scholarly journals State-of-the-Art Technologies for Understanding Brassinosteroid Signaling Networks

2020 ◽  
Vol 21 (21) ◽  
pp. 8179
Author(s):  
Haijiao Wang ◽  
Song Song ◽  
Huaqiang Cheng ◽  
Yan-Wen Tan
Keyword(s):  
Signaling Pathway ◽  
Single Molecule ◽  
New Technologies ◽  
Kinase Inhibitor ◽  
Signaling Networks ◽  
Plant Signaling ◽  
The Past ◽  
Brassinosteroid Signaling ◽  
Signaling Components

Brassinosteroids, the steroid hormones of plants, control physiological and developmental processes through its signaling pathway. The major brassinosteroid signaling network components, from the receptor to transcription factors, have been identified in the past two decades. The development of biotechnologies has driven the identification of novel brassinosteroid signaling components, even revealing several crosstalks between brassinosteroid and other plant signaling pathways. Herein, we would like to summarize the identification and improvement of several representative brassinosteroid signaling components through the development of new technologies, including brassinosteroid-insensitive 1 (BRI1), BRI1-associated kinase 1 (BAK1), BR-insensitive 2 (BIN2), BRI1 kinase inhibitor 1 (BKI1), BRI1-suppressor 1 (BSU1), BR signaling kinases (BSKs), BRI1 ethyl methanesulfonate suppressor 1 (BES1), and brassinazole resistant 1 (BZR1). Furthermore, improvement of BR signaling knowledge, such as the function of BKI1, BES1 and its homologous through clustered regularly interspaced short palindromic repeats (CRISPR), the regulation of BIN2 through single-molecule methods, and the new in vivo interactors of BIN2 identified by proximity labeling are described. Among these technologies, recent advanced methods proximity labeling and single-molecule methods will be reviewed in detail to provide insights to brassinosteroid and other phytohormone signaling pathway studies.

scholarly journals Regorafenib-Attenuated, Bleomycin-Induced Pulmonary Fibrosis by Inhibiting the TGF-β1 Signaling Pathway

2021 ◽  
Vol 22 (4) ◽  
pp. 1985
Author(s):  
Xiaohe Li ◽  
Ling Ma ◽  
Kai Huang ◽  
Yuli Wei ◽  
Shida Long ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Kinase Inhibitor ◽  
In Vivo Experiments ◽  
Age Related ◽  
And Migration ◽  
Tgf Β1

Idiopathic pulmonary fibrosis (IPF) is a fatal and age-related pulmonary disease. Nintedanib is a receptor tyrosine kinase inhibitor, and one of the only two listed drugs against IPF. Regorafenib is a novel, orally active, multi-kinase inhibitor that has similar targets to nintedanib and is applied to treat colorectal cancer and gastrointestinal stromal tumors in patients. In this study, we first identified that regorafenib could alleviate bleomycin-induced pulmonary fibrosis in mice. The in vivo experiments indicated that regorafenib suppresses collagen accumulation and myofibroblast activation. Further in vitro mechanism studies showed that regorafenib inhibits the activation and migration of myofibroblasts and extracellular matrix production, mainly through suppressing the transforming growth factor (TGF)-β1/Smad and non-Smad signaling pathways. In vitro studies have also indicated that regorafenib could augment autophagy in myofibroblasts by suppressing TGF-β1/mTOR (mechanistic target of rapamycin) signaling, and could promote apoptosis in myofibroblasts. In conclusion, regorafenib attenuates bleomycin-induced pulmonary fibrosis by suppressing the TGF-β1 signaling pathway.

scholarly journals The PI3K Inhibitor XH30 Enhances Response to Temozolomide in Drug-Resistant Glioblastoma via the Noncanonical Hedgehog Signaling Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Ming Ji ◽  
Zhihui Zhang ◽  
Songwen Lin ◽  
Chunyang Wang ◽  
Jing Jin ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Hedgehog Signaling ◽  
Kinase Inhibitor ◽  
Therapeutic Option ◽  
Hedgehog Signaling Pathway ◽  
Orthotopic Mouse Model ◽  
Cycle Arrest ◽  
The Central Nervous System

Glioblastoma multiforme (GBM) is the most common malignant tumor of the central nervous system. Temozolomide (TMZ)–based adjuvant treatment has improved overall survival, but clinical outcomes remain poor; TMZ resistance is one of the main reasons for this. Here, we report a new phosphatidylinositide 3-kinase inhibitor, XH30; this study aimed to assess the antitumor activity of this compound against TMZ-resistant GBM. XH30 inhibited cell proliferation in TMZ-resistant GBM cells (U251/TMZ and T98G) and induced cell cycle arrest in the G1 phase. In an orthotopic mouse model, XH30 suppressed TMZ-resistant tumor growth. XH30 was also shown to enhance TMZ cytotoxicity both in vitro and in vivo. Mechanistically, the synergistic effect of XH30 may be attributed to its repression of the key transcription factor GLI1 via the noncanonical hedgehog signaling pathway. XH30 reversed sonic hedgehog–triggered GLI1 activation and decreased GLI1 activation by insulin-like growth factor 1 via the noncanonical hedgehog signaling pathway. These results indicate that XH30 may represent a novel therapeutic option for TMZ-resistant GBM.

scholarly journals SUN-087 FGFR-Selective Tyrosine Kinase Inhibitors, Such as Infigratinib, Show Potency and Selectivity for FGFR3 at Pharmacologically Relevant Doses for the Potential Treatment of Achondroplasia

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Katherine Dobscha ◽  
Ge Wei ◽  
Carl L Dambkowski ◽  
Daniela Rogoff
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Kinase Inhibitor ◽  
Survival Advantage ◽  
In Vivo Studies ◽  
Low Doses ◽  
Skeletal Dysplasias ◽  
The Past ◽  
Preclinical Efficacy

Abstract BACKGROUND: Germline mutations in fibroblast growth factor receptor (FGFR) genes 1-3 can cause skeletal dysplasias and craniosynostoses. Achondroplasia (ACH), the most common form of disproportionate short stature, is caused primarily by an autosomal dominant G380R substitution in FGFR3 [Horton WA et al. Lancet 2007]. Infigratinib (BGJ398), a potent and selective FGFR1-3 tyrosine kinase inhibitor (TKI), demonstrated preclinical efficacy at low doses in an ACH mouse model [Demuynck et al. 2019; Komla-Ebri et al. 2016]. The objective of this analysis is to evaluate the dose dependency and toxicity profiles of FGFR-selective TKIs like infigratinib in preclinical skeletal dysplasia models. Methods: A review of the literature was performed to investigate non-clinical data from studies of infigratinib and other FGFR-selective TKIs relevant to FGFR-driven skeletal dysplasias. Major databases (e.g., PubMed, Medline [NLM Catalog]) were searched for relevant articles from the past 10 years and conference archives (e.g., ENDO, ESPE, ISDS, ASHG, ASBMR) for relevant abstracts from the past 5 years. Full text was included where possible. Key words included in the searches were based on the following: achondroplasia, FGFR inhibition, infigratinib, BGJ398, tyrosine kinase inhibitor. Results: Of the 683 publications identified, 10 relevant articles and 2 abstracts were selected for review. Due to direct relevance, 2 additional articles were included, bringing the total to 14 publications. Key results from studies of infigratinib, the most commonly identified TKI, included: FGFR3 IC50 1.0 nM, FGFR3-K650E IC50 4.9 nM. In vitro data showed inhibition of FGFR1-3 activity at concentrations of 5 to 100 nM, including reversal of established growth arrest in chondrocytes at 7 nM. In vivo studies revealed dose-dependent improvements in foramen magnum and long bone length in Fgfr3Y367C/+ mice at doses of 0.2-2 mg/kg/day. No studies reported a survival disadvantage and one showed a significant survival advantage for infigratinib-treated ACH mice. In relation to other FGFR TKIs, one study showed that AZD4547 decreased survival in mice treated at doses of 1x106 to 2x106 nM, and another showed limb malformation in chicken embryos treated with PD173074 at doses of 1x106 to 50x106 nM. While one study suggested toxicity with infigratinib and other FGFR-selective TKIs, the results were not produced at pharmacologically relevant doses for ACH nor were they replicated in the literature. Furthermore, in vivo studies reporting treatment in mice with low doses of infigratinib did not result in any of the abnormal findings observed in this study. Conclusions: Recent studies indicate preclinical efficacy of infigratinib, including a survival advantage in Fgfr3Y367C/+ mice. Given the totality of evidence, low-dose infigratinib appears to be a potentially safe option for further development in children with ACH.

KW-2449, a Novel Multi-Kinase Inhibitor, Suppresses the Growth of Imatinib-Resistant Ph+ Leukemia Including BCR-ABL/T315I Both in Vitro and in Vivo.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1640-1640 ◽  
Author(s):  
Yukimasa Shiotsu ◽  
Hitoshi Kiyoi ◽  
Ryohei Tanizaki ◽  
Yosuke Minami ◽  
Akihiro Abe ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Kinase Inhibitor ◽  
Imatinib Treatment ◽  
Wild Type ◽  
Growth Inhibitory ◽  
Imatinib Resistant ◽  
Blast Cells ◽  
T315i Mutation

Abstract Background: KW-2449 is a multi-kinase inhibitor against FLT3, ABL and ABL/T315I and Aurora kinases with IC50 values of 0.007, 0.014, 0.004 and 0.048 micro mol/L, respectively. We reported a possible mode of action of KW-2449 with respect to its anti-leukemic effects on FLT3-mutated and FLT3-wild type leukemia cells via FLT3 and Aurora inhibition, respectively (1). Currently KW-2449 is being investigated in a Phase 1/2 study in patients with acute myeloid leukemia. In this report, we investigated the activity of KW-2449 or imatinib in imatinib-resistant leukemia with the T315I mutation. Methods and results: We evaluated the effects of KW-2449 in vitro and in vivo on imatinib-resistant Ph+ leukemia. While imatinib suppressed the growth of K562 (Ph+CML with wild-type BCR-ABL) and TCC-Y (Ph+ALL with wild-type BCR-ABL) with GI50 values of 0.20 and 0.18 micro mol/L, it had little inhibitory effects on TCC-Y/sr (Ph+ALL with BCR-ABL/T315I) with a GI50 value of 24 micro mol/L. On the other hand, KW-2449 showed equivalent growth inhibitory activities against K562, TCC-Y and TCC-Y/sr giving the GI50 values of 0.2–0.6 micro mol/L. In addition, KW-2449 showed potent growth inhibitory activity against IL-3 dependent cells transfected with BCR-ABL and BCR-ABL/T315I with GI50 values below 0.50 micro mol/L, whereas imatinib had no growth inhibition in BCR-ABL/T315I cells. When we examined the ABL-signaling pathway, imatinib had no effects on the expression of phosphorylated BCR-ABL (P-BCR-ABL) and STAT5 (P-STAT5), a key downstream signal molecules of BCR-ABL in TCC-Y/sr cells. Furthermore, no obvious apoptosis or cell cycle effects were observed in BCR-ABL/T315I cells after imatinib treatment. In addition, the exposure to KW-2449 induced reduction of P-BCR-ABL and P-STAT5 at 0.25 micro mol/L and induced G2/M arrest and apoptosis over the GI50 value (0.50–1.0 micro mol/L). These data provide the evidence that BCR-ABL inhibition at a lower concentration of KW-2449 modulates its signaling pathway and that Aurora inhibition at a higher concentration may play a critical role in the anti-proliferative effects in imatinib-resistant CML and Ph+ALL. To assess the anti-leukemia activity of KW-2449 in vivo, the SCID mice intravenously inoculated with TCC-Y/sr leukemia were orally treated with KW-2449 or imatinib. While KW-2449 prolonged the survival, imatinib treatment had no effects in this model. Furthermore, anti-proliferative activity of KW-2449 was examined in primary samples from blast crisis CML patients who had BCR-ABL/T315I mutation. After inoculation of blast cells into NOG mice, KW-2449 or imatinib treatment started. In this model, oral treatments with KW-2449 decreased peripheral copy number of BCR-ABL mRNA and CD45+ blast cells in the bone marrow, though imatinib treatment showed limited activity. Conclusion: KW-2449 demonstrated anti-leukemia activity against imatinib resistant leukemia both in vitro and in vivo. These results suggest that KW-2449 would be effective against imatinib-resistant CML or Ph+ALL because of its potent and unique kinase inhibition profile.

scholarly journals Insights into the Structure, Function, and Dynamics of the Bacterial Cytokinetic FtsZ-Ring

2020 ◽  
Vol 49 (1) ◽  
pp. 309-341 ◽  
Author(s):  
Ryan McQuillen ◽  
Jie Xiao
Keyword(s):  
Cell Division ◽  
Structure Function ◽  
Single Molecule ◽  
Gtp Hydrolysis ◽  
Major Function ◽  
The Past ◽  
Division Site ◽  
Z Ring ◽  
Resolution Imaging

The FtsZ protein is a highly conserved bacterial tubulin homolog. In vivo, the functional form of FtsZ is the polymeric, ring-like structure (Z-ring) assembled at the future division site during cell division. While it is clear that the Z-ring plays an essential role in orchestrating cytokinesis, precisely what its functions are and how these functions are achieved remain elusive. In this article, we review what we have learned during the past decade about the Z-ring's structure, function, and dynamics, with a particular focus on insights generated by recent high-resolution imaging and single-molecule analyses. We suggest that the major function of the Z-ring is to govern nascent cell pole morphogenesis by directing the spatiotemporal distribution of septal cell wall remodeling enzymes through the Z-ring's GTP hydrolysis–dependent treadmilling dynamics. In this role, FtsZ functions in cell division as the counterpart of the cell shape–determining actin homolog MreB in cell elongation.

scholarly journals MiR-450a-5p strengthens the drug sensitivity of gefitinib in glioma chemotherapy via regulating autophagy by targeting EGFR

Oncogene ◽  
2020 ◽  
Vol 39 (39) ◽  
pp. 6190-6202 ◽  
Author(s):  
Yu Liu ◽  
Liang Yang ◽  
Fan Liao ◽  
Wei Wang ◽  
Zhi-Fei Wang
Keyword(s):  
Signaling Pathway ◽  
Drug Sensitivity ◽  
Kinase Inhibitor ◽  
Glioma Cells ◽  
Mtor Signaling ◽  
Migration And Invasion ◽  
Mtor Signaling Pathway ◽  
Glioma Growth

Abstract Glioma reported to be refractory to EGFR tyrosine kinase inhibitor is the most common malignant tumor in central nervous system. Our research showed the low expression of miR-450a-5p and high expression of EGFR in glioma tissues. MiR-450a-5p was also observed to synergize with gefitinib to inhibit the proliferation, migration and invasion and induce the apoptosis and autophagy of glioma cells. Furthermore, miR-450a-5p was demonstrated to target 3′UTR of EGFR, and regulated EGFR-induced PI3K/AKT/mTOR signaling pathway. Moreover, the above effects induced by miR-450a-5p in glioma cells were reversed by WIPI1 silencing. The inhibition role of miR-450a-5p on glioma growth was also confirmed in vivo by subcutaneous and intracranial tumor xenografts. Therefore, we conclude that miR-450a-5p synergizes with gefitinib to inhibit the glioma tumorigenesis through inducing autophagy by regulating the EGFR-induced PI3K/AKT/mTOR signaling pathway, thereby enhancing the drug sensitivity of gefitinib.

scholarly journals HJURP promotes proliferation in prostate cancer cells through increasing CDKN1A degradation via the GSK3β/JNK signaling pathway

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Wenjie Lai ◽  
Weian Zhu ◽  
Chutian Xiao ◽  
Xiaojuan Li ◽  
Yu Wang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Signaling Pathway ◽  
Kinase Inhibitor ◽  
Protein Levels ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Recognition Protein ◽  
Cancer Types

AbstractGenes with cross-cancer aberrations are most likely to be functional genes or potential therapeutic targets. Here, we found a total of 137 genes were ectopically expressed in eight cancer types, of which Holliday junction recognition protein (HJURP) was significantly upregulated in prostate cancer (PCa). Moreover, patients with higher HJURP mRNA and protein levels had poorer outcomes, and the protein levels served as an independent prognosis factor for the overall survival of PCa patients. Functionally, ectopic HJURP expression promoted PCa cells proliferation in vitro and in vivo. Mechanistically, HJURP increased the ubiquitination of cyclin-dependent kinase inhibitor 1 (CDKN1A) via the GSK3β/JNK signaling pathway and decreased its stability. This study investigated the role of HJURP in PCa proliferation and may provide a novel prognostic and therapeutic target for PCa.

scholarly journals Oncolytic HSV therapy increases trametinib access to brain tumors and sensitizes them in vivo

2019 ◽  
Vol 21 (9) ◽  
pp. 1131-1140 ◽  
Author(s):  
Ji Young Yoo ◽  
Jessica Swanner ◽  
Yoshihiro Otani ◽  
Mitra Nair ◽  
Flora Park ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Signaling Pathway ◽  
Kinase Inhibitor ◽  
Glioma Cells ◽  
Mitogen Activated Protein Kinase ◽  
Enzyme Linked Immunosorbent Assay ◽  
Cell Mediated Immunity ◽  
Necrosis Factor Alpha ◽  
Hsv 1

Abstract Background Hyperactivation of the RAS-RAF-MEK-ERK signaling pathway is exploited by glioma cells to promote their growth and evade apoptosis. MEK activation in tumor cells can increase replication of ICP34.5-deleted herpes simplex virus type 1 (HSV-1), but paradoxically its activation in tumor-associated macrophages promotes a pro-inflammatory signaling that can inhibit virus replication and propagation. Here we investigated the effect of blocking MEK signaling in conjunction with oncolytic HSV-1 (oHSV) for brain tumors. Methods Infected glioma cells co-cultured with microglia or macrophages treated with or without trametinib were used to test trametinib effect on macrophages/microglia. Enzyme-linked immunosorbent assay, western blotting, and flow cytometry were utilized to evaluate the effect of the combination therapy. Pharmacokinetic (PK) analysis of mouse plasma and brain tissue was used to evaluate trametinib delivery to the CNS. Intracranial human and mouse glioma-bearing immune deficient and immune competent mice were used to evaluate the antitumor efficacy. Result Oncolytic HSV treatment rescued trametinib-mediated feedback reactivation of the mitogen-activated protein kinase signaling pathway in glioma. In vivo, PK analysis revealed enhanced blood–brain barrier penetration of trametinib after oHSV treatment. Treatment by trametinib, a MEK kinase inhibitor, led to a significant reduction in microglia- and macrophage-derived tumor necrosis factor alpha (TNFα) secretion in response to oHSV treatment and increased survival of glioma-bearing mice. Despite the reduced TNFα production observed in vivo, the combination treatment activated CD8+ T-cell mediated immunity and increased survival in a glioma-bearing immune-competent mouse model. Conclusion This study provides a rationale for combining oHSV with trametinib for the treatment of brain tumors.

Osseointegration interface of calcified bone and endosseous implants

1992 ◽  
Vol 50 (2) ◽  
pp. 1096-1097
Author(s):  
K.E. Krizan ◽  
J.E. Laffoon ◽  
M.J. Buckley
Keyword(s):  
Structure And Function ◽  
Titanium Implants ◽  
En Bloc ◽  
Endosseous Implants ◽  
Ultrastructural Studies ◽  
The Past ◽  
Cacodylate Buffer ◽  
One Year ◽  
And Function

With increase use of tissue-integrated prostheses in recent years it is a goal to understand what is happening at the interface between haversion bone and bulk metal. This study uses electron microscopy (EM) techniques to establish parameters for osseointegration (structure and function between bone and nonload-carrying implants) in an animal model. In the past the interface has been evaluated extensively with light microscopy methods. Today researchers are using the EM for ultrastructural studies of the bone tissue and implant responses to an in vivo environment. Under general anesthesia nine adult mongrel dogs received three Brånemark (Nobelpharma) 3.75 × 7 mm titanium implants surgical placed in their left zygomatic arch. After a one year healing period the animals were injected with a routine bone marker (oxytetracycline), euthanized and perfused via aortic cannulation with 3% glutaraldehyde in 0.1M cacodylate buffer pH 7.2. Implants were retrieved en bloc, harvest radiographs made (Fig. 1), and routinely embedded in plastic. Tissue and implants were cut into 300 micron thick wafers, longitudinally to the implant with an Isomet saw and diamond wafering blade [Beuhler] until the center of the implant was reached.

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