Withanolides-Induced Breast Cancer Cell Death Is Correlated with Their Ability to Inhibit Heat Protein 90

Withanolides are a large group of steroidal lactones found in Solanaceae plants that exhibit potential anticancer activities. We have previously demonstrated that a withanolide, tubocapsenolide A, induced cycle arrest and apoptosis in human breast cancer cells, which was associated with the inhibition of heat shock protein 90 (Hsp90). To investigate whether other withanolides are also capable of inhibiting Hsp90 and to analyze the structure-activity relationships, nine withanolides with different structural properties were tested in human breast cancer cells MDA-MB-231 and MCF-7 in the present study. Our data show that the 2,3-unsaturated double bond-containing withanolides inhibited Hsp90 function, as evidenced by selective depletion of Hsp90 client proteins and induction of Hsp70. The inhibitory effect of the withanolides on Hsp90 chaperone activity was further confirmed using in vivo heat shock luciferase activity recovery assays. Importantly, Hsp90 inhibition by the withanolides was correlated with their ability to induce cancer cell death. In addition, the withanolides reduced constitutive NF-κB activation by depleting IκB kinase complex (IKK) through inhibition of Hsp90. In estrogen receptor (ER)-positive MCF-7 cells, the withanolides also reduced the expression of ER, and this may be partly due to Hsp90 inhibition. Taken together, our results suggest that Hsp90 inhibition is a general feature of cytotoxic withanolides and plays an important role in their anticancer activity

Bone Marrow Transplantation Results in Human Donor Blood Cells Acquiring and Displaying Mouse Recipient Class I MHC and CD45 Antigens on Their Surface

Background: Mouse models of human disease are invaluable for determining the differentiation ability and functional capacity of stem cells. The best example is bone marrow transplants for studies of hematopoietic stem cells. For organ studies, the interpretation of the data can be difficult as transdifferentiation, cell fusion or surface antigen transfer (trogocytosis) can be misinterpreted as differentiation. These events have not been investigated in hematopoietic stem cell transplant models. Methodology/Principal Findings: In this study we investigated fusion and trogocytosis involving blood cells during bone marrow transplantation using a xenograft model. We report that using a standard SCID repopulating assay almost 100 % of the human donor cells appear as hybrid blood cells containing both mouse and human surface antigens. Conclusion/Significance: Hybrid cells are not the result of cell-cell fusion events but appear to be due to efficient surface antigen transfer, a process referred to as trogocytosis. Antigen transfer appears to be non-random and includes all donor cells regardless of sub-type. We also demonstrate that irradiation preconditioning enhances the frequency of hybrid cell

Azole antifungal drugs and cytochrome P450 induction

SIGLEAvailable from British Library Document Supply Centre- DSC:DX179974 / BLDSC - British Library Document Supply CentreGBUnited Kingdo

Identification and determination of erucic acid in infant formula using Gas Chromatography

Background: Infant formula, depending on the source, contains various fatty acids, which may possess important nutritional and biological value for infants. The presence of some of these fatty acids in infant formula, however, can be harmful and toxic for the infant. In this regard, more attention has been paid to erucic acid since its accumulation in myocardial tissues may cause damage to the heart. Therefore, a limit has been set by the Codex Alimentarius for the presence of erucic acid in infant formula (less than 1% of total fatty acids). The purpose of the present study is to investigate amount of erucic acid present in three infant formulas used predominantly in Iran. Methods: Gas chromatography (GC) is a valuable method applied for the separation of fatty acids, including erucic acid, from oils and oily food. Three brands of infant formulas, namely Humana, Biomil and Multi, were analyzed by GC using a wall coated open tubular (WCOT) fused silica column and flame ionization detector (FID). Heneicosanoic acid was employed as an internal standard. Results: The findings showed that Humana and Biomil infant formula samples contained 0.06% and 0.002% erucic acid (from total fatty acids), respectively, while no erucic acid was detected in the Multi infant formula samples. Conclusion: The amount of erucic acid in the studied infant formulas was far below the Codex limit of 1% total fatty acids

Synthesis, radiolabelling, and biological assessment of folic acid-conjugated G-3 99mTcdendrimer as the breast cancer molecular imaging agent

Hence, in this study, the authors aimed to develop a dendrimer-based imaging agent comprised of poly(ethylene glycol) (PEG)-citrate, technetium-99 m (99mTc), and folic acid. The dendrimer-G3 was synthesised and conjugated with folic acid, which confirmed by Fourier transform infrared, proton nuclear magnetic resonance, dynamic light scattering, and transition electron microscopy. 2, 3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-Tetrazolium-5-Carboxanilide cytotoxicity assay kit was used to measure the cellular toxicity of dendrimer. Imaging and biodistribution studies were conducted on the mice bearing tumour. The results showed that the fabricated dendrimer-G3 has a size of 90 ± 3 nm, which was increased to 100 ± 4 nm following the conjugation with folic acid. The radiostablity investigation showed that the fabricated dendrimers were stable in the human serum at various times. Toxicity assessment confirmed no cellular toxicity against HEK-293 cells at 0.25, 0.5, 1, 2, 4, and 8 mg/ μl concentrations. The in vivo studies demonstrated that the synthesised dendrimers were able to provide a bright SPECT image applicable for tumour detection. In conclusion, the authors' study documented the positive aspects of PEG-citrate dendrimer conjugated with folic acid as the SPECT contrast agent for breast cancer detection. © The Institution of Engineering and Technology 2020

Technetium-99m chelator-free radiolabeling of specific glutamine tumor imaging nanoprobe: in vitro and in vivo evaluations

Seyedeh Masoumeh Ghoreishi,1,2 Ali Khalaj,1 Omid Sabzevari,3 Leila Badrzadeh,1 Pardis Mohammadzadeh,1,4 Seyed Shahaboddin Mousavi Motlagh,5 Ahmad Bitarafan-Rajabi,6 Mehdi Shafiee Ardestani1 1Department of Radiopharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran; 2Cancer Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran; 3Department of Toxicology and Pharmacology, Faculty of Pharmacy, Toxicology and Poisoning Research Centre, Tehran University of Medical Sciences, Tehran, Iran; 4Department of Genetics and Molecular Biology, Isfahan University of Medical Sciences, Isfahan, Iran; 5Biotechnology Department of Iranian Food and Drug Administration, Ministry of Health, Tehran, Iran; 6Echocardiography Research Center, Cardiovascular Interventional Research Center, Department of Nuclear Medicine, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran Introduction: Nowadays, molecular imaging radiopharmaceuticals’, nanoparticles’, and/or small-molecule biomarkers’ applications are increasing rapidly worldwide. Thus, researchers focus on providing the novel, safe, and cost-effective ones. Materials and methods: In the present experiment, technetium-99m (99mTc)-labeled PEG-citrate dendrimer-G2 conjugated with glutamine (nanoconjugate) was designed and assessed as a novel tumor imaging probe both in vitro and in vivo. Nanoconjugate was synthesized and the synthesis was confirmed by Fourier transform infrared, proton nuclear magnetic resonance, liquid chromatography-mass spectrometry, dynamic light scattering, and static light scattering techniques. The toxicity was assessed by XTT and apoptosis and necrosis methods. Results: Radiochemical purity indicates that the anionic dendrimer has a very high potential to complex formation with 99mTc and is also very stable in the human serum in different times. Results from the imaging procedures showed potential ability of nanoconjugates to detect tumor site. Conclusion: Suitable features of the anionic dendrimer show that it is a promising agent to improve nanoradiopharmaceuticals. Keywords: biodegradable, biocompatible, dendrimer, glutamine, chelator free, radiolabelin

Synthesis and characterization of novel 99mTc-DGC nano-complexes for improvement of heart diagnostic

In this research, early diagnosis of cardiovascular diseases can reduce their mortality and burden. In our study, we developed a new nano-agent, 99mTc-Dendrimer Glyco Conjugate (99mTc-DGC), and assessed its safety and capability for myocardial viability scan. To develop 99mTc-DGC, we first synthesized the dendrimer and then, glucose has been conjugated. Afterwards, we measured toxicity of the product on normal cells by XTT and apoptosis/necrosis methods. We compared the myocardial viability scan (measured by SPECT and dynamic planar imaging) in two rabbit models, with and without infarction. We also assessed the biodistribution of 99mTc-DGC in rats with no infarction. DGC synthesis was confirmed by Fourier transform infrared (FT-IR), proton nuclear magnetic resonance (1H NMR), liquid chromatography-mass spectrometry (LC-MS), dynamic light scattering (DLS) and static light scattering techniques (SLS). Then radiochemical purity (RCP) was done to present the stability and potential of DGC to complex formation with 99mTc. In vitro cytotoxicity showed nontoxic concentration up to 8 mg/mL. Single Photon Emission Computed Tomography (SPECT) and dynamic planar imaging clearly showed the accumulation of 99mTc-DGC in myocardial. Biodistribution result showed the 2.60 accumulation of 99mTc-DGC in myocardial after 2 h. Our findings indicated 99mTc-DGC to be safe and can accurately diagnose myocardial infarctions at early stages. Human studies to further assess such effects are critical. © 2020 Elsevier Inc

Impact of Gold Nanoparticles on Amyloid β-Induced Alzheimer's Disease in a Rat Animal Model: Involvement of STIM Proteins

Alzheimer's disease (AD) is the most common type of neurodegenerative amyloid disorder causing progressive cognitive decline and memory loss. A considerable number of therapies for AD rely on inhibition/delay/dissociation of amyloid beta (Aβ) oligomers and fibrils. In this case, nanoparticles (NPs) demonstrated substantial effects on the Aβ fibrillation process; however, their effects on progressive cognitive decline and memory have been poorly investigated in vivo. In this study, acquisition and retention of spatial learning and memory are studied in a rat animal model of AD after intrahippocampal (IH) and intraperitoneal (IP) injections of a model NP, i.e., gold NPs (AuNPs). The outcomes revealed that the AuNPs could improve the acquisition and retention of spatial learning and memory in Aβ treated rats as indicated by decreased time (Aβ: 39.60 ± 3.23 s vs Aβ+AuNPs: 25.78 ± 2.80 s) and distance (Aβ: 917.98 ± 50.81 cm vs Aβ+AuNPs: 589.09 ± 65.96 cm) of finding the hidden platform during training days and by increased time spent in the target quadrant (Aβ: 19.40 ± 0.98 s vs Aβ+AuNPs: 29.36 ± 1.14 s) in the probe test in Morris water maze (MWM). Expression of brain-derived neurotrophic factor, BDNF, cAMP response element binding protein, CREB, and stromal interaction molecules, e.g., STIM1 and STIM2 was also increased, supporting improved neural survival. Our outcomes may pave a way for mechanistic insights toward the role of NPs on retrieval of the deteriorated behavioral functions in brain tissue after AD outbreak