Characterization of the inclusion complex of zerumbone with hydroxypropyl--cyclodextrin

In this paper we investigated the inclusion complexation between zerumbone (ZER) and hydroxylpropyl- -cyclodextrin (HPCD) at four different temperatures: 293–318 ◦K. The thermodynamic parameters (H, S and G) for the formation of the complex were obtained from the van’t Hoff equation. The complex with HPCD was characterized by differential scanning calorimetry (DSC), X-ray diffractometry (XRD), Fourier transform infrared spectroscopy (FT-IR), and molecular modeling using PM6. The solubility of ZER was enhanced >30 fold after complexation. Calculations show that ZER penetrates completely into the cavity of HPCD. The complex retained its cytotoxic activity as shown by in vitro cell survival assay on human cervical cancer (Hela), breast cancer (MCF7 and MDA-MB 231) and human leukemic (CEMss) cell lines. HPCD is, therefore, a suitable encapsular capable of forming thermodynamically stable complex with ZER for save delivery of the compound as an anticancer drug in the future

Liquid chromatography - tandem mass spectroscopic method for the determination Of zerumbone in human plasma and its application to Pharmacokinetics

A rapid, sensitive, specific and selective LC-MS/MS method for the determination of zerumbone (ZER) in human plasma using 2,4-diamino-6-(4-methoxyphenyl)-1,3,5-triazine (DMTZ) as an internal standard (IS) has been developed and validated. ZER was chromatographed on C8 column using a mobile phase of acetonitrile/water (80:20, v/v) at a flow rate of 0.25 ml min(-1) . Quantitation was achieved using ESI+ interface, employing multiple reaction monitoring (MRM) mode at m/z 219 > 81 and 218 > 134 for ZER and IS, respectively. The calibration standards were linear over a range of 5-3000 ng ml(-1) (r(2)=0.9994) with an LLOQ of 5 ng ml(-1) (RSD %; 11.4% and bias%; 9.5%). Intra- and inter-day precision of ZER assay ranged from 0.18 to 3.56% with accuracy (bias) that varied between -5.09 and 4.3%, demonstrating good precision and accuracy. Recoveries of ZER and the IS from human plasma were above 85%. The developed method was validated for the determination of ZER in rat plasma. Linearity, stability of ZER and the ME on rat plasma were discussed. The applicability of the developed method was demonstrated by measuring ZER in rat plasma samples following intravenous and intraperitoneal administration of ZER prepared in hydroxypropyl-β-cyclodextrin (HPβCD) and sodium carboxymethyl cellulose (CMC), respectively, in 20 mg kg(-1) and this study indicated a clear significant difference (p<0.05) in pharmacokinetic parameters of ZER in ZER/HPβCD complex compared with ZER in CMC preparation

Characterization, drug release profile and cytotoxicity of dentatin-hydroxypropyl-β-cyclodextrin complex

This current work has been conducted mainly to increase solubility and drug release properties for high hydrophobic Dentatin (DEN) by incorporation it into Hydroxypropyl-β-Cyclodextrin (HPβCD) cavity. To confirm that inclusion be succeeded, the produced complex were installed onto different machines. The latter includes: Fourier transform infrared spectroscopy (FT-IR), X-ray diffractometry (XRD), differential scanning calorimetry (DSC), and field emission-scanning electron microscopy (FE-SEM). The hydrodynamic diameter and zeta potential of DEN-HPβCD complex were 2.025 ± 0.39 nm and −33.6 mV, respectively. Ultra-violet spectroscopy was employed to further confirmation of complexation process as well as to determine drug release profile. The result showed an initial burst release (19.9% within first two minutes) and then a continuous release for an extended period of 41 h (100%). The solubility of DEN was enhanced by >300 fold following complexation when a compared to DEN alone. Moreover, MTT finding showed that this complexation did not reduce cytotoxicity of DEN after applying on prostate cancer (LNCaP), human adenocarcinoma breast cancer (MDA-MB-231) and human gastric adenocarcinoma cell line (HDT). However, further investigations are required to validate efficacy of our produced inclusion using molecular analysis and in vivo studies

Cytotoxicity of nickel zinc ferrite nanoparticles on cancer cells of epithelial origin

In this study, in vitro cytotoxicity of nickel zinc (NiZn) ferrite nanoparticles against human colon cancer HT29, breast cancer MCF7, and liver cancer HepG2 cells was examined. The morphology, homogeneity, and elemental composition of NiZn ferrite nanoparticles were investigated by scanning electron microscopy, transmission electron microscopy, and energy dispersive X-ray spectroscopy, respectively. The exposure of cancer cells to NiZn ferrite nano-particles (15.6-1,000 μg/mL; 72 hours) has resulted in a dose-dependent inhibition of cell growth determined by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. The quantification of caspase-3 and -9 activities and DNA fragmentation to assess the cell death pathway of the treated cells showed that both were stimulated when exposed to NiZn ferrite nanoparticles. Light microscopy examination of the cells exposed to NiZn ferrite nanoparticles demonstrated significant changes in cellular morphology. The HepG2 cells were most prone to apoptosis among the three cells lines examined, as the result of treatment with NiZn nanoparticles. In conclusion, NiZn ferrite nanoparticles are suggested to have potential cytotoxicity against cancer cells

Induction of apoptosis in cancer cells by NiZn ferrite nanoparticles through mitochondrial cytochrome C release

The long-term objective of the present study was to determine the ability of NiZn ferrite nanoparticles to kill cancer cells. NiZn ferrite nanoparticle suspensions were found to have an average hydrodynamic diameter, polydispersity index, and zeta potential of 254.2±29.8nm, 0.524 ±0.013, and -60±14mV, respectively. We showed that NiZn ferrite nanoparticles had selective toxicity towards MCF-7, HepG2, and HT29cells, with a lesser effect on normal MCF 10A cells. The quantity of Bcl-2, Bax, p53, and cytochrome C in the cell lines mentioned above was determined by colorimetric methods in order to clarify the mechanism of action of NiZn ferrite nanoparticles in the killing of cancer cells. Our results indicate that NiZn ferrite nanoparticles promote apoptosis in cancer cells via caspase-3 and caspase-9, downregulation of Bcl-2, and upregulation of Bax and p53, with cytochrome C translocation. There was a concomitant collapse of the mitochondrial membrane potential in these cancer cells when treated with NiZn ferrite nanoparticles. This study shows that NiZn ferrite nanoparticles induce glutathione depletion in cancer cells, which results in increased production of reactive oxygen species and eventually, death of cancer cells

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Proteomic profile of acute myeloid leukaemia: a review update

Proteome analysis is a complex and dynamic process that encompasses several analytical platforms that include protein sequencing, structural or expression proteomics, protein modification, sub-cellular protein localization, protein-protein interaction and biological functional proteomics. In fact, expression proteomics is extensively applied in a majority of biomarker detection studies because it provides a detailed overview of differentially expressed proteins in cellular pathways and disease processes. Proteomics are also effective and dynamic in protein-protein interactions and cross-talks between interacting molecules of the cell. Proteomics has evolved into a crucial tool used to investigate the biochemical changes that possibly lead to development of cancer biomarkers. This review draws attention to the progress and advancements in cancer proteomics technology with the aim of simplifying the understanding of the mechanisms underlying the disease and to contribute to detection of biomarkers in addition to the development of novel treatments. Given that proteome is a dynamic entity of cellular functions in health and disease, it is capable of reflecting the immediate environmental state of cells and tissues as shown in this review. The review shows the possibility of elucidating the pathophysiology of acute myeloid leukaemia (AML) through proteome expressions, thus confirming the viability of proteome analysis in profiling AML

Zerumbone binding to estrogen receptors : an in-silico investigation

Breast cancer is the most frequent malignancy among females worldwide. Estrogen receptor (ER) mediate important pathophysiological signaling pathways induced by estrogens, and is regarded as a promising target for the treatment of breast cancer. Zerumbone (2,6,9,9-tetramethylcycloundeca-2,6,10-trien-1-one; ZER), a chemical constituent present in the Zingiber zerumbet is known to exhibit anti-breast cancer activity by modulating several proteins to induce apoptosis. Medicinal chemists usually exploit lead compounds of natural origin to develop molecules with improved pharmacological properties. Current study is intended to utilize molecular modeling techniques to investigate the interaction of ZER with estrogen receptors. AutoDock was used to predict the binding modes of ZER and target receptors. Stability of the ZER-ER complex was verified by molecular dynamics simulation using Desmond software. Docked ZER was further optimized by density functional theory (DFT) using Gaussian09 program. Analysis of docked conformations in terms of binding energy disclosed estrogen receptor-β (ERβ) as more promising than estrogen receptor-α (ERα). Evaluation of MD trajectories of ZER bound to both ERα and ERβ showed appreciable stability with minimum Cα-atom root mean square deviation shifts. DFT based global reactivity descriptors such as electron affinity, hardness, chemical potential, electronegativity and electrophilicity index, calculated from the energies of highest occupied and lowest unoccupied molecular orbitals underscored the electronic features governing viability of the ZER for interaction with the target receptors. In conclusion, these findings can be exploited to design and develop novel anticancer agents based on the lead compound, ZER

An in-silico analysis of ivermectin interaction with potential SARS-CoV-2 targets and host nuclear importin ?

Ivermectin (IVM) is a broad-spectrum antiparasitic agent, having inhibitory potential against wide range of viral infections. It has also been found to hamper SARS-CoV-2 replication in vitro, and its precise mechanism of action against SARS-CoV-2 is yet to be understood. IVM is known to interact with host importin (IMP)α directly and averts interaction with IMPβ1, leading to the prevention of nuclear localization signal (NLS) recognition. Therefore, the current study seeks to employ molecular docking, molecular mechanics generalized Born surface area (MM-GBSA) analysis and molecular dynamics simulation studies for decrypting the binding mode, key interacting residues as well as mechanistic insights on IVM interaction with 15 potential drug targets associated with COVID-19 as well as IMPα. Among all COVID-19 targets, the non-structural protein 9 (Nsp9) exhibited the strongest affinity to IVM showing −5.30 kcal/mol and −84.85 kcal/mol binding energies estimated by AutoDock Vina and MM-GBSA, respectively. However, moderate affinity was accounted for IMPα amounting −6.9 kcal/mol and −66.04 kcal/mol. Stability of the protein-ligand complexes of Nsp9-IVM and IMPα-IVM was ascertained by 100 ns trajectory of all-atom molecular dynamics simulation. Structural conformation of protein in complex with docked IVM exhibited stable root mean square deviation while root mean square fluctuations were also found to be consistent. In silico exploration of the potential targets and their interaction profile with IVM can assist experimental studies as well as designing of COVID-19 drugs