Glycogen Synthase Kinase-3 (GSK-3)-Targeted Therapy and Imaging

Theranostics, Год журнала: 2016, Номер 6(4), С. 571 - 593

Опубликована: Янв. 1, 2016

Glycogen synthase kinase-3 (GSK-3) is associated with various key biological processes, including glucose regulation, apoptosis, protein synthesis, cell signaling, cellular transport, gene transcription, proliferation, and intracellular communication.Accordingly, GSK-3 has been implicated in a wide variety of diseases specifically targeted for both therapeutic imaging applications by large number academic laboratories pharmaceutical companies.Here, we review the structure, function, expression levels, ligand-binding properties its connection to diseases.A selected list highly potent inhibitors, IC 50 <20 nM adenosine triphosphate (ATP)-competitive inhibitors <5 μM non-ATP-competitive were analyzed structure activity relationships.Furthermore, ubiquitous possible impact on therapy are also highlighted.Finally, rational perspective route selective effective discussed.

Язык: Английский

---

‘WNT-er is coming’: WNT signalling in chronic lung diseases

Thorax, Год журнала: 2017, Номер 72(8), С. 746 - 759

Опубликована: Апрель 17, 2017

Chronic lung diseases represent a major public health problem with only limited therapeutic options. An important unmet need is to identify compounds and drugs that target key molecular pathways involved in the pathogenesis of chronic diseases. Over last decade, there has been extensive interest investigating Wingless/integrase-1 (WNT) signalling pathways; WNT signal alterations have linked pulmonary disease progression. Here, we comprehensively review cumulative evidence for pathway pathologies, including idiopathic fibrosis, arterial hypertension, asthma COPD. While many studies focused on canonical WNT/β-catenin pathway, recent reports highlight non-canonical may also significantly contribute pathologies; these will be particularly featured this review. We further discuss advances uncovering role early life, potential pharmaceutically modulating (pre)clinical describing promising new therapies

Язык: Английский

---

Butyrate induces ROS-mediated apoptosis by modulating miR-22/SIRT-1 pathway in hepatic cancer cells

Redox Biology, Год журнала: 2017, Номер 12, С. 340 - 349

Опубликована: Март 7, 2017

Butyrate is one of the short chain fatty acids, produced by gut microbiota during anaerobic fermentation dietary fibres. It has been shown that it can inhibit tumor progression via suppressing histone deacetylase and induce apoptosis in cancer cells. However, comprehensive pathway which butyrate mediates growth arrest cells still remains unclear. In this study, role miR-22 butyrate-mediated ROS release induction was determined hepatic Intracellular expression increased when Huh 7 were incubated with sodium butyrate. Over-expression or addition inhibited SIRT-1 enhanced production. Incubation anti-miR-22 reversed effects induced production, cytochrome c activation caspase-3, whereas N-acetyl cysteine these butyrate-induced effects. Furthermore, cell proliferation, changes. The PTEN gsk-3 found to be while p-akt β-catenin decreased significantly These data showed modulated both proliferation

Язык: Английский

---

Neuroprotective Functions for the Histone Deacetylase SIRT6

Cell Reports, Год журнала: 2017, Номер 18(13), С. 3052 - 3062

Опубликована: Март 1, 2017

The histone deacetylase SIRT6 promotes DNA repair, but its activity declines with age a concomitant accumulation of damage. Furthermore, knockout mice exhibit an accelerated aging phenotype and die prematurely. Here, we report that brain-specific SIRT6-deficient survive present behavioral defects major learning impairments by 4 months age. Moreover, the brains these show increased signs damage, cell death, hyperphosphorylated Tau—a critical mark in several neurodegenerative diseases. Mechanistically, regulates Tau protein stability phosphorylation through activation kinase GSK3α/β. Finally, mRNA levels are reduced patients Alzheimer’s disease. Taken together, our results suggest is to maintain genomic brain loss leads toxic phosphorylation. Therefore, downstream signaling could be targeted disease age-related neurodegeneration.

Язык: Английский

---

Glycogen synthase kinase‐3β is a pivotal mediator of cancer invasion and resistance to therapy

Cancer Science, Год журнала: 2016, Номер 107(10), С. 1363 - 1372

Опубликована: Авг. 3, 2016

Tumor cell invasion and resistance to therapy are the most intractable biological characteristics of cancer and, therefore, challenging for current research treatment paradigms. Refractory cancers, including pancreatic glioblastoma, show an inextricable association between highly invasive behavior tumor cells their chemotherapy, radiotherapy targeted therapies. These aggressive properties share distinct cellular pathways that connected each other by several molecular hubs. There is increasing evidence glycogen synthase kinase ( GSK )‐3β aberrantly activated in various types this has emerged as a potential therapeutic target. In many but not all types, aberrant 3β sustains survival, immortalization, proliferation cells, while also rendering them insensitive or resistant chemotherapeutic agents radiation. Here we review studies describe associations stimuli/resistance induction pro‐invasive phenotypes types. Such cancers largely responsive targets 3β. This focuses on role hub connects responsible therapy, thus highlighting its major We discuss putative involvement determining stemness underpins both resistance, leading refractory with dismal patient outcomes.

Язык: Английский

---

Effects of mutations in Wnt/β-catenin, hedgehog, Notch and PI3K pathways on GSK-3 activity—Diverse effects on cell growth, metabolism and cancer

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Год журнала: 2016, Номер 1863(12), С. 2942 - 2976

Опубликована: Сен. 10, 2016

Язык: Английский

---

Targeting Apoptosis and Multiple Signaling Pathways with Icariside II in Cancer Cells

International Journal of Biological Sciences, Год журнала: 2015, Номер 11(9), С. 1100 - 1112

Опубликована: Янв. 1, 2015

Cancer is the second leading cause of deaths worldwide.Despite concerted efforts to improve current therapies, prognosis cancer remains dismal.Highly selective or specific blocking only one signaling pathways has been associated with limited sporadic responses.Using targeted agents inhibit multiple emerged as a new paradigm for anticancer treatment.Icariside II, flavonol glycoside, major components Traditional Chinese Medicine Herba epimedii and possesses biological pharmacological properties including anti-inflammatory, anti-osteoporosis, anti-oxidant, anti-aging, activities.Recently, activity Icariside II extensively investigated.Here, in this review, our aim give perspective on status discuss its natural sources, activity, molecular targets mechanisms action emphasis apoptosis which may help further design conduct preclinical clinical trials.Icariside found induce various human cell lines different origin by targeting STAT3, PI3K/AKT, MAPK/ERK, COX-2/PGE2 β-Catenin are frequently deregulated cancers, suggesting that collective rather than just single effect play an important role developing into potential lead compound therapy.This review suggests provides novel opportunity treatment but additional investigations trials still required fully understand mechanism therapeutic effects validate it anti-tumor therapy.

Язык: Английский

---

Roles of EGFR and KRAS and their downstream signaling pathways in pancreatic cancer and pancreatic cancer stem cells

Advances in Biological Regulation, Год журнала: 2015, Номер 59, С. 65 - 81

Опубликована: Июль 18, 2015

Язык: Английский

---

GSK3β regulates epithelial-mesenchymal transition and cancer stem cell properties in triple-negative breast cancer

Breast Cancer Research, Год журнала: 2019, Номер 21(1)

Опубликована: Март 7, 2019

Abstract Background Triple-negative breast cancers (TNBCs), which lack receptors for estrogen, progesterone, and amplification of epidermal growth factor receptor 2, are highly aggressive. Consequently, patients diagnosed with TNBCs have reduced overall disease-free survival rates compared to other subtypes cancer. characterized by the presence cancer cells mesenchymal properties, indicating that epithelial transition (EMT) plays a major role in progression this disease. The EMT program has also been implicated chemoresistance, tumor recurrence, induction stem cell (CSC) properties. Currently, there no targeted therapies TNBC, hence, it is critical identify novel targets treat TNBC. Methods A library compounds was screened their ability inhibit phenotype as assessed using previously described Z-cad reporters. Of several drugs tested, GSK3β inhibitors were identified inhibitors. effects on properties TNBC qRT-PCR, flow cytometry, western blot, mammosphere, migration viability assays. Publicly available datasets analyzed examine if expression correlates patients. Results We inhibitor, BIO, drug screen one most potent EMT. BIO two inhibitors, TWS119 LiCl, decreased markers different lines phenotype. Further, inhibition EMT-related migratory To determine target mesenchymal-like affecting CSC population, we employed mammosphere assays profiled cell-related surface marker CD44+/24− after exposure found indeed types treated selectively kill attributes while sparing patient data genes predictive poor clinical outcome could serve therapeutic Wnt signaling pathway EMT, but among various factors known be involved signaling, only higher correlated poorer survival. Conclusions Taken together, our demonstrate potential suggest selective treatment subset aggressive should tested use combination standard-of-care preclinical models.

Язык: Английский

---

Polydatin Prevents Lipopolysaccharide (LPS)-Induced Parkinson's Disease via Regulation of the AKT/GSK3β-Nrf2/NF-κB Signaling Axis

Frontiers in Immunology, Год журнала: 2018, Номер 9

Опубликована: Ноя. 5, 2018

Parkinson’s disease (PD) is a common neurodegenerative characterized by selective loss of dopaminergic neurons in the substantia nigra (SN). Neuroinflammation induced over-activation microglia leads to death pathogenesis PD. Therefore, downregulation microglial activation may aid treatment Polydatin (PLD) has been reported pass through blood-brain barrier and protect against motor degeneration SN. However, molecular mechanisms underlying effects PLD PD remain unclear. The present study aimed determine whether protects neurodegeneration inhibiting rat model lipopolysaccharide (LPS)-induced Our findings indicated that protected ameliorated dysfunction release pro-inflammatory mediators. Furthermore, significantly increased levels p-AKT, p-GSK-3βSer9, Nrf2, suppressed NF-κB SN rats with LPS-induced To further explore neuroprotective mechanism PLD, we investigated effect on activated BV-2 cells. inhibited production mediators pathways Moreover, our results enhanced Nrf2 After cells were pretreated MK2206 (an inhibitor AKT), NP-12 GSK-3β), or Brusatol (BT; an Nrf2), signaling via AKT/GSK3β-Nrf2 axis. Taken together, are first demonstrate prevents due regulation AKT/GSK3β-Nrf2/NF-κB

Язык: Английский

---