scholarly journals Activating the Intrinsic Pathway of Apoptosis Using BIM BH3 Peptides Delivered by Peptide Amphiphiles with Endosomal Release

Materials ◽  
2019 ◽  
Vol 12 (16) ◽  
pp. 2567
Author(s):  
Mathew R. Schnorenberg ◽  
Joseph A. Bellairs ◽  
Ravand Samaeekia ◽  
Handan Acar ◽  
Matthew V. Tirrell ◽  
...  
Keyword(s):  
Immune Modulation ◽  
Death Domain ◽  
Intracellular Accumulation ◽  
Intrinsic Pathway ◽  
Peptide Amphiphile ◽  
New Strategy ◽  
Full Complement ◽  
Hydrophobic Tail ◽  
Endosomal Release ◽  
Dose Dependent

Therapeutic manipulation of the BCL-2 family using BH3 mimetics is an emerging paradigm in cancer treatment and immune modulation. For example, peptides mimicking the BIM BH3 helix can directly target the full complement of anti- and pro-apoptotic BCL-2 proteins to trigger apoptosis. This study has incorporated the potent BH3 α-helical death domain of BIM into peptide amphiphile (PA) nanostructures designed to facilitate cellular uptake and induce cell death. This study shows that these PA nanostructures are quickly incorporated into cells, are able to specifically bind BCL-2 proteins, are stable at physiologic temperatures and pH, and induce dose-dependent apoptosis in cells. The incorporation of a cathepsin B cleavable linker between the BIM BH3 peptide and the hydrophobic tail resulted in increased intracellular accumulation and mitochondrial co-localization of the BIM BH3 peptide while also improving BCL-2 family member binding and apoptotic reactivation. This PA platform represents a promising new strategy for intracellular therapeutic peptide delivery for the disruption of intracellular protein:protein interactions.

scholarly journals Gene dose-dependent control of hematopoiesis and hematologic tumor suppression by CBP

2000 ◽  
Vol 14 (3) ◽  
pp. 272-277 ◽  
Author(s):  
Andrew L. Kung ◽  
Vivienne I. Rebel ◽  
Roderick T. Bronson ◽  
Lian-Ee Ch'ng ◽  
Colin A. Sieff ◽  
...  
Keyword(s):  
Experimental Evidence ◽  
Loss Of Heterozygosity ◽  
Tumor Suppression ◽  
Genetic Background ◽  
Hematologic Malignancies ◽  
Hematopoietic Differentiation ◽  
Wild Type ◽  
Gene Dose ◽  
Full Complement ◽  
Dose Dependent

Mice with monoallelic inactivation of the CBP gene develop highly penetrant, multilineage defects in hematopoietic differentiation and, with advancing age, an increased incidence of hematologic malignancies. The latter are characterized, at least in some cases, by loss of heterozygosity (LOH) at the CBP locus. No such pathology was observed in wild-type or p300 heterozygous null mice of the same age and genetic background. Thus, a full complement of CBP, but not p300, is required for normal hematopoietic differentiation. These results also provide the first experimental evidence for the hypothesis that CBP has tumor-suppressing activity.

scholarly journals Tigecycline-induced coagulopathy: a literature review

2019 ◽  
Vol 41 (6) ◽  
pp. 1408-1413 ◽  
Author(s):  
Nannan Cui ◽  
Hongliu Cai ◽  
Zhitao Li ◽  
Yuting Lu ◽  
Guobin Wang ◽  
...  
Keyword(s):  
Adverse Reactions ◽  
Case Reports ◽  
Specific Treatment ◽  
Drug Clearance ◽  
Coagulation System ◽  
Dependent Manner ◽  
Intrinsic Pathway ◽  
Severe Infections ◽  
The Common ◽  
Dose Dependent

Abstract Background Several adverse reactions to tigecycline, which is widely used in patients with severe infections, have been documented. Coagulopathy is a lesser known side effect of tigecycline. Aim of the review We summarize the characteristics, possible mechanisms, and treatment of tigecycline-induced coagulopathy. Method PubMed, Ovid, Embase, ISI Web of Knowledge, CNKI, and Wanfang were searched up to March 5, 2019. All articles concerning coagulopathy induced by tigecycline were included. The article types and languages were not limited. The retrieved articles were screened by two experienced clinicians by reading the titles, abstracts, and full texts. Results Ultimately, 17 articles were targeted, including 13 case reports and 4 retrospective observational studies. Tigecycline-induced coagulopathy usually manifests as the dose-dependent prolongation of prothrombin time and activated partial thromboplastin time and a reduction in the fibrinogen level. Tigecycline and its metabolites may have multiple effects on coagulation, influencing the extrinsic or intrinsic pathway and even the common pathway. There is no specific treatment for tigecycline-induced coagulopathy, but it can be reversed by withdrawing tigecycline. Conclusion Tigecycline acts on the coagulation system in a dose-dependent manner, and the most severe adverse event is bleeding. Overdose and prolonged use should be avoided, suspected coagulopathy must be recognized in time, and tigecycline should be withdrawn to prevent severe adverse events. Also, drug clearance disorders can develop in patients with liver and/or renal dysfunction. For patients with severe hepatic or renal impairment, the maintenance dose should be reduced, and indicators of coagulation function should be closely monitored.

Dose-dependent progressive sunscreens. A new strategy for photoprotection?

2010 ◽  
Vol 9 (4) ◽  
pp. 530 ◽  
Author(s):  
Adaya Gallardo ◽  
Jordi Teixidó ◽  
Ricardo Miralles ◽  
Manuel Raga ◽  
Antonio Guglietta ◽  
...  
Keyword(s):  
New Strategy ◽  
Dose Dependent

Dose-dependent intracellular accumulation of endogenous bile acids in cyclosporine A-treated HepaRG hepatocytes

2015 ◽  
Vol 238 (2) ◽  
pp. S301-S302
Author(s):  
A. Sharanek ◽  
A. Burban ◽  
L. Humber ◽  
P. Bachour-El Azzi ◽  
N. Felix-Gomes ◽  
...  
Keyword(s):  
Bile Acids ◽  
Cyclosporine A ◽  
Intracellular Accumulation ◽  
Dose Dependent

Enhanced red luminescence and improved crystallinity in NaEu(WO4)2 phosphors: an electron beam irradiation study

2018 ◽  
Vol 42 (4) ◽  
pp. 2726-2732 ◽  
Author(s):  
Archana K. Munirathnappa ◽  
Vikash C. Petwal ◽  
Jishnu Dwivedi ◽  
Nalini G. Sundaram
Keyword(s):  
Electron Beam ◽  
Band Gap ◽  
Fluorescence Intensity ◽  
Electron Beam Irradiation ◽  
Beam Irradiation ◽  
Band Gap Engineering ◽  
New Strategy ◽  
Red Luminescence ◽  
Dose Dependent

Band gap engineering in NaEu(WO4)2 red phospors via dose-dependent EB irradiation: a new strategy for improving fluorescence intensity.

Genotoxicity of Different tert-Butylcalix[4]crowns

2009 ◽  
Vol 64 (3-4) ◽  
pp. 167-175 ◽  
Author(s):  
Ahmad Khalil ◽  
Ahmed Maslat ◽  
Abeer Hafiz ◽  
Shehadeh Mizyed ◽  
Muhammad Ashram
Keyword(s):  
Chromosomal Abnormalities ◽  
Positive Control ◽  
Negative Control ◽  
Root Tips ◽  
Meristematic Cells ◽  
Chromosome Breaks ◽  
Root Meristematic Cells ◽  
Full Complement ◽  
Chromosome Bridges ◽  
Dose Dependent

The ability of two calix[4]arene derivatives, namely 25,27-p-tert-butylcalix[4]dithiooxabenzocrown (1) and 25,27-p-tert-butylcalix[4]trithiooxabenzocrown (2), to produce chromosomal aberrations in root meristematic cells of Allium cepa and micronuclei (MN) in normochromatic erythrocytes (NCE) of Balb/c mice was investigated. NCE are normal mature red blood cells with a full complement of hemoglobin but lack ribosomes. In the first test, the root tips were treated with a series of concentrations of the two test chemicals ranging from 10 - 7 to 10 - 4 M for 24 or 48 h. Both compounds caused concentration-dependent increases in the percentage of aberrant cells and reductions in the mitotic index. These effects depended, to some extent, on the duration of the treatment. The most conspicuous chromosomal abnormalities were c-mitosis, chromosome bridges, chromosome breaks, chromosome lags as well as micronuclei and multinuclei. In the second test, acridine orange fluorescent staining was applied to evaluate the incidence of MN in NCE of mice intraperitoneally injected with varying contents of the two test chemicals (0.02 - 0.08 mg/mouse). The two chemicals induced dose-dependent MN formation as compared to the negative control. The second compound had more pronounced cytogenetic influence than the first one. Mitomycin C (MMC, 14 mg/kg body weight), employed as positive control, produced more obvious effects on the parameters investigated.

scholarly journals Antimicrobial Activity of Quinazolin Derivatives of 1,2-Di(quinazolin-4-yl)diselane against Mycobacteria

2017 ◽  
Vol 2017 ◽  
pp. 1-7
Author(s):  
Bikui Tang ◽  
Meili Wei ◽  
Qun Niu ◽  
Yinjiu Huang ◽  
Shuo Ru ◽  
...  
Keyword(s):  
New Drugs ◽  
Dependent Manner ◽  
Anticancer Activities ◽  
Quinazoline Derivative ◽  
Damage Level ◽  
New Strategy ◽  
Quinazoline Derivatives ◽  
Clinical Drugs ◽  
Dose Dependent ◽  
Derivatives Of

Mycobacterium tuberculosis (M. tuberculosis) is one of the leading causes of morbidity and mortality. Currently, the emergence of drug resistance has an urgent need for new drugs. In previous study, we found that 1,2-di(quinazolin-4-yl)diselane (DQYD), a quinazoline derivative, has anticancer activities against many cancers. However, whether DQYD has the activity of antimycobacterium is still little known. Here our results show that DQYD has a similar value of the minimum inhibitory concentration with clinical drugs against mycobacteria and also has the ability of bacteriostatic activity with dose-dependent and time-dependent manner. Furthermore, the activities of DQYD against M. tuberculosis are associated with intracellular ATP homeostasis. Meanwhile, mycobacterium DNA damage level was increased after DQYD treatment. But there was no correlation between survival of mycobacteria in the presence of DQYD and intercellular reactive oxygen species. This study enlightens the possible benefits of quinazoline derivatives as potential antimycobacterium compounds and furtherly suggests a new strategy to develop new methods for searching antituberculosis drugs.

The Role of 5-HT1A/BAutoreceptors in the Antinociceptive Effect of Systemic Administration of Acetaminophen

2003 ◽  
Vol 98 (3) ◽  
pp. 741-747 ◽  
Author(s):  
Aránzazu Roca-Vinardell ◽  
Antonio Ortega-Alvaro ◽  
Juan Gibert-Rahola ◽  
Juan A. Micó
Keyword(s):  
Antinociceptive Effect ◽  
Serotonin Release ◽  
Hot Plate ◽  
Hot Plate Test ◽  
Plate Test ◽  
Way 100635 ◽  
New Strategy ◽  
Dose Dependent ◽  
Different Doses

Background It has been proposed that serotonin participates in the central antinociceptive effect of acetaminophen. The serotonin activity in the brainstem is primarily under the control of 5-HT1A somatodendritic receptors, although some data also suggest the involvement of 5-HT1B receptors. In the presence of serotonin, the blockade of 5-HT(1A/B) receptors at the level of the raphe nuclei leads to an increase in serotonin release in terminal areas, thus improving serotonin functions. This study examines the involvement of 5-HT(1A/B) receptors in the antinociceptive effect of acetaminophen in mice. Methods The effects of acetaminophen (600 mg/kg intraperitoneal) followed by different doses of antagonists (WAY 100635 [0.2-0.8 mg/kg subcutaneous] and SB 216641 [0.2-0.8 mg/kg subcutaneous]) or agonists (8-OH-DPAT [0.25-1 mg/kg subcutaneous] and CP 93129 [0.125-0.5 mg/kg subcutaneous]) of 5-HT1A and 5-HT1B receptors, respectively, were determined in the hot-plate test in mice. Results Acetaminophen (300-800 mg/kg) showed a dose-dependent antinociceptive effect in the hot-plate test in mice. WAY 100635 (0.2-0.8 mg/kg; 5-HT1A antagonist) induced an increase in the antinociceptive effect of 600 mg/kg acetaminophen, but this increase was not dose related. Conversely, 8-OH-DPAT (0.25-1 mg/kg; 5-HT1A agonist) decreased the antinociceptive effect of acetaminophen. SB 216641 (0.2-0.8 mg/kg; 5-HT1B antagonist) induced a dose-related increase in the antinociceptive effect of acetaminophen, and CP 93129 (0.25 mg/kg; 5-HT1B agonist) significantly decreased the antinociceptive effect of acetaminophen. Conclusions These results suggest that the combination of acetaminophen with compounds having 5-HT1A and 5-HT1B antagonist properties could be a new strategy to improve the analgesia of acetaminophen, thanks to its mild serotonergic properties.

scholarly journals (E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one (BCI) induces apoptosis via the intrinsic pathway in H1299 lung cancer cells

2017 ◽  
Author(s):  
Jong-Woon Shin ◽  
Sae-Bom Kwon ◽  
Yesol Bak ◽  
Sangku Lee ◽  
Do-Young Yoon
Keyword(s):  
Lung Cancer ◽  
Cell Viability ◽  
Morphological Changes ◽  
A549 Cells ◽  
Fluorescein Isothiocyanate ◽  
Receptor Expression ◽  
Dependent Manner ◽  
Intrinsic Pathway ◽  
Extrinsic Pathway ◽  
Dose Dependent

Abstract(E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one (BCI) is known as a dual specific phosphatase 1/6 or MAPK inhibitor. However, its precise anti-lung cancer mechanism remains unknown. In this study, the effects of BCI on cell viability were investigated in the non-small cell lung cancer cell lines NCI-H1299, A549, and NCI-H460. We confirmed that BCI significantly inhibited the cell viability of NCI-H1299 compared to those of NCI-H460 and A549 cells. The anti-cancer effects of BCI were evaluated by MTS assay, annexin V-fluorescein isothiocyanate/propidium iodide staining, cell cycle analysis, reverse transcription-PCR, western blotting, and JC-1 staining in NCI-H1299 cells. BCI induced cellular morphological changes and inhibited viability of NCI-H1299 cells in a dose-dependent manner. BCI enhanced Bax expression and induced processing of caspase-9, caspase-3, and poly (ADP-ribose) polymerase as well as the release of cytochrome c from the mitochondria into the cytosol. BCI also down-regulated Bcl-2 expression but enhanced Bax expression in a dose-dependent manner in NCI-H1299 cells. In addition, BCI did not modulate death receptor expression or the extrinsic factor caspase-8 and Bid, a linker between the intrinsic and extrinsic apoptotic pathways in NCI-H1299 cells. On the basis of these results, we conclude that BCI induces apoptosis through a mediated intrinsic pathway, but not extrinsic pathway in NCI-H1299 cells. These results suggest that BCI can be used as a therapeutic agent in lung cancer.

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