and FoxO signaling pathway. In addition to this, the most important reactome enrichment pathways were R−BTA−373813 receptor CXCR2 binding ligands CXCL1 to 7, R−BTA−373791 receptor CXCR1 binding CXCL6 and CXCL8 ligands, R−BTA−210991 basigin interactions, R−BTA−380108 chemokine receptors binding chemokines, R−BTA−445704 calcium binding caldesmon, and R−BTA−5669034 TNFs binding their physiological receptors. Furthermore, the expression trend of the DEGs in these pathways were also exploited. Moreover, the bta-miR-149-5p significantly (p < 0.01) downregulated the mRNA levels of adipogenic marker genes such as CCND2, KLF6, ACSL1, Cdk2, SCD, SIK2, and ZEB1 in bovine adipocytes. In conclusion, our results suggest that bta-miR-149-5p regulates lipid metabolism in bovine adipocytes. The results of this study provide a basis for studying the function and molecular mechanism of the bta-miR-149-5p in regulating bovine adipogenesis.
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Zou, Yu-Feng, Chun-Wei Xie, Shi-Xin Yang, and Jian-Ping Xiong. "AMPK activators suppress breast cancer cell growth by inhibiting DVL3-facilitated Wnt/β-catenin signaling pathway activity." Molecular Medicine Reports 15, no. 2 (December 29, 2016): 899–907. http://dx.doi.org/10.3892/mmr.2016.6094.
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Stanishevska, N. V. "Signaling pathways involved in pancreatic stellate cells activity and interaction with pancreatic cancer cells." Morphologia 15, no. 2 (December 21, 2021): 7–15. http://dx.doi.org/10.26641/1997-9665.2021.2.7-15.
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Background. The activation, proliferation and migration capabilities of stellate pancreatocytes are guaranteed by a number of signaling molecular mechanisms that support the interaction of tumor cells with the PSC and determine the neoplastic process. Objective The review is a continuation of aт articles series devoted to the modern understanding of the role and functions of stellate pancreatocytes, namely, their involvement in interaction with cancer cells and signaling molecular pathways that provide synergism of the stellate pancreatocyte-cancer cell system. Methods. Data processing was carried out by the method of complex material analysis. Results. The Нedgehog signaling pathway provides interaction between PSC and tumor cells, which involves the leading mediator of this pathway - sHH (sonic hedgehog), the overexpression of which is recorded in the tumor tissue of the pancreas and ensures the formation of the tumor stroma. Stellate pancreatocytes also trigger the HGF / c-Met / survivin signaling pathway for invasion and metastasis. The activation of the PSCs themselves may be mediated by serotonin via the RhoA / ROCK signaling pathway. While the proliferation and migration of these cells, activated by alcohol, HNE (human neutrophil elastase), PDGF, IL-33 PSC are regulated by the MAP kinase and PI3K pathways. The Wnt signaling pathway promotes collagen accumulation. Through the AMPK / mTOR pathway, factor FTY720 induces apoptosis and inhibits the autophagy of stellate pancreatocytes. The interaction of PSC and tumor cells is also mediated through Notch and TGF-β, and through the Hippo signaling pathway with the participation of YAP / TAZ factors, it is possible to suppress the fibrotic activity of PSC. The interaction of stellate pancreatocytes and tumor cells is reflected in a direct correlation between a decrease in autophagy and apoptosis of stellate pancreatocytes and suppression of invasion and migration of tumor cells. This interaction can be mediated by ERK1 / 2 kinase. Among the factors secreted by tumor cells and causing PSC activation are: growth factor β1 (TGF-β1), PAI-1 protein, translation initiation factor 4E (eIF4E), sHH (involving PSC in pain deployment), Exo-Pan and Exo-Mia exosomes (engaging PSCs in carcinogenesis). Deactivation is mediated by colony stimulating factor 1 (CSF1R, cytokine). In turn, stellate pancreatocytes secrete the chemokine CXCL1, which stimulates the migration and invasion of tumor cells, exosomes with multiple miRNAs, which stimulate the proliferation and migration of cancer cells. Сonclusion. The activation of stellate pancreatocytes, which is necessary for the implementation of their fibrotic functions, is mediated through the RhoA / ROCK signaling pathway via serotonin. The Hippo pathway (activation) and AMPK / mTOR (suppression of autophagy and activation of apoptosis) are also involved in the regulation of the activity of stellate pancreatocytes. The interaction between the tumor cell and stellate pancreatocyte occurs through the Hedgehog, Notch, and TGF-β signaling pathways; regulation of invasion and metastasis of cancer cells provides the HGF / c-Met / survivin signaling pathway.
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Ha, Seungmin, Kyung Woon Kim, So Min Lee, Chang Ho Lee, and So Young Kim. "MicroRNA Dysregulation in the Hippocampus of Rats with Noise-Induced Hearing Loss." Oxidative Medicine and Cellular Longevity 2021 (September 6, 2021): 1–11. http://dx.doi.org/10.1155/2021/1377195.
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Although hippocampal changes due to noise-induced hearing loss have been suggested, little is known about the miRNA levels due to these hippocampal changes. Three-week-old Sprague-Dawley rats were divided into noise and control groups ( n = 20 per group). The noise group rats were exposed to white Gaussian noise (115 dB SPL, 4 hours per day) for three days. One day after noise exposure, the hippocampi of rats were harvested and miRNA expressions were analyzed using the Affymetrix miRNA 4.0 microarray ( n = 6 per group). The predicted target genes of each miRNA were retrieved, and the pathways related to the predicted target genes were analyzed. miR-758-5p, miR-210-5p, miR-370-5p, miR-652-5p, miR-3544, miR-128-1-5p, miR-665, miR-188-5p, and miR-874-5p expression increased in the hippocampal tissue of the noise group compared to that in the control group. The overlapping predicted target genes included Bend4, Creb1, Adcy6, Creb5, Kcnj9, and Pten. The pathways related to these genes were the estrogen signaling pathway, vasopressin-regulated water reabsorption, thyroid hormone synthesis, aldosterone synthesis and secretion, insulin secretion, circadian entrainment, insulin resistance, cholinergic synapse, dopaminergic synapse, cGMP-PKG signaling pathway, cAMP signaling pathway, PI3K-Akt signaling pathway, TNF signaling pathway, and AMPK signaling pathway. miR-448-3p, miR204-5p, and miR-204-3p expression decreased in the hippocampal tissue of the noise group compared to that in the control group. The overlapping predicted target genes of these three miRNAs were Rps6kas, Nfactc3, Rictor, Spred1, Cdh4, Cdh6, Dvl3, and Rcyt1b. Pathway analysis suggested that the Wnt signaling pathway is related to Dvl3 and Nfactc3. Noise-induced hearing loss dysregulates miR-758-5p, miR210-5p, miR370-5p, miR-652-5p, miR-3544, miR-128-1-5p, miR-665, miR-188-5p, miR-874-5p, miR-448-3p, miR-204-5p, miR-204-3p, and miR-140-5p expression in the hippocampus. These miRNAs have been predicted to be associated with hormonal, inflammatory, and synaptic pathways.
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Fei, Xiaojuan, Meilin Jin, Yuqin Wang, Taotao Li, Zengkui Lu, Zehu Yuan, Huihua Wang, et al. "Transcriptome reveals key microRNAs involved in fat deposition between different tail sheep breeds." PLOS ONE 17, no. 3 (March 1, 2022): e0264804. http://dx.doi.org/10.1371/journal.pone.0264804.
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MicroRNA (miRNA) is a kind of noncoding RNA whose function involved in various biological processes in neuronal maturation and adipocyte cells, such as differentiation, proliferation, development, apoptosis, and metabolism. Herein, miRNA-Seq was used to identify miRNAs in the tail fat tissue of Hu sheep (short-fat-tailed) and Tibetan sheep (short-thin-tailed). In this study, 155 differentially expression miRNAs (DE miRNAs) were identified, including 78 up-regulated and 77 down-regulated. Among these DE miRNAs, 17 miRNAs were reported and related with lipid metabolism. MiRanda and RNAhybrid software were used to predict the target genes of DE miRNAs, obtaining the number of targeting relationships is 38553. Target genes were enriched by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). 742 terms and 302 single pathways are enriched, including lipid metabolic process, response to lipid, cellular lipid catabolic process, lipid catabolic process, cellular lipid metabolic process, inositol lipid-mediated signaling, calcium channel activity, PI3K-Akt signaling pathway, MAPK signaling pathway, ECM-receptor interaction, AMPK signaling pathway, Wnt signaling pathway and TGF-beta signaling pathway. Notably, miR-379-5p was associated with tail fat deposition of sheep. Dual-Luciferase reporter assays showed miR-379-5p and HOXC9 had targeted relationship. The result of RT-qPCR showed that the expression trend of miR-379-5p and HOXC9 was opposite. miR-379-5p was down-regulated and highly expressed in tail adipose tissue of Tibetan sheep. HOXC9 was highly expressed in adipose tissue of Hu sheep. These results could provide a meaningful theoretical basis for studying the molecular mechanisms of sheep tail adipogenesis.
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Guo, Panpan, Xuerui Yao, Xin Jin, Yongnan Xv, Junfang Zhang, Qiang Li, Changguo Yan, Xiangzi Li, and Namhyung Kim. "Interference with DGAT Gene Inhibited TAG Accumulation and Lipid Droplet Synthesis in Bovine Preadipocytes." Animals 13, no. 13 (July 6, 2023): 2223. http://dx.doi.org/10.3390/ani13132223.
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Triacylglycerol (TGA) is the primary component of intramuscular fat. Expression of diacylglyceryl transferase (DGAT) determines the polyester differentiation ability of precursor adipocytes. The two DGAT isoforms (DGAT1 and DGAT2) play different roles in TAG metabolism. This study investigates the roles of DGAT1 and DGAT2 in signaling pathways related to differentiation and lipid metabolism in Yanbian bovine preadipocytes. sh-DGAT1 (sh-1), sh-DGAT2 (sh-2), and sh-DGAT1 + sh-DGAT2 (sh-1 + 2) were prepared using short interfering RNA (siRNA) interference technique targeting DGAT1 and DGAT2 genes and infected bovine preadipocytes. Molecular and transcriptomic techniques, including differentially expressed genes (DEGs) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway analysis, were used to investigate the effects on the differentiation of Yanbian bovine preadipocytes. After interference with DGAT1 and DGAT2 genes, the contents of TAG and adiponectin were decreased. The TAG content in the sh-2 and sh-1 + 2 groups was significantly lower than that in the sh-NC group. RNA sequencing (RNA-seq) results showed 2070, 2242, and 2446 DEGs in the sh-1, sh-2, and sh-1 + 2 groups, respectively. The DEGs of the sh-2 group were mainly concentrated in the PPAR, AMPK, and Wnt signaling pathways associated with adipocyte proliferation and differentiation. These results demonstrated that at the mRNA level, DGAT2 plays a more important role in lipid metabolism than DGAT1.
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Li, Shijun, Sayed Haidar Abbas Raza, Chunping Zhao, Gong Cheng, and Linsen Zan. "Overexpression of PLIN1 Promotes Lipid Metabolism in Bovine Adipocytes." Animals 10, no. 11 (October 22, 2020): 1944. http://dx.doi.org/10.3390/ani10111944.
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Perilipin 1 (PLIN1) is a protein encoded by the PLIN1 gene in eukaryotes. PLIN1 is a member of the PAT protein family, a family of proteins related to lipid droplet (LD) surface proteins. PLIN1 phosphorylation plays a vital role during fat metabolism of adipose tissue lipolysis and fat storage in adipocytes. However, to further explore the regulation of the PLIN1 gene on the proliferation, differentiation and lipid metabolism of bovine adipocytes. In this study, the mRNA expression of PLIN1, at day six, was the highest during bovine adipocyte differentiation. Moreover, PLIN1 can promote the proliferation and differentiation of preadipocytes in cattle. On the sixth day, after transfection with, and overexpression of, the PLIN1 gene in bovine preadipocytes via adenovirus, cell samples were collected, and transcriptome sequencing was performed. A total of 1923 differentially expressed genes were detected. Through GO and KEGG pathway analysis, the differentially expressed genes were established to be mainly enriched in the AMPK, Wnt, and PPAR signaling pathways related to fat proliferation and differentiation. In conclusion, at the transcriptional level, PLIN1 plays an important role in regulating fat proliferation and metabolism. Additionally, the sequencing results screened new differentially expressed genes related to fat metabolism, providing theoretical support for molecular breeding of Qinchuan beef cattle.
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Jiating, Lin, Ji Buyun, and Zhang Yinchang. "Role of Metformin on Osteoblast Differentiation in Type 2 Diabetes." BioMed Research International 2019 (November 26, 2019): 1–6. http://dx.doi.org/10.1155/2019/9203934.
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Metformin, an effective hypoglycemic, can modulate different points of malignant mass, polycystic ovary syndrome (PCOS), cardiovascular diseases, tuberculosis, and nerve regeneration. Recently, the effect of metformin on bone metabolism has been analyzed. Metformin relies on organic cation transporters (OCT1), a polyspecific cell membrane of the solute carrier 22A (SLC22A) gene family, to facilitate its intracellular uptake and action on complex I of the respiratory chain of mitochondria. These changes activate the cellular energy sensor AMP-activated protein kinase (AMPK). Thus, the increased cellular AMP/ATP ratio causes a dramatic and progressive activation of insulin and lysosomes, resulting in a decrease in intracellular glucose level, which promotes osteoblast proliferation and differentiation. AMPK also phosphorylates runt-related transcription factor 2 (Runx2) at S118, the lineage-specific transcriptional regulators, to promote osteogenesis. Metformin phosphorylates extracellular signal-regulated kinase (ERK), stimulates endothelial and inducible nitric oxide synthases (e/iNOS), inhibits the GSK3β/Wnt/β-catenin pathway, and promotes osteogenic differentiation of osteoblasts. The effect of metformin on hyperglycemia decreases intracellular reactive oxygen species (ROS) and advanced glycation end-products (AGEs) in collagen, and reduced serum levels of insulin-like growth factors (IGF-1) were beneficial for bone formation. Metformin has a certain effect on microangiopathy and anti-inflammation, which can induce osteoporosis, activate the activity of osteoclasts, and inhibit osteoblast activity, and has demonstrated extensive alteration in bone and mineral metabolism. The aim of this review was to elucidate the mechanisms of metformin on osteoblasts in insulin-deficient diabetes.
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Yu, Wanchen, Haijun Zhao, Xin Zong, Xuming Ji, Xiaochun Han, Yanfang Wang, Yanan Zhang, Ke Ma, Ning Cui, and Shijun Wang. "The Effects of Radix Astragali Water Abstract on Energy Metabolism in Rat Yang-Deficiency Cold Syndrome Model through PPAR Signaling Pathway." Evidence-Based Complementary and Alternative Medicine 2018 (November 1, 2018): 1–19. http://dx.doi.org/10.1155/2018/9194362.
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Radix Astragali (RA) herb with warm property and significant “tonifying qi” effects is indicated for the syndrome of internal cold due to Yang deficiency. The purpose of this research was to explore effects of Radix Astragali (RA) through PPAR signaling pathway on gene expression profiles related to energy metabolism in rats with the Yang-deficiency cold (YDC) syndrome, for identifying the pathological mechanism of Yang-deficiency cold (YDC) syndrome and the effects mechanism of RA. The results indicated that RA could significantly increase body weight (BM), cold and heat tendency (CT), overall temperature (OT), rectum temperature (RT), toe temperature (TT), energy intake (EI), and V(O2)/V(CO2) ratio (which indicates basal metabolism, BM) (P<0.05), enhancing the depressed metabolic function in YDC syndrome model rat. Our data also indicated differentially expressed genes (DEGs) related to energy metabolism involving lipids, carbohydrates, and amino acids metabolic process; the expression of CPT-1 and FABP4 (ap2) was improved; PPAR, Glycolysis, Wnt, cAMP, MAPK, AMPK, and fatty acid degradation signaling pathway may be related to energy metabolism. However, the Chinese herbal medicine RA plays a certain role in promoting the metabolism of substances and energy in rats by its warming and beneficial effect. Our results suggest that the mechanism underlying the function of RA may take effect through the regulation of PPAR signaling pathway and related gene expression. Lipids, carbohydrates, and amino acids metabolic process may be affected to adjust the reduced metabolic function in the model animals. In general, results indicate that RA could promote energy metabolism in rats with the YDC syndrome via PPAR signaling pathway regulating the expression of CPT-1 and FABP4 (ap2), which reflected the warm and qi tonifying properties of RA.
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Zang, Shimada, Nakayama, Kim, Chu, Juneja, Kuroyanagi, and Nishimura. "RNA-seq Based Transcriptome Analysis of the Anti-Obesity Effect of Green Tea Extract Using Zebrafish Obesity Models." Molecules 24, no. 18 (September 6, 2019): 3256. http://dx.doi.org/10.3390/molecules24183256.
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Green tea is a popular beverage that is rich in polyphenolic compounds such as catechins. Its major content, (-)-epigallocatechin-3-gallate, has been shown to have beneficial effects on several diseases including cancer, metabolic syndrome, cardiovascular diseases, and neurodegenerative diseases. The aim of this study was to assess the anti-obesity effects and the underlying molecular mechanisms of green tea extract (GTE) using zebrafish larva and adult obesity models. We administered 100 μg/mL GTE to zebrafish larvae and performed a short-term obesogenic test. GTE significantly decreased the visceral adipose tissue volume induced by a high-fat diet. Oral administration (250 µg/g body weight/day) of GTE to adult diet-induced obese zebrafish also significantly reduced their visceral adipose tissue volume, with a reduction of plasma triglyceride and total cholesterol levels. To investigate the molecular mechanism underlying the GTE effects, we conducted RNA sequencing using liver tissues of adult zebrafish and found that GTE may ameliorate the obese phenotypes via the activation of Wnt/β-catenin and adenosine monophosphate-activated protein kinase (AMPK) pathway signaling. In addition, the comparative transcriptome analysis revealed that zebrafish and mammals may share a common molecular response to GTE. Our findings suggest that daily consumption of green tea may be beneficial for the prevention and treatment of obesity.
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AL-Ishaq, Raghad Khalid, Anthony J. Overy, and Dietrich Büsselberg. "Phytochemicals and Gastrointestinal Cancer: Cellular Mechanisms and Effects to Change Cancer Progression." Biomolecules 10, no. 1 (January 8, 2020): 105. http://dx.doi.org/10.3390/biom10010105.
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Gastrointestinal (GI) cancer is a prevailing global health disease with a high incidence rate which varies by region. It is a huge economic burden on health care providers. GI cancer affects different organs in the body such as the gastric organs, colon, esophagus, intestine, and pancreas. Internal and external factors like smoking, obesity, urbanization, genetic mutations, and prevalence of Helicobacter pylori and Hepatitis B and Hepatitis C viral infections could increase the risk of GI cancer. Phytochemicals are non-nutritive bioactive secondary compounds abundantly found in fruits, grains, and vegetables. Consumption of phytochemicals may protect against chronic diseases like cardiovascular disease, neurodegenerative disease, and cancer. Multiple studies have assessed the chemoprotective effect of selected phytochemicals in GI cancer, offering support to their potential towards reducing the pathogenesis of the disease. The aim of this review was to summarize the current knowledge addressing the anti-cancerous effects of selected dietary phytochemicals on GI cancer and their molecular activities on selected mechanisms, i.e., nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), detoxification enzymes, adenosine monophosphate activated protein kinase (AMPK), wingless-related integration site/β-catenin (wingless-related integration site (Wnt) β-catenin, cell apoptosis, phosphoinositide 3-kinases (PI3K)/ protein kinase B AKT/ mammalian target of rapamycin (mTOR), and mitogen-activated protein kinase (MAPK). In this review phytochemicals were classified into four main categories: (i) carotenoids, including lutein, lycopene, and β-carotene; (ii) proanthocyanidins, including quercetin and ellagic acid; (iii) organosulfur compounds, including allicin, allyl propyl disulphide, asparagusic acid, and sulforaphane; and (iv) other phytochemicals including pectin, curcumins, p-coumaric acid and ferulic acid. Overall, phytochemicals improve cancer prognosis through the downregulation of β-catenin phosphorylation, therefore enhancing apoptosis, and upregulation of the AMPK pathway, which supports cellular homeostasis. Nevertheless, more studies are needed to provide a better understanding of the mechanism of cancer treatment using phytochemicals and possible side effects associated with this approach.
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Lee, Michael Sangmin, Callisia Clarke, Zhi-Qin Jiang, Ganiraju C. Manyam, Feng Tian, Yiling Lu, Jeffrey Morris, et al. "Proteomic signatures of colorectal cancer to identify distinct and reproducible subgroups independent of oncogenic mutations." Journal of Clinical Oncology 33, no. 3_suppl (January 20, 2015): 580. http://dx.doi.org/10.1200/jco.2015.33.3_suppl.580.
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580 Background: While colorectal cancer (CRC) has classically been categorized on the basis of oncogenic mutations such as KRAS and BRAF, proteomic analyses directly elucidate the functional state of the cancer cell’s protein signaling, as recently described in a pan-cancer cohort and with mass-spectroscopy in a small CRC cohort. We performed an antibody-based proteomic analysis (reverse-phase protein array; RPPA) of a large cohort at MD Anderson (MDACC) and The Cancer Genome Atlas (TCGA) to determine patterns of protein expression in CRC. Methods: 725 archived CRC tumor samples (263 MDACC discovery set, and 462 TCGA validation set) underwent protein extraction and RPPA at MDACC to determine levels of 127 proteins. With unsupervised hierarchical clustering, samples dichotomized with distinct patterns of protein expression. The proteins with highest discriminatory utility were identified by LIMMA in the discovery set and confirmed in the validation set. Clinical variables and DNA sequencing results were available for correlation. Results: Among the top 30 discriminant proteins for the dichotomized groups in each dataset, 18 were common to both and tended to correlate with each other. One group was notable for high EMT (high fibronectin and collagen VI, low E-cadherin), while the other group was notable for high Akt/TSC/MTOR (high AKT, MTOR, Tuberin), and high RTK pathway components (high BRAF, HER2, HER3). This latter group also was notable for elevated beta-catenin and low CHK1, implicating differential activation of Wnt and cell cycle pathways, and intriguingly had elevated phospho-AMPK and phospho-NFkB. In the MDACC cohort, this latter group was more likely to have mucinous histology (p=0.009 by Fisher’s exact test) and lack lymphovascular invasion (p=0.026). When both TCGA and MDACC cohorts were examined, there was no significant difference in microsatellite instability, PIK3CA, KRAS, or BRAF mutations between the two proteomic groups. Conclusions: CRCs appear to be classifiable into distinct subsets by proteomic features. These findings reflect distinct differences in cellular signaling that are independent of common oncogenic driver mutations.
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Chakravarti, Sayak, Harish Kumar, Suman Mazumder, Sabyasachi Sanyal, Brian G. Van Ness, and Amit Kumar Mitra. "The Anti-Leprosy Drug Clofazimine Synergizes with BTK Inhibitors and Proteasome Inhibitors in Drug-Resistant Mantle Cell Lymphoma." Blood 138, Supplement 1 (November 5, 2021): 1190. http://dx.doi.org/10.1182/blood-2021-154377.
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Abstract Mantle Cell Lymphoma (MCL) is a difficult to cure, highly heterogeneous, and aggressive form of non-Hodgkin lymphoma comprising roughly 7% of all cases with a high recurrence rate and poor long-term prognosis. The reported progression-free survival is about 1-2 years, and median overall survival/OS <3 years. Current first-line MCL therapies include combination regimens like R-CHOP, R-DHAP, Hyper-CVAD, VcR-CAP, etc. However, although patients respond well to initial treatment, most eventually progress to relapsed disease state. BTKis (Bruton's tyrosine kinase inhibitors) such as Ibrutinib are standard targeted therapeutic options for refractory or relapsed (R/R) MCL. The proteasome inhibitor (PI) drug Bortezomib/Velcade/Bz is another FDA-approved targeted drug for R/R MCL. However, despite these recent advances in the treatment landscape, R/R MCL still remains incurable with limited therapeutic options and a median OS<10-15 months. Therefore, there is an unmet need to discover novel drugs against R/R MCL. Previously, we have demonstrated that Clofazimine (CLF), an anti-leprosy drug, could potentially be repurposed for the treatment of chronic myeloid leukemia and PI/IMiD resistant multiple myeloma that also targets subclones representing putative stem-like-cells (CSCs). Notably, using single-cell analysis and high dimensional immunophenotyping or CyTOF (Cytometry Time of Flight), we have also identified molecular networks underpinning CLF+PI synergy. We hypothesize that CLF has strong potential to be repurposed as a novel anti-MCL drug, particularly in a relapsed/refractory setting. For this purpose, we used MCL cell lines representing drug-sensitive (JEKO1, MINO), innate PI/BTKi-resistance (Z138; representing refractory patients), and clonally-derived acquired PI/BTKi-resistance (MINO-R; representing relapse patients) as in vitro model systems and showed i) the efficacy of CLF as a single agent (IC 50= 6.9±3.6 uM) and ii) in combination with PIs (Bz) and BTKis (Ibrutinib, Acalabrutinib) against innate and acquired resistant MCL (Fig.1), as well as iii) the unique targeting of putative CSCs by CLF. Remarkably, CLF+BTKi/PI combination lowered the effective BTKi and PI doses required to achieve desired therapeutic response by >10-folds (estimated dose reduction index for BTKi and PI were 12.43 and 10.99, respectively). Further, mRNA-sequencing followed by differential gene expression analysis using DESeq2 and EdgeR revealed that the top significantly upregulated genes following PI+CLF treatment were GSR, DAP3, and DOK1, which have reported anti-tumorigenic activity. The top significantly downregulated genes EHD1, CBX8, DDX17, SOX12, and COMMD3 have reported pro-survival function. Ingenuity pathway analysis revealed protein ubiquitination pathway and cell cycle arrest at the G2/M phase as the top canonical pathways. Causal network analysis showed synergistic drug action significantly elevated the levels of oxidative stress and unfolded protein response. Additionally, PI+CLF combination potentiated AMPK mediated down-regulation of the mTOR signaling pathway, which further led to direct reduction of Cyclin D1 (aberrantly expressed in MCL) and the downregulation of eIF4-p70S6K signaling. The synergistic drug activity also led to the downregulation of oncogenic pathways like p38 MAPK and NF-kB signaling. Recent studies have indicated that intra-tumor heterogeneity due to the presence of stem-like cells in MCL (MCL-CSCs), including CD45+CD19- MCL-initiating cells (MCL-ICs), relatively quiescent-highly clonogenic aldehyde dehydrogenase (ALDH)+ cells and side populations (SP) may drive drug resistance and disease relapse. Notably, we found that several of the differentially regulated genes are critical for the maintenance and functioning of CSCs. For example, PI+CLF combination downregulates Wnt/β catenin signaling, which is found to be frequently overexpressed in MCL-ICs. HIPPO, another signaling pathway involved in the maintenance of cancer stem-ness and emergence of drug resistance, was also down-regulated. Currently, we are validating the specific targeting of putative MCL-CSCs by CLF. Next, we plan to replicate our findings using PDX models of MCL. CLF is an FDA-approved drug as well as on WHO's List of Essential Medicines. Thus, our study introduces CLF as a novel, safe, and inexpensive therapeutic option for the management of R/R MCL. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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Conza, Domenico, Paola Mirra, Francesca Fiory, Luigi Insabato, Antonella Nicolò, Francesco Beguinot, and Luca Ulianich. "Metformin: A New Inhibitor of the Wnt Signaling Pathway in Cancer." Cells 12, no. 17 (August 30, 2023): 2182. http://dx.doi.org/10.3390/cells12172182.
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The biguanide drug metformin is widely used in type 2 diabetes mellitus therapy, due to its ability to decrease serum glucose levels, mainly by reducing hepatic gluconeogenesis and glycogenolysis. A considerable number of studies have shown that metformin, besides its antidiabetic action, can improve other disease states, such as polycystic ovary disease, acute kidney injury, neurological disorders, cognitive impairment and renal damage. In addition, metformin is well known to suppress the growth and progression of different types of cancer cells both in vitro and in vivo. Accordingly, several epidemiological studies suggest that metformin is capable of lowering cancer risk and reducing the rate of cancer deaths among diabetic patients. The antitumoral effects of metformin have been proposed to be mainly mediated by the activation of the AMP-activated protein kinase (AMPK). However, a number of signaling pathways, both dependent and independent of AMPK activation, have been reported to be involved in metformin antitumoral action. Among these, the Wingless and Int signaling pathway have recently been included. Here, we will focus our attention on the main molecular mechanisms involved.
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Zhou, Xinpei, Ximin Tang, Tao Li, Dandan Li, Zhiting Gong, Xiujun Zhang, Yanjiao Li, Jianhua Zhu, Yong Wang, and Bensi Zhang. "Inhibition of VDAC1 Rescues Aβ1-42-Induced Mitochondrial Dysfunction and Ferroptosis via Activation of AMPK and Wnt/β-Catenin Pathways." Mediators of Inflammation 2023 (February 10, 2023): 1–13. http://dx.doi.org/10.1155/2023/6739691.
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Beta-amyloid (Aβ) accumulation in the brains of Alzheimer’s disease (AD) patients leads to mitochondrial dysfunction and ferroptosis in neurons. Voltage-dependent anion channel 1 (VDAC1) is a major protein in the mitochondrial outer membrane. It has been reported that VDAC1 associated with mitochondrial dysfunction and ferroptosis. However, the mechanism by which VDAC1 regulates mitochondrial dysfunction and ferroptosis of neurons in AD remains unclear. This study is aimed at investigating the mechanism of action of VDAC1 in mitochondrial dysfunction and ferroptosis in neurons of the AD model. In this study, we determined cell viability after treatment with Aβ1-42 via the MTT assay. The SOD, MDA, ROS, and MMP production was measured via the SOD kit, MDA kit, DCFDA staining, and JC-1 staining. The memory abilities of mice were detected via the Morris water maze test. The expression of AMPK/mTOR, Wnt/β-catenin, and GPX4 regulated by VDAC1 was detected via western blotting. Our present study showed that PC12 cells had decreased cell viability, increased LDH release, and decreased GPX4 expression after Aβ1-42 treatment. Meanwhile, Aβ1-42 induced MMP and SOD downregulation and increased MDA and ROS generation in PC12 cells. In addition, the expression of VDAC1 is increased in the brain tissue of AD mice and Aβ1-42-treated PC12 cells. Further investigation of the role of VDAC1 in regulating AD found that all effects induced by Aβ1-42 were reversed by inhibition of VDAC1. Additionally, inhibition of VDAC1 activates the AMPK/mTOR and Wnt/β-catenin pathways. Taken together, these findings demonstrate that inhibition of VDAC1 alleviates mitochondrial dysfunction and ferroptosis in AD neurons by activating AMPK/mTOR and Wnt/β-catenin.
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Kang, Hee Eun, Yoojeong Seo, Jun Seop Yun, Sang Hyun Song, Dawool Han, Eunae Sandra Cho, Sue Bean Cho, et al. "Metformin and Niclosamide Synergistically Suppress Wnt and YAP in APC-Mutated Colorectal Cancer." Cancers 13, no. 14 (July 9, 2021): 3437. http://dx.doi.org/10.3390/cancers13143437.
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The Wnt and Hippo pathways are tightly coordinated and understanding their reciprocal regulation may provide a novel therapeutic strategy for cancer. Anti-helminthic niclosamide is an effective inhibitor of Wnt and is now in a phase II trial for advanced colorectal cancer (CRC) patients. We found that Axin2, an authentic target gene of canonical Wnt, acts as aYAP phosphorylation activator in APC-mutated CRC. While niclosamide effectively suppresses Wnt, it also inhibits Hippo, limiting its therapeutic potential for CRC. To overcome this limitation, we utilized metformin, a clinically available AMPK activator. This combinatory approach not only suppresses canonical Wnt activity, but also inhibits YAP activity in CRC cancer cells and in patient-derived cancer organoid through the suppression of cancer stemness. Further, combinatory oral administration suppressed in vivo tumorigenesis and the cancer progression of APC-MIN mice models. Our observations provide not only a reciprocal link between Wnt and Hippo, but also clinically available novel therapeutics that are able to target Wnt and YAP in APC-mutated CRC.
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Meads, Mark B., Paula Oliveira, Allison Distler, Maria Silva, Karen Burger, Bin Fang, Aunshka Collins, et al. "Identification of Target Pathways Induced By the Multiple Myeloma Tumor Microenvironment Using Activity-Based Protein Profiling and Ex Vivo Protein Kinase Inhibitor Screening." Blood 128, no. 22 (December 2, 2016): 3288. http://dx.doi.org/10.1182/blood.v128.22.3288.3288.
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Abstract Multiple myeloma (MM) is a heterogeneous plasma cell neoplasm that remains all but incurable despite recent advances in treatment. Indeed, nearly all patients eventually experience disease progression or relapse due to a reservoir of residual myeloma cells that appear to persist through pro-survival signaling from interactions with the tumor microenvironment (TME), leading to eventual clonal expansion. Thus, identifying targets that are induced in MM by the TME may reveal new and important targets amenable to therapeutic intervention. To develop a non-biased method to screen bone marrow specimens from myeloma patients for activated targets throughout the course of disease, we used a combination of activity-based protein profiling (ABPP) and a high-throughput protein kinase inhibitor (PKI) screen using a platform that recapitulates the TME. Target validation was then performed using ex vivo functional screens of pathways using MM patient specimens. The MM cell lines MM1.S, H929, and OPM2 were grown in mono-culture or co-culture with HS5 bone marrow stroma cells for 24h and lysates were enriched for ATP binding proteins by affinity purification versus a chemical probe (ActivX, Thermo). Tryptic peptides were measured using discovery proteomics (nano-UPLC and QExactive Plus mass spectrometer). Using this method, 176, 136, and 85 kinases out of a total of 1511, 1409, and 1281 proteins were preferentially enriched by 2-fold change from MM1.S, H929, and OPM2 myeloma cells grown in co-culture conditions with HS5 bone marrow stroma, respectively. Of these, 42 kinases were common to all three and 87 were common to two of three MM cell lines. Kinases were chosen for target validation after pathway analysis using the Kyoto Encyclopedia of Genes and Genomes database to identify signaling networks. To identify functionally relevant signaling networks identified via ABPP experiments, the same MM cell lines were simultaneously screened with 30 protein kinase inhibitors (PKIs) in a novel high throughput viability assay. This label-free method measures the viability of MM cells grown in a collagen matrix with bone marrow stroma cells in 384-well plates to simulate the TME by capturing brightfield images every 30 minutes for 96h using a motorized microscope equipped with an incubation chamber. Digital image analysis software measures live cell numbers by detecting membrane motion and generates viability curves as a function of drug concentration and exposure time (Khin et al. Cancer Research 2014). This functional screen confirming known MM survival networks, validated 12 kinases/PKIs in the context of the TME and highlighted novel targetable pathways. To provide an additional level of screening, the same PKIs were tested in CD138-MACS-selected cells from 15 MM patient specimens in a high-throughput viability assay. Eight PKIs targeting IGFR, PLK1, Abl, mTOR, FAK/Pyk2, ALK, Akt, and Casein Kinase-1δ (CK1δ)/CK1ε also showed significant activity in the 15 primary MM specimens. Our three-tiered pharmaco-proteomic screen identified eight kinases critical to MM survival in the context of the TME. Notably, a highly specific in-house inhibitor of Casein Kinase 1δ/CK1ε, SR-3029, which targets the Wnt/β-catnenin pathway, was identified as the most effective compound assessed as a single agent in our ex vivo viability assay in all patients with an average 36h LD50 of 290nM. This compound is under further investigation in MM (Submitted Abstract: Burger, et al, ASH 2016). Additional studies are underway to functionally interrogate the pathways identified in this screen, including ErbB1/EGFR, EphA1 and AMPK. Future work will optimize this method for evaluation of primary bone marrow specimens with ABPP followed by functional validation to better predict potential clinical response at different disease stages. We anticipate that this iterative "at the moment of care" approach is critical because drug resistant tumor phenotypes fluctuate with therapy, and this strategy can track and define clinically relevant changes in tumor cells in situ after the selection pressures applied by exposure to therapy. Disclosures Shain: Novartis: Speakers Bureau; Amgen/Onyx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda/Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Signal Genetics: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.
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Kostadinov, Rumen, Midhat Farooqi, Byunggil Yoo, Emily Farrow, Shannon Kelley, Margaret Gibson, Neil Miller, Erin M. Guest, and Patrick Brown. "Landscape of Somatic Mutations and Gene Expression Changes in Relapsed Infant MLL-Rearranged Acute Lymphoblastic Leukemia." Blood 128, no. 22 (December 2, 2016): 1735. http://dx.doi.org/10.1182/blood.v128.22.1735.1735.
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Abstract Introduction Relapse of infant ALL with MLL-rearrangement (MLL-r) is an unsolved clinical problem. Of the 80% of infants with ALL that harbor MLL-r, 60% relapse and die with current treatment. The typical pattern of failure is remission induction, followed by early relapse and very low second remission rate (<30%), suggesting rapid emergence of chemoresistant subclones. Previously, whole genome sequencing (WGS) of 22 MLL-r infant ALL cases showed only 1.3 non-silent mutations in the predominant clone at diagnosis and no significant increase of mutations at relapse in 2 diagnosis-relapse pairs (Andersson et al. (2015) Nat. Gen. 47(4):330-337). Here, we examined the extent to which relapse in infant MLL-r ALL is driven by acquisition of new somatic mutations and/or gene expression changes. We assembled a large cohort of 14 paired diagnosis-relapse (DX-RL) infant MLL-r ALL cases treated on Children's Oncology Group (COG) trial AALL0631. MLL partners were 8 AF4, 5 ENL, and 1 unspecified. Paired remission bone marrow samples (RM) served as germline controls. Methods We performed WGS and RNA sequencing (RNA-seq) on 14 DX-RM-RL trios (N=42) using Illumina Hiseq 4000 and 2500. WGS samples were sequenced to a minimum of 90Gb and RNA-seq samples to an average of 8.8Gb. Alignment and variant calling were performed using BWA, GATK. Variants present in DX and/or RL and absent in paired RM samples were considered somatic. Filters included allelic depth threshold of 7 reads, minor allele frequency ≤0.1%, and ACMG category 1-3. RNA-seq gene expression was evaluated using GSNAP, Cufflinks, and Cuffdiff. Genes were ranked by average magnitude of fold change in expression between DX and RL for each case. We combined the gene ranks across cases to identify the 300 most highly activated and inactivated genes in RL, and evaluated gene set enrichment with MSigDB and Ingenuity software. Results In total, we found 148 non-synonymous somatic variants; 20 small (<40 bp) insertions/deletions (indels) and 128 single nucleotide variants (SNVs), of which 108 were missense, 10 nonsense, 8 splicing, and 2 mitochondrial somatic mutations. The mean variant allele frequency was 0.40 ± 0.14 (range 0.15-0.93). The mean number of non-synonymous mutations per case at DX was 1.71 ± 1.21 (range 0-4). Mutations in PIK3CD and NRAS were observed, each only in a single case. No gene was recurrently mutated across diagnostic samples. At RL, the number of mutations retained was 0-3 and the number lost was 0-4 per case. A large number of mutations (mean 8 ± 11.25, range 0-41) were acquired at RL. Notably, 5 of the 14 cases acquired ≥10 mutations at RL. The total number of variants in the cohort increased by 5-fold (24 to 124) from DX to RL. Acquired mutations at RL were observed in NRAS, KRAS, FLT3, BRAF, HIF1A, NOTCH3, and APC, among others. No RL samples shared a similar pattern of SNVs, suggesting the drivers of relapse and chemoresistance are diverse for this disease. MSigDB gene set enrichment analysis showed that the 300 most highly inactivated genes at RL were enriched in gene sets that were targets of H3K27me3, EED, SUZ12, and Polycomb Repression Complex 2 (PRC2) (FDR q<9.30E-14), as well as in gene sets integral to the plasma membrane (q<8.20E-13). Additionally, these highly activated genes were enriched in sets encoding extracellular matrix-associated and other membrane-associated proteins (q<2.24E-14). Ingenuity pathway analysis revealed that the 300 most highly inactivated genes at RL were components of AMPK (p<0.04), BMP (p<0.04), NOTCH, WNT/β-catenin signaling, and B-cell development pathways, and the 300 most highly activated genes were components of IL17- (p<0.05), IL8-, and HIF1α- signaling, and granulocyte cell adhesion (p<0.01) pathways. This suggests that inactivating epigenetic events and dysregulation of cell membrane proteins are significant factors in the development of chemoresistance. Conclusion Relapsed infant MLL-r ALL is characterized by major gains in somatic variants and gene expression changes within cell signaling, adhesion, and B-cell development pathways. No single pathway or specific genomic variant was unifying across cases, but the appearance of mutations in many known cancer-associated genes and pathways suggests emergence of complex subclonal disease at relapse. Further analyses are ongoing to determine the contribution of germline mutations, structural variants, and DNA methylation changes in this cohort. Disclosures No relevant conflicts of interest to declare.
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Song, Youngwoo, Ga Hui Oh, Mi-Bo Kim, and Jae-Kwan Hwang. "Fucosterol inhibits adipogenesis through the activation of AMPK and Wnt/β-catenin signaling pathways." Food Science and Biotechnology 26, no. 2 (April 2017): 489–94. http://dx.doi.org/10.1007/s10068-017-0067-5.
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Zhou, Lei, Shiwei Sun, Tieqi Zhang, Yueming Yu, Liang Xu, Haoran Li, Minghai Wang, and Yang Hong. "ATP-binding cassette g1 regulates osteogenesis via Wnt/β-catenin and AMPK signaling pathways." Molecular Biology Reports 47, no. 10 (September 14, 2020): 7439–49. http://dx.doi.org/10.1007/s11033-020-05800-0.
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Suhail, Hamid, Rattan Ramandeep, Giri Shailendra, Ana deCarvalho, Steven Kalkanis, and Meser Ali. "CBMT-48. TARGETING METABOLIC REPROGRAMMING WITH NANOCURCUMIN IN GLIOBLASTOMA MULTIFORME." Neuro-Oncology 21, Supplement_6 (November 2019): vi43. http://dx.doi.org/10.1093/neuonc/noz175.170.
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Abstract Glioblastoma (GBM) is a highly glycolytic aggressive brain tumor characterized by increased proliferation and resistance to chemotherapy and radiotherapy. AMPK has been reported as tumor suppressor and reprograms the cellular metabolic pathways and produces a metabolic checkpoint on the cell cycle though mTORC1, p53 and other modulators involved in cell proliferation, growth, survival and autophagy. The AMPK activity is diminished in gastric, breast and ovarian tumor cells by activated PI3K-AKT pathways. Cancer cells are able to reprogram their energy metabolism to compensate their high bioenergetic demands needed for their aggressive growth and survival. Curcumin exhibits pleiotropic properties and activate MAPK and leads to suppress p53, Wnt/β-catenin, SHH and PI3K-AKT signaling pathways. Curcumin or diferuloylmethane is a yellow polyphenol extracted from the rhizome of turmeric (Curcuma longa). The absorption, biodistribution, metabolism, and elimination studies of curcumin have, unfortunately, shown only poor absorption, rapid metabolism, and elimination of curcumin as major reasons for poor bioavailability of this interesting polyphenolic compound. We have engineered a curcumin-based nanoparticle (Curc-NP) which demonstrates high water solubility. Curc-NP was effectively transported into the cells by nanoparticles through endocytosis and localized around the nuclei in the cytoplasms. In vitro studies proved that the cytotoxicity of Curc-NP is more effective against U-251 cell line in a dose-dependent manner. Systemic delivery of Curc-NP led to preferentially accumulation in an orthotopic preclinical glioma model minimizing systemic toxic effect. Multicolor microscopy images of the tumor tissue showed that Curc-NP particles were internalized inside tumor cells selectively and localized within nuclei. Curc-NP demonstrated to restore the dysregulated AMPK activity in glioma cells. Curc-NP-induced AMPK activation resulted in inhibition of oncogenic signalling pathways in glioma. Curc-NP-induced metabolic reprograming in glioma cells will be examined and the in vivo therapeutic efficacy of Curc-NP in an experimental rat model of GBM will also be evaluated.
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Balatskyi, Volodymyr V., Oksana L. Palchevska, Lina Bortnichuk, Ana-Maria Gan, Anna Myronova, Larysa L. Macewicz, Viktor O. Navrulin, et al. "β-Catenin Regulates Cardiac Energy Metabolism in Sedentary and Trained Mice." Life 10, no. 12 (December 17, 2020): 357. http://dx.doi.org/10.3390/life10120357.
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The role of canonical Wnt signaling in metabolic regulation and development of physiological cardiac hypertrophy remains largely unknown. To explore the function of β-catenin in the regulation of cardiac metabolism and physiological cardiac hypertrophy development, we used mice heterozygous for cardiac-specific β-catenin knockout that were subjected to a swimming training model. β-Catenin haploinsufficient mice subjected to endurance training displayed a decreased β-catenin transcriptional activity, attenuated cardiomyocytes hypertrophic growth, and enhanced activation of AMP-activated protein kinase (AMPK), phosphoinositide-3-kinase–Akt (Pi3K–Akt), and mitogen-activated protein kinase/extracellular signal-regulated kinases 1/2 (MAPK/Erk1/2) signaling pathways compared to trained wild type mice. We further observed an increased level of proteins involved in glucose aerobic metabolism and β-oxidation along with perturbed activity of mitochondrial oxidative phosphorylation complexes (OXPHOS) in trained β-catenin haploinsufficient mice. Taken together, Wnt/β-catenin signaling appears to govern metabolic regulatory programs, sustaining metabolic plasticity in adult hearts during the adaptation to endurance training.
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Cui, Meng-Ying, Xing Yi, Zhen-Zhen Cao, Dan-Xia Zhu, and Jun Wu. "Targeting Strategies for Aberrant Lipid Metabolism Reprogramming and the Immune Microenvironment in Esophageal Cancer: A Review." Journal of Oncology 2022 (September 5, 2022): 1–27. http://dx.doi.org/10.1155/2022/4257359.
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Esophageal cancer is of high importance to occurrence, development, and treatment resistance. As evidenced by recent studies, pathways (e.g., Wnt/β-catenin, AMPK, and Hippo) are critical to the proliferation, differentiation, and self-renewal of esophageal cancer. In addition, the above pathways play a certain role in regulating esophageal cancer and act as potential therapeutic targets. Over the past few years, the function of lipid metabolism in controlling tumor cells and immune cells has aroused extensive attention. It has been reported that there are intricate interactions between lipid metabolism reprogramming between immune and esophageal cancer cells, whereas molecular mechanisms should be studied in depth. Immune cells have been commonly recognized as a vital player in the esophageal cancer microenvironment, having complex crosstalk with cancer cells. It is increasingly evidenced that the function of immune cells in the tumor microenvironment (TME) is significantly correlated with abnormal lipid metabolism. In this review, the latest findings in lipid metabolism reprogramming in TME are summarized, and the above findings are linked to esophageal cancer progression. Aberrant lipid metabolism and associated signaling pathways are likely to serve as a novel strategy to treat esophageal cancer through lipid metabolism reprogramming.
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Sun, Xingwei, Weiwei Zheng, Chen Qian, Qin Wu, Yuefeng Hao, and Guohai Lu. "Focal adhesion kinase promotes BMP2‐induced osteogenic differentiation of human urinary stem cells via AMPK and Wnt signaling pathways." Journal of Cellular Physiology 235, no. 5 (October 29, 2019): 4954–64. http://dx.doi.org/10.1002/jcp.29374.
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Chen, Yen-Lin, I.-Chuan Yen, Kuen-Tze Lin, Feng-Yi Lai, and Shih-Yu Lee. "4-Acetylantrocamol LT3, a New Ubiquinone from Antrodia cinnamomea, Inhibits Hepatocellular Carcinoma HepG2 Cell Growth by Targeting YAP/TAZ, mTOR, and WNT/β-Catenin Signaling." American Journal of Chinese Medicine 48, no. 05 (January 2020): 1243–61. http://dx.doi.org/10.1142/s0192415x20500615.
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4-acetylantrocamol LT3 (4AALT3), a new ubiquinone from the mycelium of Antrodia cinnamomea (Polyporaceae), has been recently shown to possess anticancer activity. However, the detailed mechanisms of such action remain unclear. In this study, the molecular mechanisms of 4AALT3 on hepatocellular carcinoma cells (HCC) were investigated. Human hepatocellular carcinoma cell line HepG2 cells were treated with concentrations of 4AALT3. Cell viability, colony formation, and the underlying mechanisms were then analyzed by CCK-8, colony formation, qPCR, and Western blotting assays. We found that 4AALT3 significantly decreased cell viability and colony formation in a dose-dependent manner. Accordingly, 4AALT3 significantly decreased protein levels of cyclin B, E1, D1, and D3, thereby facilitating cell cycle arrest. In addition, 4AALT3 significantly suppressed the nuclear localization of Yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ), mammalian target of rapamycin (mTOR), and WNT/[Formula: see text]-catenin signaling pathways, all of which are well-known signaling pathways that contribute to the malignant properties of HCC. These effects are associated with activation of 5′ AMP-activated protein kinase (AMPK) and autophagy. Our findings indicate that 4AALT3 exerts inhibitory effects on HepG2 cell growth via multiple signaling pathways and may be a potential agent for HCC therapy.
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Leskoske, Kristin, Krystine Garcia-Mansfield, Aparna Krishnan, Ritin Sharma, Jessica Rusert, Jill Mesirov, Robert Wechsler-Reya, and Patrick Pirrotte. "OMIC-05. PHOSPHOPROTEOMIC ANALYSIS IDENTIFIES SUBGROUP ENRICHED PATHWAYS AND KINASE SIGNATURES IN MEDULLOBLASTOMA." Neuro-Oncology 23, Supplement_1 (June 1, 2021): i37—i38. http://dx.doi.org/10.1093/neuonc/noab090.152.
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Abstract Medulloblastoma (MB) is classified into four molecular subgroups: wingless (WNT), sonic hedgehog (SHH), Group 3 (G3) and Group 4 (G4), each with different molecular profiles and patient outcomes. Subgroup heterogeneity and low mutational burdens have hindered the identification of actionable therapeutic targets, especially in G3 MB which has a particularly poor prognosis. Therefore, we took a (phospho)-proteomics approach to identify active pathways and potential therapeutic opportunities in twenty orthotopic patient-derived xenograft (PDX) models of MB comprising SHH, G3 and G4 subtypes. Through our enrichment analysis, we identified processes and pathways specifically upregulated in each MB subgroup. We also utilized neural network derived kinase-substrate predictions and kinase activity scores inferred by a heuristic machine learning algorithm to further characterize phosphosignaling activity. We found that MB PDX models recapitulate many features of primary MB tumors including two distinct proteomic subtypes of G3. G3a was enriched for transcription, translation and MYC target genes while G3b was enriched for axon guidance and neurotrophin signaling pathways. Notably, both G3a and G3b contained higher abundance of mitochondrial proteins, suggesting altered tumor metabolism in G3 MB. SHH PDXs displayed increased NFκB and JNK-MAPK signaling. Group 4 MBs most closely resembled differentiated neuronal cells and were enriched for PKC and AMPK signaling as well as DNA repair pathways. In conclusion, we have provided a comprehensive proteomic and phosphoproteomic characterization of commonly studied MB PDX models and revealed new insights into subgroup enriched pathways and kinase activity in MB.
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Dong, Zhen, Muhammad Nadeem Abbas, Saima Kausar, Jie Yang, Lin Li, Li Tan, and Hongjuan Cui. "Biological Functions and Molecular Mechanisms of Antibiotic Tigecycline in the Treatment of Cancers." International Journal of Molecular Sciences 20, no. 14 (July 22, 2019): 3577. http://dx.doi.org/10.3390/ijms20143577.
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As an FDA-approved drug, glycylcycline tigecycline has been used to treat complicated microbial infections. However, recent studies in multiple hematologic and malignant solid tumors reveal that tigecycline treatment induces cell cycle arrest, apoptosis, autophagy and oxidative stress. In addition, tigecycline also inhibits mitochondrial oxidative phosphorylation, cell proliferation, migration, invasion and angiogenesis. Importantly, combinations of tigecycline with chemotherapeutic or targeted drugs such as venetoclax, doxorubicin, vincristine, paclitaxel, cisplatin, and imatinib, have shown to be promising strategies for cancer treatment. Mechanism of action studies reveal that tigecycline leads to the inhibition of mitochondrial translation possibly through interacting with mitochondrial ribosome. Meanwhile, this drug also interferes with several other cell pathways/targets including MYC, HIFs, PI3K/AKT or AMPK-mediated mTOR, cytoplasmic p21 CIP1/Waf1, and Wnt/β-catenin signaling. These evidences indicate that antibiotic tigecycline is a promising drug for cancer treatment alone or in combination with other anticancer drugs. This review summarizes the biological function of tigecycline in the treatment of tumors and comprehensively discusses its mode of action.
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Roelands, Jessica, Wouter Hendrickx, Gabriele Zoppoli, Raghvendra Mall, Mohamad Saad, Kyle Halliwill, Giuseppe Curigliano, et al. "Oncogenic states dictate the prognostic and predictive connotations of intratumoral immune response." Journal for ImmunoTherapy of Cancer 8, no. 1 (April 2020): e000617. http://dx.doi.org/10.1136/jitc-2020-000617.
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BackgroundAn immune active cancer phenotype typified by a T helper 1 (Th-1) immune response has been associated with increased responsiveness to immunotherapy and favorable prognosis in some but not all cancer types. The reason of this differential prognostic connotation remains unknown.MethodsTo explore the contextual prognostic value of cancer immune phenotypes, we applied a multimodal pan-cancer analysis among 31 different histologies (9282 patients), encompassing immune and oncogenic transcriptomic analysis, mutational and neoantigen load and copy number variations.ResultsWe demonstrated that the favorable prognostic connotation conferred by the presence of a Th-1 immune response was abolished in tumors displaying specific tumor-cell intrinsic attributes such as high transforming growth factor-beta (TGF-β) signaling and low proliferation capacity. This observation was independent of mutation rate. We validated this observation in the context of immune checkpoint inhibition. WNT-βcatenin, barrier molecules, Notch, hedgehog, mismatch repair, telomerase activity and AMPK signaling were the pathways most coherently associated with an immune silent phenotype together with mutations of driver genes includingIDH1/2, FOXA2, HDAC3, PSIP1, MAP3K1, KRAS, NRAS, EGFR, FGFR3, WNT5AandIRF7.ConclusionsThis is the first systematic study demonstrating that the prognostic and predictive role of a bona fide favorable intratumoral immune response is dependent on the disposition of specific oncogenic pathways. This information could be used to refine stratification algorithms and prioritize hierarchically relevant targets for combination therapies.
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Hsieh, Mei-Jen, Ching-Chieh Weng, Yu-Chun Lin, Chia-Chen Wu, Li-Tzong Chen, and Kuang-Hung Cheng. "Inhibition of β-Catenin Activity Abolishes LKB1 Loss-Driven Pancreatic Cystadenoma in Mice." International Journal of Molecular Sciences 22, no. 9 (April 28, 2021): 4649. http://dx.doi.org/10.3390/ijms22094649.
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Pancreatic cancer (PC) is the seventh leading cause of cancer death worldwide, and remains one of our most recalcitrant and dismal diseases. In contrast to many other malignancies, there has not been a significant improvement in patient survival over the past decade. Despite advances in our understanding of the genetic alterations associated with this disease, an incomplete understanding of the underlying biology and lack of suitable animal models have hampered efforts to develop more effective therapies. LKB1 is a tumor suppressor that functions as a primary upstream kinase of adenine monophosphate-activated protein kinase (AMPK), which is an important mediator in the regulation of cell growth and epithelial polarity pathways. LKB1 is mutated in a significant number of Peutz–Jeghers syndrome (PJS) patients and in a small proportion of sporadic cancers, including PC; however, little is known about how LKB1 loss contributes to PC development. Here, we report that a reduction in Wnt/β-catenin activity is associated with LKB1 tumor-suppressive properties in PC. Remarkably, in vivo functional analyses of β-catenin in the Pdx-1-Cre LKB1L/L β-cateninL/L mouse model compared to LKB1 loss-driven cystadenoma demonstrate that the loss of β-catenin impairs cystadenoma development in the pancreas of Pdx-1Cre LKB1L/L mice and dramatically restores the normal development and functions of the pancreas. This study further determined the in vivo and in vitro therapeutic efficacy of the β-catenin inhibitor FH535 in suppressing LKB1 loss-driven cystadenoma and reducing PC progression that delineates the potential roles of Wnt/β-catenin signaling in PC harboring LKB1 deficiency.
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Salem, Mohamed A., Barbara Budzyńska, Joanna Kowalczyk, Nesrine S. El Sayed, and Suzan M. Mansour. "Tadalafil and bergapten mitigate streptozotocin-induced sporadic Alzheimer's disease in mice via modulating neuroinflammation, PI3K/Akt, Wnt/β-catenin, AMPK/mTOR signaling pathways." Toxicology and Applied Pharmacology 429 (October 2021): 115697. http://dx.doi.org/10.1016/j.taap.2021.115697.
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Oh, Jung Hwan, Fatih Karadeniz, Mi-Soon Jang, Hojun Kim, Youngwan Seo, and Chang-Suk Kong. "Loliolide from Artemisia princeps Suppresses Adipogenesis in Human Bone Marrow-Derived Mesenchymal Stromal Cells via Activation of AMPK and Wnt/β-catenin Pathways." Applied Sciences 11, no. 12 (June 11, 2021): 5435. http://dx.doi.org/10.3390/app11125435.
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Regulating the adipogenic differentiation mechanism is a valid and promising mechanism to battle obesity. Natural products, especially phytochemicals as nutraceuticals, are important lead molecules with significant activities against obesity. Loliolide is a monoterpenoid hydroxyl lactone found in many dietary plants. The effect of loliolide on adipogenic differentiation is yet to be determined. Therefore, the present study aimed to evaluate its anti-adipogenic potential using human bone marrow-derived mesenchymal stromal cells (hBM-MSCs) and assess its mechanism of action. Adipo-induced hBM-MSCs were treated with or without loliolide and their adipogenic characteristics were examined. Loliolide treatment decreased the lipid accumulation and expression of adipogenic transcription factors, PPARγ, C/EBPα, and SREBP1c. Adipo-induced hBM-MSCs also displayed increased AMPK phosphorylation and suppressed MAPK activation following loliolide treatment according to immunoblotting results. Importantly, loliolide could stimulate Wnt10b expression and active β-catenin translocation to exert PPARγ-linked adipogenesis suppression. In conclusion, loliolide was suggested to be a potential anti-adipogenic agent which may be utilized as a lead compound for obesity treatment or prevention.
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Elango, Ramu, Babajan Banaganapalli, Abdulrahman Mujalli, Nuha AlRayes, Sarah Almaghrabi, Majid Almansouri, Ahmed Sahly, et al. "Potential Biomarkers for Parkinson Disease from Functional Enrichment and Bioinformatic Analysis of Global Gene Expression Patterns of Blood and Substantia Nigra Tissues." Bioinformatics and Biology Insights 17 (January 2023): 117793222311662. http://dx.doi.org/10.1177/11779322231166214.
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The Parkinson disease (PD) is the second most common neurodegenerative disorder affecting the central nervous system and motor functions. The biological complexity of PD is yet to reveal potential targets for intervention or to slow the disease severity. Therefore, this study aimed to compare the fidelity of blood to substantia nigra (SN) tissue gene expression from PD patients to provide a systematic approach to predict role of the key genes of PD pathobiology. Differentially expressed genes (DEGs) from multiple microarray data sets of PD blood and SN tissue from GEO database are identified. Using the theoretical network approach and variety of bioinformatic tools, we prioritized the key genes from DEGs. A total of 540 and 1024 DEGs were identified in blood and SN tissue samples, respectively. Functional pathways closely related to PD such as ERK1 and ERK2 cascades, mitogen-activated protein kinase (MAPK) signaling, Wnt, nuclear factor-κB (NF-κB), and PI3K-Akt signaling were observed by enrichment analysis. Expression patterns of 13 DEGs were similar in both blood and SN tissues. Comprehensive network topological analysis and gene regulatory networks identified additional 10 DEGs functionally connected with molecular mechanisms of PD through the mammalian target of rapamycin (mTOR), autophagy, and AMP-activated protein kinase (AMPK) signaling pathways. Potential drug molecules were identified by chemical-protein network and drug prediction analysis. These potential candidates can be further validated in vitro/in vivo to be used as biomarkers and/or novel drug targets for the PD pathology and/or to arrest or delay the neurodegeneration over the years, respectively.
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Yan, Huimin, Xin Duan, Hua Pan, Nilsson Holguin, Muhammad Farooq Rai, Antonina Akk, Luke E. Springer, Samuel A. Wickline, Linda J. Sandell, and Christine T. N. Pham. "Suppression of NF-κB activity via nanoparticle-based siRNA delivery alters early cartilage responses to injury." Proceedings of the National Academy of Sciences 113, no. 41 (September 28, 2016): E6199—E6208. http://dx.doi.org/10.1073/pnas.1608245113.
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Osteoarthritis (OA) is a major cause of disability and morbidity in the aging population. Joint injury leads to cartilage damage, a known determinant for subsequent development of posttraumatic OA, which accounts for 12% of all OA. Understanding the early molecular and cellular responses postinjury may provide targets for therapeutic interventions that limit articular degeneration. Using a murine model of controlled knee joint impact injury that allows the examination of cartilage responses to injury at specific time points, we show that intraarticular delivery of a peptidic nanoparticle complexed to NF-κB siRNA significantly reduces early chondrocyte apoptosis and reactive synovitis. Our data suggest that NF-κB siRNA nanotherapy maintains cartilage homeostasis by enhancing AMPK signaling while suppressing mTORC1 and Wnt/β-catenin activity. These findings delineate an extensive crosstalk between NF-κB and signaling pathways that govern cartilage responses postinjury and suggest that delivery of NF-κB siRNA nanotherapy to attenuate early inflammation may limit the chronic consequences of joint injury. Therapeutic benefits of siRNA nanotherapy may also apply to primary OA in which NF-κB activation mediates chondrocyte catabolic responses. Additionally, a critical barrier to the successful development of OA treatment includes ineffective delivery of therapeutic agents to the resident chondrocytes in the avascular cartilage. Here, we show that the peptide–siRNA nanocomplexes are nonimmunogenic, are freely and deeply penetrant to human OA cartilage, and persist in chondrocyte lacunae for at least 2 wk. The peptide–siRNA platform thus provides a clinically relevant and promising approach to overcoming the obstacles of drug delivery to the highly inaccessible chondrocytes.
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Zhang, Xuancheng, Zhuochang Cai, Minghu Wu, Xiaoqiao Huangfu, Juehong Li, and Xudong Liu. "Adipose Stem Cell–Derived Exosomes Recover Impaired Matrix Metabolism of Torn Human Rotator Cuff Tendons by Maintaining Tissue Homeostasis." American Journal of Sports Medicine 49, no. 4 (March 2021): 899–908. http://dx.doi.org/10.1177/0363546521992469.
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Background: Adipose stem cell–derived exosomes (ASC-Exos) are reported to effectively prevent muscle atrophy and degeneration of torn rat rotator cuff, but their influence on human samples and their potential mechanism are still unclear. Purpose: We aimed to investigate the effects of ASC-Exos on the metabolic activities of torn human rotator cuff tendons and explore the potential mechanism behind it. Study Design: Controlled laboratory study. Methods: Diseased supraspinatus tendons were harvested from 15 patients with a mean ± SD age of 65.8 ± 3.2 years who underwent reverse shoulder arthroplasty for chronic rotator cuff tears associated with glenohumeral pathological changes. Each tendon was dissected into 3 × 4 × 4–mm explants: the ones derived from the same tendon were placed into 12-well plates and cultured in complete culture media (control) or in complete culture media supplemented with ASC-Exos for 72 hours. Afterward, the concentrations of cytokines secreted into the culture media—including interleukin 1β (IL-1β), IL-6, IL-8, and matrix metalloproteinase 9 (MMP-9)—were measured using enzyme-linked immunosorbent assay (ELISA). Tendons were stained with hematoxylin and eosin and immunohistochemistry (type I and III collagens) for histological analyses. Moreover, the expression of anabolic genes ( TIMP-1 and TIMP-3; type I and III collagen encoding) and catabolic genes ( MMP-9 and MMP-13) in tendons were measured using real-time quantitative polymerase chain reaction. Phosphorylated AMPKα and Wnt/β-catenin pathways were assayed by western blotting to explore the potential mechanism of action of ASC-Exos. Results: Secretion of proinflammatory cytokines, including IL-1β, IL-6, and MMP-9, was significantly reduced in the ASC-Exos group as compared with the control group. Supraspinatus tendons in the ASC-Exos group exhibited superior histological properties, as demonstrated by higher tendon maturing scores and more type I collagen content, but there was no significant difference in type III collagen content between groups. Expression of MMP-9 and MMP-13 genes was decreased in the ASC-Exos group versus the control group. Increased expression of type I and III collagens and an elevated type I/III ratio were found in the ASC-Exos group when compared with the control group. There was no significant difference in the secretion of IL-8 and expression of TIMP-1 and TIMP-3 genes between the ASC-Exos and control groups. Western blotting revealed that ASC-Exos enhanced phosphorylated AMPKα and decreased β-catenin levels to prevent tendon degeneration. Conclusion: ASC-Exos maintained metabolic homeostasis of torn human rotator cuff tendons to improve their histological properties, which might be achieved by enhancing AMPK signaling to suppress Wnt/β-catenin activity. Clinical Relevance: ASC-Exos could be used as an effective biological tool to promote healing in torn human rotator cuff tendons.
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Deutsch, Yehuda E., Aymee Perez, Ana Rodrigues, Ezra S. Blumenthal, Elena Cubedo, Justin M. Watts, Ronan T. Swords, and Arthur Zelent. "Sodium Salicylate Has a Priming Effect When Combined with Azacitidine in Pre-Clinical Models of AML." Blood 124, no. 21 (December 6, 2014): 2300. http://dx.doi.org/10.1182/blood.v124.21.2300.2300.
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Abstract Introduction: Current therapy for acute myeloid leukemia (AML) is inadequate. Treatment of older patients considered unfit for standard induction therapy is particularly challenging (Juliusson et al. Blood 2009). Hypomethylating agents (HMA) are commonly used alternatives for these patients (Fenaux et al. JCO 2010). In the case of azacitidine, complete and partial response rates range between 15-30% (Maurillo et al. Cancer 2012) and the addition of other drugs (e.g. lenalidomide and vorinostat) has been limited by toxicity. In this study, we sought to improve the activity of azacitidine by adding the non-steroidal anti-inflammatory drug (NSAID), sodium salicylate (NSal). NSAIDs exert anti-cancer effects through impaired signal transduction (inhibition of NF-kB and Wnt/B catenin pathways) (Kop et al. Science 1994; Reya et al. Nature 2003), epigenetic modulation and disruption of cellular metabolism (activation of AMPK) (Wang et al. CMLS 2013). In addition, previous reports have demonstrated that NSal combines synergistically with established anti-leukemic agents (daunorubicin) (Klampfer et al. Blood 1999), through down-regulation of the anti-apoptotic protein Mcl-1. Importantly, NSal has no effect on platelet function and a small pilot trial (N=11) confirmed the clinical feasibility of this agent in patients with refractory myeloid neoplasms (Klimek et al. Leukemia Research 2012). In this study, therapeutic plasma concentrations of NSal were safely achieved without excessive NSAID class effects (GI and renal toxicity, bleeding). Here, we report the in vitro effects of NSal combined with azacitidine and suggest a rationale for exploring this combination further in the clinic. Methods: AML cell lines (HL-60, KG-1a and THP-1) were treated with increasing concentrations of NSal (0.2–20mM), azacitidine (0.02-10µM) and both agents combined. Consequent effects on cell viability were measured by trypan blue exclusion and cell proliferation assay (MTT based). Apoptosis was measured by FACS analysis for propidium iodide (PI) and annexin V binding. Synergistic lethality was calculated using the Chou-Talalay method (Calcusyn software). Critical mediators underlying mechanism were measured by immunoblotting (Mcl-1). Results: The degree of apoptosis in AML cells treated with sub-lethal concentrations of NSal (0.2-20mM) and azacitidine (0.02-10µM) was compared to the degree of apoptosis induced by the combination. Little effect on the viability of HL-60, KG-1a and THP-1 cell lines was observed after 48 hours exposure to either agent alone, however, in the presence of 2 µM azacitidine and 2mM NSal, 39.2% of THP-1 cells were dead at 48 hours (annexin V binding). The combination of 0.2 µM azacitidine and 2mM NSal had significantly inhibited cell proliferation at 72 hours. Cell proliferation decreased by 47.4%, 25%, and 66.1% in HL-60, KG-1a, and THP-1, cell lines, respectively. Combination index (CI) values (Calcusyn software) were less than 1 indicating synergistic activity. The expression of Mcl-1 decreased in a dose- and time-dependent manner in salicylate treated cells which might account for its ability to enhance cell killing by azacitidine. Conclusions: Sodium salicylate has a priming effect when combined with azacitidine in pre-clinical models of AML. Despite the high pre-clinical concentrations of NSal evaluated, previous studies have confirmed the feasibility of achieving therapeutically active plasma concentrations in patients (Klimek et al. Leukemia Research 2012). This study forms a rationale for a clinical investigation of this approach. Additional in vitro mechanistic studies elucidating the combined effects of NSal and azacitidine will be presented. Disclosures No relevant conflicts of interest to declare.
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Chang, Bill H., Jessica Leonard, Joelle Wolf, Michelle Degnin, Kyle Lenz, Beth Wilmot, Charles G. Mullighan, et al. "Significant In Vivo Sensitivity to Aurora Kinase Inhibition in TCF3-Hlf rearranged Acute Lymphoblastic Leukemia." Blood 132, Supplement 1 (November 29, 2018): 4026. http://dx.doi.org/10.1182/blood-2018-99-115706.
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Abstract Acute Lymphoblastic Leukemia (ALL) harboring the t(17;19)(q22;p13) is a rare subtype of leukemia with a dismal prognosis. This recurring translocation produces an aberrant TCF3-HLF fusion with distinct gene expression profiles and drug sensitivity. Recent studies have shown that this subtype of ALL might be targeted using therapies inhibiting BCL-2 and the pre-B cell receptor through inhibition of SRC family kinases. However, preliminary validation of these studies have revealed significant heterogeneity of response to BCL-2 and SRC inhibitors. As such, we sought to identify other possible targets that could overcome this heterogeneity and improve response to therapy. Methods: One local as well as four other samples from the Children's Oncology Group's ALL Biorepository with TCF3-HLF ALL were expanded in immunodeficient NSG mice. All samples were verified by RT-PCR and Sanger sequencing for the fusion transcript. Samples were then interrogated with our functional drug screen that is comprised of compounds with activity against two-thirds of the tyrosine kinome as well as other non-tyrosine kinase pathways, including RAF/MEK/MAPKs, PI3K/AKT/mTOR, AMPK, ATM, Aurora kinases, CAMKs, CDKs, GSK3a/b, IKK, PKA, PKC, PLK1, and RAF as well as BCL2 family, BRD4, IDH1/2, Hedgehog, HSP90, NOTCH/g-secretase, proteasome, survivin, STAT3, and WNT/b-catenin. The samples were sequenced using the Agilent SureSelect Strand-Specific RNA Library Preparation Kit on the Bravo robot (Agilent). All five patient samples successfully engrafted into NSG mice and were tested for in vivo sensitivity as assessed for disease burden or survival. Results: Three patient samples were identified to carry Type I translocations fusing exon 13 of TCF3 with variable intronic insertions followed by exon 4 of HLF. All three type I translocations produced different fusions due to different lengths within the variable region. One sample predicted a truncation product of TCF3 ending in exon 13 with an early stop codon within the variable region. Two patient samples carried the identical type II translocation fusing Exon 12 of TCF3 with exon 4 of HLF. RNA-seq results of the five samples identified other individual translocations, but none involved other specific disease related lesions. Results from our drug screen showed significant heterogeneity in response to the majority of drugs assayed including the ABL/SRC inhibitor dasatinib and the BCL-2 inhibitor venetoclax. Further, in vivo studies exposing cohorts of animals to vehicle (n=5), dasatinib (40mg/kg/day; n=5), venetoclax (25-100mg/kg/day; n=5) or combination of dasatinib and venetoclax (n=5) identified only two samples with treatment benefit. Interestingly, review of the results of the drug screen suggested hypersensitivity to aurora kinase inhibitors. Each sample was tested in vivo in cohorts of vehicle (n=5) and alisertib (30mg/kg/day; n=5). All five ALL samples showed significant response (p<0.01 for all five samples compared to their respective vehicle controls by Chi Square analysis). All animals tolerated treatment and no animal showed significant hematologic toxicity from treatment with drugs. Conclusion: Our results suggest that TCF3-HLF ALL is a heterogeneous subset of ALL with both different gene expression patterns from TCF3-HLF to other fusions as well as functional drug response. In vivo validation in the murine model with these five samples suggests significant heterogeneity to current pursued targets such as BCL-2 and SRC compared to previously published reports. Most intriguing, all samples tested with alisertib identified significant in vivo response suggesting unique preclinical support to pursue further clinical testing within this rare and lethal subtype of ALL. Disclosures Leonard: Amgen: Research Funding. Mullighan:Loxo Oncology: Research Funding; Pfizer: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Abbvie: Research Funding; Cancer Prevention and Research Institute of Texas: Consultancy. Tyner:Takeda: Research Funding; Vivid Biosciences: Membership on an entity's Board of Directors or advisory committees; Array: Research Funding; Genentech: Research Funding; Incyte: Research Funding; Constellation: Research Funding; Aptose: Research Funding; Janssen: Research Funding; AstraZeneca: Research Funding; Gilead: Research Funding. Druker:GRAIL: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Research Funding; Leukemia & Lymphoma Society: Membership on an entity's Board of Directors or advisory committees, Research Funding; Patient True Talk: Consultancy; Fred Hutchinson Cancer Research Center: Research Funding; ARIAD: Research Funding; Beta Cat: Membership on an entity's Board of Directors or advisory committees; Oregon Health & Science University: Patents & Royalties; McGraw Hill: Patents & Royalties; Novartis Pharmaceuticals: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; Vivid Biosciences: Membership on an entity's Board of Directors or advisory committees; ALLCRON: Consultancy, Membership on an entity's Board of Directors or advisory committees; MolecularMD: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Henry Stewart Talks: Patents & Royalties; Blueprint Medicines: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Monojul: Consultancy; Celgene: Consultancy; Third Coast Therapeutics: Membership on an entity's Board of Directors or advisory committees; Aileron Therapeutics: Consultancy; Aptose Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Cepheid: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millipore: Patents & Royalties.
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Wang, Qinghua, Zuming Mao, Zhuang Liu, Man Xu, Shuai Huang, Yin Wang, Yanran Xu, Longju Qi, Mei Liu, and Yan Liu. "Akt/mTOR integrate energy metabolism with Wnt signal to influence wound epithelium growth in Gekko Japonicus." Communications Biology 5, no. 1 (September 27, 2022). http://dx.doi.org/10.1038/s42003-022-04004-5.
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AbstractThe formation of wound epithelium initiates regeneration of amputated tail in Gekko japonicus. Energy metabolism is indispensable for the growth of living creatures and typically influenced by temperature. In this study, we reveal that low temperature lowers energy metabolism level and inhibits the regeneration of amputated tails of Gekko japonicus. We further find that low temperature attenuates the activation of protein kinase B (Akt) and mammalian target of rapamycin (mTOR) in regenerated tissues upon injury signals, and the inhibition of Akt hinders proliferation of the wound epithelium. Additionally, wingless/integrated (Wnt) inhibition suppresses epithelium proliferation and formation by inhibiting Akt activation. Finally, low temperature elevates the activity of adenylate-activated kinase (AMPK) pathway and in turn attenuates wound epithelium formation. Meanwhile, either mTOR downregulation or AMPK upregulation is associated with worse wound epithelium formation. Summarily, low temperature restricts wound epithelium formation by influencing energy sensory pathways including Akt/mTOR and AMPK signaling, which is also modulated by injury induced Wnt signal. Our results provide a mechanism that incorporates the injury signals with metabolic pathway to facilitate regeneration.