scholarly journals Elaiophylin Is a Potent Hsp90/ Cdc37 Protein Interface Inhibitor with K-Ras Nanocluster Selectivity

Biomolecules ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 836
Author(s):  
Farid A. Siddiqui ◽  
Vladimir Vukic ◽  
Tiina A. Salminen ◽  
Daniel Abankwa
Keyword(s):  
Biological Activities ◽  
Chorioallantoic Membrane ◽  
Protein Interface ◽  
Strong Inhibition ◽  
Spheroid Formation ◽  
Potent Effect ◽  
N Terminus ◽  
Galectin 3 ◽  
Direct Target ◽  
Systematic Explanation

The natural product elaiophylin is a macrodiolide with a broad range of biological activities. However, no direct target of elaiophylin in eukaryotes has been described so far, which hinders a systematic explanation of its astonishing activity range. We recently showed that the related conglobatin A, a protein–protein interface inhibitor of the interaction between the N-terminus of Hsp90 and its cochaperone Cdc37, blocks cancer stem cell properties by selectively inhibiting K-Ras4B but not H-Ras. Here, we elaborated that elaiophylin likewise disrupts the Hsp90/ Cdc37 interaction, without affecting the ATP-pocket of Hsp90. Similarly to conglobatin A, elaiophylin decreased expression levels of the Hsp90 client HIF1α, a transcription factor with various downstream targets, including galectin-3. Galectin-3 is a nanocluster scaffold of K-Ras, which explains the K-Ras selectivity of Hsp90 inhibitors. In agreement with this K-Ras targeting and the potent effect on other Hsp90 clients, we observed with elaiophylin treatment a submicromolar IC50 for MDA-MB-231 and MIA-PaCa-2 3D spheroid formation. Finally, a strong inhibition of MDA-MB-231 cells grown in the chorioallantoic membrane (CAM) microtumor model was determined. These results suggest that several other macrodiolides may have the Hsp90/ Cdc37 interface as a target site.

scholarly journals Disordered clusters of Bak dimers rupture mitochondria during apoptosis

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Rachel T Uren ◽  
Martin O’Hely ◽  
Sweta Iyer ◽  
Ray Bartolo ◽  
Melissa X Shi ◽  
...  
Keyword(s):  
Linkage Analysis ◽  
Outer Membrane ◽  
Structural Heterogeneity ◽  
Mitochondrial Outer Membrane ◽  
Protein Interface ◽  
Unknown Mechanism ◽  
The Core ◽  
Mathematical Simulations ◽  
N Terminus ◽  
Comprehensive Survey

During apoptosis, Bak and Bax undergo major conformational change and form symmetric dimers that coalesce to perforate the mitochondrial outer membrane via an unknown mechanism. We have employed cysteine labelling and linkage analysis to the full length of Bak in mitochondria. This comprehensive survey showed that in each Bak dimer the N-termini are fully solvent-exposed and mobile, the core is highly structured, and the C-termini are flexible but restrained by their contact with the membrane. Dimer-dimer interactions were more labile than the BH3:groove interaction within dimers, suggesting there is no extensive protein interface between dimers. In addition, linkage in the mobile Bak N-terminus (V61C) specifically quantified association between dimers, allowing mathematical simulations of dimer arrangement. Together, our data show that Bak dimers form disordered clusters to generate lipidic pores. These findings provide a molecular explanation for the observed structural heterogeneity of the apoptotic pore.

Serum levels of galectin-3 in idiopathic inflammatory myopathies: a potential biomarker of disease activity

Rheumatology ◽  
2020 ◽  
Vol 60 (1) ◽  
pp. 322-332
Author(s):  
Eri Watanabe ◽  
Kazunori Kato ◽  
Takahisa Gono ◽  
Emiko Chiba ◽  
Chihiro Terai ◽  
...  
Keyword(s):  
Disease Activity ◽  
Interstitial Pneumonia ◽  
Activity Index ◽  
Biological Activities ◽  
Inflammatory Cells ◽  
Serum Levels ◽  
Idiopathic Inflammatory Myopathies ◽  
Inflammatory Myopathies ◽  
Potential Biomarker ◽  
Galectin 3

Abstract Objectives Galectin-3 is involved in various biological activities, including immune activations and fibrosis. Idiopathic inflammatory myopathies (IIMs) are autoimmune diseases of unknown aetiology, often complicated by interstitial lung disease (ILD). The aim of this study was to evaluate the expression of galectin-3 in sera and tissues of patients with IIM and assess the associations of galectin-3 with patient characteristics and disease activity. Results Serum galectin-3 levels were significantly higher in IIM patients than in healthy controls. The serum galectin-3 levels positively correlated with serum levels of inflammatory markers and proinflammatory cytokines/chemokines and the Myositis Intention-to-Treat Activity Index. Stratification analysis revealed that patients with IIM-associated ILD (IIM-ILD) had significantly higher levels of serum galectin-3 than those without IIM-ILD. In addition, patients with acute/subacute interstitial pneumonia had significantly higher levels of serum galectin-3 than those with chronic interstitial pneumonia. Furthermore, serum galectin-3 levels in IIM-ILD patients correlated with the radiological assessments of parenchymal lung involvement and treatment response. Immunohistochemical analysis revealed that galectin-3 was expressed in inflammatory cells of myositis and dermatitis sections, whereas in ILD sections, galectin-3 was expressed in interstitial fibrosis and inflammatory cells. Conclusion Galectin-3 may be involved in the pathogenesis of inflammatory and fibrotic conditions in IIM and can serve as a potential biomarker of disease activity, especially in patients with IIM-ILD.

scholarly journals Malagasy Liverworts, Source of New and Biologically Active Compounds

2007 ◽  
Vol 2 (6) ◽  
pp. 1934578X0700200 ◽  
Author(s):  
Liva Harinantenaina ◽  
Yoshinori Asakawa
Keyword(s):  
Antibacterial Activity ◽  
Secondary Metabolites ◽  
Aromatic Compounds ◽  
Biological Activities ◽  
Biologically Active ◽  
Raw 264.7 Cells ◽  
No Production ◽  
Raw 264.7 ◽  
Strong Inhibition ◽  
Phytochemical Investigation

The phytochemical investigation of eight Jungermaniales liverwort species: Bazzania decrescens, B. madagassa (Lepidoziaceae), Plagiochila barteri, P. terebrans (Plagiochilaceae), Isotachis aubertii (Isotachidaceae), Mastigophora diclados (Lepicoleaceae), Radula appressa (Radulaceae), and Thysananthus spathulistipus (Lejeuneaceae), collected from Madagascar, has been carried out to afford new and structurally interesting terpenoids and aromatic compounds. The biological activities of the isolated secondary metabolites were determined and the herbertene-type sesquiterpenoids were shown to have antibacterial activity. A new ent-clerodane diterpene from Thysananthus spathulistipus and bis-bibenzyls-type aromatic compounds exhibited strong inhibition of NO production in RAW 264.7 cells, while marchantin C produced moderate α-glucosidase inhibition. The chemosystematics of the studied species are discussed.

scholarly journals Galectin-3 as a Next-Generation Biomarker for Detecting Early Stage of Various Diseases

Biomolecules ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 389 ◽  
Author(s):  
Akira Hara ◽  
Masayuki Niwa ◽  
Kei Noguchi ◽  
Tomohiro Kanayama ◽  
Ayumi Niwa ◽  
...  
Keyword(s):  
Early Stage ◽  
Biological Activities ◽  
Biological Fluids ◽  
Inflammatory Cells ◽  
Tumor Formation ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Galectin 3 ◽  
Binding Lectin

Galectin-3 is a β-galactoside-binding lectin which is important in numerous biological activities in various organs, including cell proliferation, apoptotic regulation, inflammation, fibrosis, and host defense. Galectin-3 is predominantly located in the cytoplasm and expressed on the cell surface, and then often secreted into biological fluids, like serum and urine. It is also released from injured cells and inflammatory cells under various pathological conditions. Many studies have revealed that galectin-3 plays an important role as a diagnostic or prognostic biomarker for certain types of heart disease, kidney disease, viral infection, autoimmune disease, neurodegenerative disorders, and tumor formation. In particular, it has been recognized that galectin-3 is extremely useful for detecting many of these diseases in their early stages. The purpose of this article is to review and summarize the recent literature focusing on the biomarker characteristics and long-term outcome predictions of galectin-3, in not only patients with various types of diseases, but associated animal models.

scholarly journals Nymphaeol-A Isolated from Okinawan Propolis Suppresses Angiogenesis and Induces Caspase-Dependent Apoptosis via Inactivation of Survival Signals

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Ikumi Tsuchiya ◽  
Takahiro Hosoya ◽  
Motoko Ushida ◽  
Kazuhiro Kunimasa ◽  
Toshiro Ohta ◽  
...  
Keyword(s):  
Screening Program ◽  
Biological Activities ◽  
Umbilical Vein ◽  
Chorioallantoic Membrane ◽  
Tube Formation ◽  
Mitogen Activated Protein Kinase ◽  
Cam Assay ◽  
Prenylated Flavonoids

Propolis, a resinous substance that honeybees collect to protect their beehive from enemies, is reported to have various biological activities. In our screening program to search for antiangiogenic compounds from propolis, the ethanol extracts of Okinawan propolis (EEOP) showed significant antiangiogenic activities in a tube formation assay with human umbilical vein endothelial cells (HUVECs)in vitroat 3.13 μg/mL and chorioallantoic membrane (CAM) assayin vivoat 25 μg/egg. To elucidate the active compounds of EEOP and their mode of action, we isolated some prenylated flavonoids from EEOP and found that nymphaeol-A had the strongest antiangiogenic activity among them. Nymphaeol-A significantly reducedin vivoneovessel formation in the CAM assay at 25 μg/egg. At the molecular level, nymphaeol-A markedly inactivated mitogen-activated protein kinase/ERK kinase 1/2 (MEK1/2) and extracellular signal-regulated kinase 1/2 (ERK1/2), whose molecular activations signal new vessel formation in HUVECs. In addition, nymphaeol-A dose- and time-dependently induced caspase-dependent apoptosis in tube-forming HUVECs. Taken together, nymphaeol-A was shown to inhibit angiogenesis at least in part via inactivation of MEK1/2–ERK1/2 signaling and induction of caspase-dependent apoptosis. Okinawan propolis and its major component, nymphaeol-A, may be useful agents for preventing tumor-induced angiogenesis.

scholarly journals UPLC-ESI-MS/MS Profile and Antioxidant, Cytotoxic, Antidiabetic, and Antiobesity Activities of the Aqueous Extracts of Three Different Hibiscus Species

2020 ◽  
Vol 2020 ◽  
pp. 1-17
Author(s):  
Hanan M. Al-Yousef ◽  
Wafaa H. B. Hassan ◽  
Sahar Abdelaziz ◽  
Musarat Amina ◽  
Rasha Adel ◽  
...  
Keyword(s):  
Cytotoxic Activity ◽  
Aqueous Extract ◽  
Biological Activities ◽  
Biological Effects ◽  
Aqueous Extracts ◽  
Potent Effect ◽  
Esi Ms ◽  
Biological Studies ◽  
Hct 116

The aqueous extracts of Hibiscus calyphyllus (HcA), Hibiscus micranthus (HmA), and Hibiscus deflersii (HdA) growing in Saudi Arabia did not receive enough attention in phytochemical and biological studies. This inspired the authors to investigate the phytochemicals of these extracts for the first time using UPLC-ESI-MS/MS in negative and positive ionization modes. The analysis afforded the tentative identification of 103 compounds including phenolic compounds, flavonoids, and anthocyanins. Moreover, in vitro evaluations of their cytotoxic, antioxidant, antidiabetic, and antiobesity activities were carried out. The results showed that aqueous extract of Hibiscus calyphyllus had the highest activity as an antioxidant agent (SC50 = 111 ± 1.5 μg/mL) compared with ascorbic acid (SC50 = 14.2 ± 0.5 μg/mL). MTT assay was used to evaluate cytotoxic activity compared to cisplatin. Hibiscus deflersii showed the most potent cytotoxic effect against A-549 (human lung carcinoma) with IC50 = 50 ± 5.1 μg/mL, and Hibiscus micranthus showed a close effect with IC50 = 60.4 ± 1.7 μg/mL. Hibiscus micranthus showed the most potent effect on HCT-116 (human colon carcinoma) with IC50 = 56 ± 1.9 μg/mL compared with cisplatin (IC50 = 7.53 ± 3.8 μg/mL). HcA and HdA extracts showed weak cytotoxic activity against A-549 and HCT-116 cell lines compared to the other extracts. Eventually, Hibiscus deflersii showed astonishing antidiabetic (IC50 = 56 ± 1.9 μg/mL) and antiobesity (IC50 = 95.45 ± 1.9 μg/mL) activities using in vitro α-amylase inhibitory assay (compared with acarbose (IC50 = 34.71 ± 0.7 μg/mL)) and pancreatic lipase inhibitory assay (compared with orlistat (IC50 = 23.8 ± 0.7 μg/mL)), respectively. In conclusion, these findings are regarded as the first vision of the phytochemical constituents and biological activities of different Hibiscus aqueous extracts. Hibiscus deflersii aqueous extract might be a hopeful origin of functional constituents with anticancer (on A-549 cell line), antidiabetic, and antiobesity activities. It might be a natural alternative remedy and nutritional policy for diabetes and obesity treatment without negative side effects. Isolation of the bioactive phytochemicals from the aqueous extracts of aerial parts of Hibiscus calyphyllus, Hibiscus micranthus, and Hibiscus deflersii and estimation of their biological effects are recommended in further studies.

scholarly journals Rice Calcium/Calmodulin-Dependent Protein Kinase Directly Phosphorylates a Mitogen-Activated Protein Kinase Kinase to Regulate Abscisic Acid Responses

2020 ◽  
Author(s):  
Min Chen ◽  
Lan Ni ◽  
Jing Chen ◽  
Manman Sun ◽  
Caihua Qin ◽  
...  
Keyword(s):  
Abscisic Acid ◽  
Protein Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Activation Loop ◽  
Aba Signaling ◽  
Dependent Protein Kinase ◽  
N Terminus ◽  
Mitogen Activated Protein ◽  
Dependent Protein ◽  
Direct Target

ABSTRACTCa2+/calmodulin (CaM)-dependent protein kinase (CCaMK) is an important positive regulator of abscisic acid (ABA) and abiotic stress signaling in plants and is believed to act upstream of mitogen-activated protein kinase (MAPK) in ABA signaling. However, it is unclear how CCaMK activates MAPK in ABA signaling. Here, we show that OsDMI3, a rice (Oryza sativa) CCaMK, directly interacts with and phosphorylates OsMKK1, a MAPK kinase (MKK) in rice, in vitro and in vivo. OsDMI3 was found to directly phosphorylate Thr-25 in the N-terminus of OsMKK1, and this Thr-25 phosphorylation is OsDMI3-specific in ABA signaling. The activation of OsMKK1 and its downstream kinase OsMPK1 is dependent on Thr-25 phosphorylation of OsMKK1 in ABA signaling. Moreover, ABA treatment also induces the phosphorylation in the activation loop of OsMKK1, and the two phosphorylations in the N-terminus and in the activation loop are independent. Further analyses revealed that OsDMI3-mediated phosphorylation of OsMKK1 positively regulates ABA responses in seed germination, root growth, and tolerance to both water stress and oxidative stress. Our results indicate that OsMKK1 is a direct target of OsDMI3, and OsDMI3-mediated phosphorylation of OsMKK1 plays an important role in the activation of MAPK cascade and ABA signaling.One-sentence summaryOsMKK1 is a direct target of OsDMI3, and OsDMI3-mediated phosphorylation of OsMKK1 plays an important role in the activation of MAPK cascade and ABA signaling.The author responsible for distribution of materials integral to the findings presented in this article in accordance with the policy described in the Instructions for Authors (www.plantcell.org) is: Mingyi Jiang ([email protected])

scholarly journals Multi-state structure determination and dynamics analysis reveals a new ubiquitin-recognition mechanism in yeast ubiquitin C-terminal hydrolase

2021 ◽  
Author(s):  
Mayu Okada ◽  
Yutaka Tateishi ◽  
Eri Nojiri ◽  
Tsutomu Mikawa ◽  
Sundaresan Rajesh ◽  
...  
Keyword(s):  
Structure Determination ◽  
Active Site ◽  
Residual Dipolar Couplings ◽  
Biological Activities ◽  
Protein Structure Determination ◽  
Paramagnetic Nmr ◽  
Structural Basis ◽  
Recognition Mechanism ◽  
N Terminus ◽  
Large Motion

Despite accumulating evidence that protein dynamics is indispensable for understanding the structural basis of biological activities, it remains challenging to visualize the spatial description of the dynamics and to associate transient conformations with their molecular functions. We have developed a new NMR protein structure determination method for the inference of multi-state conformations using multiple types of NMR data, including paramagnetic NMR and residual dipolar couplings, as well as conventional NOEs. Integration of these data in the structure calculation permits delineating accurate ensemble structures of biomacromolecules. Applying the method to the protein yeast ubiquitin hydrolase 1 (YUH1), we find large dynamics of its N-terminus and crossover loop surrounding the active site for ubiquitin-recognition and proteolysis. The N-terminus gets into and out of the crossover loop, suggesting their underlying functional significance. Our results, including those from biochemical analysis, show that large motion surrounding the active site contributes strongly to the efficiency of the enzymatic activity.

Mitogenic activity of chicken chorioallantoic fluid is temporally correlated to vascular growth in the chorioallantoic membrane and related to fibroblast growth factors

Development ◽  
1991 ◽  
Vol 111 (3) ◽  
pp. 683-690
Author(s):  
I. Flamme ◽  
K. Schulze-Osthoff ◽  
H.J. Jacob
Keyword(s):  
Growth Factors ◽  
Biological Activities ◽  
Chorioallantoic Membrane ◽  
Mitogenic Activity ◽  
Fibroblast Growth ◽  
Vascular Growth ◽  
Capillary Growth ◽  
Temporally Correlated ◽  
Chorioallantoic Membrane Assay

The chorioallantoic membrane (CAM) is one of the most vascularized tissues in the chicken embryo. Capillary growth proceeds until day 10 of development and thereafter abruptly regresses. As it is generally accepted that the formation of new blood vessel is regulated by growth factors, we have investigated the presence of angiogenic and mitogenic factors in the chicken chorioallantois. In the present study, we show that chorioallantoic fluid (CAF) contains angiogenic substances that are probably synthesized in the CAM or the embryonic kidney. When applied in the chorioallantoic membrane assay, CAF from 9 day chicken embryos elicits a strong angiogenic response. This angiogenic activity of CAF is associated with pronounced mitogenic effects in vitro. Comparison of different embryonic fluids reveals that mitogenic activity is particularly evident in the CAF but not detectable in embryonic serum and amnion fluid. Expression of mitogenic activity is found to be temporally correlated with vascular growth in the CAM. High activity is detected in CAF prior to day 10 and then sharply decreases, thus preceding termination of capillary growth by one day. Heparin-sepharose affinity chromatography suggests that the biological activities of CAF probably correspond to the presence of acidic and basic fibroblast growth factor (aFGF and bFGF). In Western blot analyses of CAF, an immunoreactive bFGF-like protein of about 17 × 10(3) Mr is recognized by a monospecific anti-bFGF antiserum. This protein elutes at 2.4 M NaCl from the heparin-sepharose. The mitogenic activity of the CAF can be specifically blocked by the anti-bFGF antibody indicating bFGF to be the active mitogenic principle of the CAF. These results strongly suggest that basic and probably acidic FGF play an important role in the regulation of chorioallantoic vascular growth.

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