Search

Cancer stem cells (CSCs) are mainly responsible for tumorigenesis, chemoresistance, and cancer recurrence. CSCs growth and progression are regulated by multiple signaling cascades including Wnt/β-catenin and Hh/GLI-1, which acts independently or via crosstalk. Targeting the crosstalk of signaling pathways would be an effective approach to control the CSC population. Both Wnt/β-catenin and Hh/GLI-1 signaling cascades are known to be regulated by p53/p21-dependent mechanism. However, it is interesting to delineate whether p21 can induce apoptosis in a p53-independent manner. Therefore, utilizing various subtypes of oral CSCs (SCC9-PEMT p53+/+p21+/+, SCC9-PEMT p53−/−p21+/+, SCC9-PEMT p53+/+p21−/− and SCC9-PEMT p53−/−p21−/−), we have examined the distinct roles of p53 and p21 in Resveratrol nanoparticle (Res-Nano)-mediated apoptosis. It is interesting to see that, besides the p53/p21-mediated mechanism, Res-Nano exposure also significantly induced apoptosis in oral CSCs through a p53-independent activation of p21. Additionally, Res-Nano-induced p21-activation deregulated the β-catenin-GLI-1 complex and consequently reduced the TCF/LEF and GLI-1 reporter activities. In agreement with in vitro data, similar experimental results were obtained in in vivo mice xenograft model. Schematic representation of Res-Nano deregulating the crosstalk of β-catenin-GLI-1 through activation of p21. (I) Plausible mechanism of β-catenin-GLI-1 interaction before Res-Nano treatment. (1a&1b) Co-localization of Wnt/β-catenin and Hh/GLI-1 pathways proteins along with p21. (2) β-catenin and GLI-1 release from their negative regulators like GSK3β, CK1α, AXIN, APC, and SUFU. (3) Formation of β-catenin-GLI-1 complex. (4) Nuclear localization of β-catenin-GLI-1 complex. (5) β-catenin and GLI-1 bind to their respective promoter binding region. (6) Activation of transcriptional target genes. (7) Cell growth and proliferation. (II) Plausible mechanism of β-catenin-GLI-1 interaction in the regulation of apoptosis after Res-Nano treatment. (1a&1b) Co-localization of Wnt/β-catenin and Hh/GLI-1 pathways proteins along with p21. (2) Res-Nano activates p21. (3) Activated p21 deregulates β-catenin-GLI-1 complex. (4) β-catenin and GLI-1 degraded in cytoplasm. (5) β-catenin and GLI-1 are unable to enter into the nucleus. (6) Downregulation of target genes. (7) Induction of apoptosis. [ABSTRACT FROM AUTHOR]

Ionospheric plasma introduces nonlinear perturbations in regular EM wave propagation which in turn affects the signal transmission in a highly nonlinear manner. Often the signals are distorted by a varied degree of nonlinearity. The wireless communication mechanism is affected by small perturbations which take gigantic rogue wave structures with the possibility of damaging sophisticated equipments. To study the evolution of rogue wave-type solitons starting from initial small-amplitude perturbations, we have considered a three-component electron–ion plasma system with degeneracy pressure as well as quantum diffraction effects. A solitary wave structure is formed due to the interplay of nonlinear and dispersive forces. Such a formation under an external force gets modified and the stability criteria are altered. The interesting fact thus obtained here shows that relativistic and thermal degeneracy favour stability whereas quantum diffraction leads to instability. In this paper, we have studied how solitary wave structures behave under an external force. Next, we study how the nonlinear effects cause an amplitude modulation and the envelope soliton is formed. Such an envelope soliton is studied by the nonlinear Schrödinger equation that we derive in the later part of the work. We have carried out simulation studies and compared our results with the analytical findings of other workers. [ABSTRACT FROM AUTHOR]

Recently, we reported that a combination of a natural, bioactive compound Resveratrol (RES) and a PARP inhibitor Olaparib (OLA) deregulated the homologous recombination (HR) pathway, and enhanced apoptosis in BRCA1-wild-type, HR-proficient breast cancer cells. Upon DNA damage, chromatin relaxation takes place, which allows the DNA repair proteins to access the DNA lesion. But whether chromatin remodeling has any role in RES + OLA-mediated HR inhibition is not known. By using in vitro and ex vivo model systems of breast cancer, we have investigated whether RES + OLA inhibits chromatin relaxation and thereby blocks the HR pathway. It was found that RES + OLA inhibited PARP1 activity, terminated PARP1-BRCA1 interaction, and deregulated the HR pathway only in the chromatin fraction of MCF-7 cells. DR-GFP reporter plasmid-based HR assay demonstrated marked reduction in HR efficiency in I-SceI endonuclease-transfected cells treated with OLA. RES + OLA efficiently trapped PARP1 at the DNA damage site in the chromatin of MCF-7 cells. Unaltered expressions of HR proteins were found in the chromatin of PARP1-silenced MCF-7 cells, which confirmed that RES + OLA-mediated DNA damage response was PARP1-dependent. Histone Acetyltransferase (HAT) activity and histone H4 acetylation assays showed reduction in HAT activity and H4 acetylation in RES + OLA-treated chromatin fraction of cells. Western blot analysis showed that the HAT enzyme TIP60, P400 and acetylated H4 were downregulated after RES + OLA exposure. In the co-immunoprecipitation assay, it was observed that RES + OLA caused abolition of PARP1-TIP60-BRCA1 interaction, which suggested the PARP1-dependent TIP60-BRCA1 association. Unaltered expressions of PAR, BRCA1, P400, and acetylated H4 in the chromatin of TIP60-silenced MCF-7 cells further confirmed the role of TIP60 in PARP1-mediated HR activation in the chromatin. Similar results were obtained in ex vivo patient-derived primary breast cancer cells. Thus, the present study revealed that RES + OLA treatment inhibited PARP1 activity in the chromatin, and blocked TIP60-mediated chromatin relaxation, which, in turn, affected PARP1-dependent TIP60-BRCA1 association, resulting in deregulation of HR pathway in breast cancer cells. [ABSTRACT FROM AUTHOR]

The presence of cancer stem cells (CSCs) in the tumor microenvironment (TME) is majorly responsible for the development and recurrence of cancer. Earlier reports suggested that upon DNA damage, poly-(ADP-ribose) polymerase-1 (PARP-1) helps in chromatin modulation and DNA repair process, thereby promoting CSC survival. But whether a combination of DNA damaging agents along with PARP inhibitors can modulate chromatin assembly, inhibit DNA repair processes, and subsequently target CSCs is not known. Hence, we have investigated the effect of nontoxic bioactive compound quinacrine (QC) and a potent PARP inhibitor Talazoparib in patient-derived oral mucosa CSCs (OM-CSCs) and in vivo xenograft mice preclinical model systems. Data showed that QC + Talazoparib inhibited the PARP-1-mediated chromatin remodelers' recruitment and deregulated HAT activity of GCN5 (general control nonderepressible-5) and P300 at DNA damage site, thereby preventing the access of repair proteins to the damaged DNA. Additionally, this combination treatment inhibited topoisomerase activity, induced topological stress, and induced apoptosis in OM-CSCs. Similar results were observed in an in vivo xenograft mice model system. Collectively, the data suggested that QC + Talazoparib treatment inhibited BER pathway, induced genomic instability and triggered apoptosis in OM-CSCs through the deregulation of PARP-1-mediated chromatin remodelers (GCN5 and P300) activity. Schematic representation of QC + Talazoparib-induced apoptosis in oral mucosa CSCs. (1) Induction of DNA damage takes place after QC treatment (2) PARP1-mediated PARylation at the site of DNA damage, which recruits multiple chromatin remodelers (3) Acetylation at the histone tails relax the structure of chromatin and recruits the BER pathway proteins at the site of DNA damage. (4) BER pathway activated at the site of DNA damage. (5) CSCs survive after successful repair of DNA damage. (6) Treatment of QC-treated CSCs with PARP inhibitor Talazoparib (7) Inhibition of PARylation results in failure of chromatin remodelers to interact with PARP1. (8) Inhibition of acetylation status leads to chromatin compaction. (9) BER pathway proteins are not recruited at the site of DNA damage, resulting in inhibition of BER pathway and accumulation of unrepaired DNA damage, leading to apoptosis and cell death. [ABSTRACT FROM AUTHOR]

Cancer stem cells (CSCs) cause drug resistance in cancer due to its extensive drug efflux, DNA repair and self-renewal capability. ATP binding cassette subfamily G member 2 (ABCG2) efflux pump afford protection to CSCs in tumors, shielding them from the adverse effects of chemotherapy. Although the role of ABCG2 in cancer progression, invasiveness, recurrence are known but its role in metastasis and angiogenesis are not clear. Here, using in vitro (CSCs enriched side population [SP] cells), ex vivo (patient derived primary cells), in ovo (fertilized egg embryo) and in vivo (patient derived primary tissue mediated xenograft (PDX)) system, we have systematically studied the role of ABCG2 in angiogenesis and the regulation of the process by Curcumin (Cur) and Quinacrine (QC). Cur + QC inhibited the proliferation, invasion, migration and expression of representative markers of metastasis and angiogenesis. Following hypoxia, ABCG2 enriched cells released angiogenic factor vascular endothelial growth factor A (VEGF A) and induced the angiogenesis via PI3K-Akt-eNOS cascade. Cur + QC inhibited the ABCG2 expression and thus reduced the angiogenesis. Interestingly, overexpression of ABCG2 in SP cells and incubation of purified ABCG2 protein in media induced the angiogenesis but knockdown of ABCG2 decreased the vascularization. In agreement with in vitro results, ex vivo data showed similar phenomena. An induction of vascularization was noticed in PDX mice but reduction of vascularization was also observed after treatment of Cur + QC. Thus, data suggested that in hypoxia, ABCG2 enhances the production of angiogenesis factor VEGF A which in turn induced angiogenesis and Cur + QC inhibited the process by inhibiting ABCG2 in breast cancer. [ABSTRACT FROM AUTHOR]

Nonlinear analysis for the finite amplitude electron acoustic wave is considered in a magnetized viscous plasma. The quantum hydrodynamic model is used to describe the thickly and thinly populated electron species with the Kappa distributive ion. Viscous effects have been considered for the thickly populated electron. By employing the standard reductive perturbation technique, the KdV–Burger equation has been derived, which exhibits shock waves. KdV–B equation transforms into the KdV equation when there is no viscous term. The form of the effective magnetic field is the Earth-like magnetospheric magnetic field. The shock fronts and the solitary structures have been studied with a variety of different plasma parameters. The results are essential in explaining the various phenomena in the inner magnetosphere. [ABSTRACT FROM AUTHOR]

In this work, the nonlinear KdV solitary structures have been studied in electron acoustic waves in a thermal magnetoplasma with Kappa-distributed ions by employing a reductive perturbation technique. Relativistic streaming effects are also incorporated. External forcing term on the KdV soliton is studied via the forced KdV equation. Further nonlinear self-interactions have been studied through the nonlinear Schrödinger equation. Dynamical systems have been studied and the parametric phase portraits are graphically analyzed. The results will be helpful in the laboratory plasmas where magnetic confinement is employed. High-energy plasma at greater density can be studied with our model problem. [ABSTRACT FROM AUTHOR]

The present work deals with the study of chemical synthesis of tetrabutylammonium hexanitrate Ce(III) (TBA3[Ce(NO3)6]) derived from ammonium cerium (IV) nitrate, syn-2-pyridinealdoxime, tetrabutylammonium bromide in 6:9:4 stoichiometric ratio and a mixture of acetic acid and water (10/30, v/v) in a single pot reaction. The structure of the TBA3[Ce(NO3)6] is characterized using FTIR, UV–Visible and Single X-ray Crystallography technique. Its crystal structure and BVS calculation confirm the oxidation state of cerium ion. The complex TBA3[Ce(NO3)6] consists of central metal atom cerium (III) ion, which was bound to six nitrate moieties through the coordinate bond with an oxygen atom and the whole moiety is surrounded by three tetrabutylammonium anions and formulates a salt structure. The symmetry point group of complex TBA3[Ce(NO3)6] is P21/n (14). From optical measurement, we have calculated the band gap energy of TBA3[Ce(NO3)6] (4.3 eV), which indicates the complex has semiconductor properties. We have also reported the binding ability of TBA3[Ce(NO3)6] with CT-DNA through intercalation mode, and the binding constant (Kb) is found to be 1.182 × 103 M−1. The cytotoxicity effect and chromosomal aberration in Allium cepa L. root tip cells confirmed the complex's biological activity. Density Function Theory (DFT) is finding out the theoretical evidence of structural and electronic parameters of the complex (by using cif) such as ionization potential (I), electron affinity (A), HOMO–LUMO energy gap, hardness (η) and softness (σ). The EHOMO, ELUMO, hardness (η), softness (σ) and dipole moment (µ) are − 3.442 eV, − 2.231 eV, 1.211 eV, 0.603 eV, 1.657 eV−1, and 3.830 Debye. [ABSTRACT FROM AUTHOR]

Advance in computational rheology allows for in silico predictions of the viscoelastic responses of arbitrarily branched polymer melts. While detailed branching structure is required for the rheology predictions, rheology itself is often the most sensitive tool to detect low levels of branching. With rheological experiments and computational modeling of a set of nominally linear and model comb ethylene-butene copolymers, we show that coupled models for the synthesis and rheology can integrate diverse measurements, incorporating inherent experimental uncertainties. This approach allows us to achieve tight bounds on the branching structures of the constituent molecules. Next, we numerically explore the effects of the numbers and molar masses of side arms in comb polymers on the viscoelastic responses in both the linear and nonlinear regimes. Such computational exploration can aid in designing specific polymers suitable for a given processing scenario. Graphical abstract Coupled models for synthesis and rheology allow tight bounds on branching architecture and parametric exploration of flow properties of statistically branched polymers. [ABSTRACT FROM AUTHOR]

Hierarchical computational schemes based on tube theories enable calculation of rheological properties for polymers of arbitrary topology. In this study, such a scheme is used to systematically explore key rheological features of model long-chain branched systems. Empirical relations between molecular structure and rheology typically use overall molar mass and branching averages as structural variables, due to lack of knowledge on details of the topological structure or to limited structural variability between available experimental samples. The present approach clarifies the effect of additional structural variation beyond overall molar mass and branching level. For the polymer structures under consideration, arm length is found to dominate zero-shear viscosity, whereas the recoverable compliance scales with the ratio of total molar mass and backbone molar mass. Different topologies are found to lead to a different shear thinning/elasticity balance. The simulation approach provides clear hints for polymer designers that look to obtain specific property balances via topological modifications. This complements the classical empirical approach. Merging the different approaches is expected to synergistically speed up new product development. [ABSTRACT FROM AUTHOR]