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Bcl-2 has been shown to promote survival of cancer cells by maintaining a slight pro-oxidant state through elevated mitochondrial respiration during basal conditions. On oxidative stress, Bcl-2 moderates mitochondrial respiration through cytochrome c oxidase (COX) activity to prevent an excessive buildup of reactive oxygen species (ROS) by-production from electron transport activities. However, the underlying molecular mechanism(s) of Bcl-2-mediated ROS regulation and its impact on carcinogenesis remain unclear. In this study, we show that Bcl-2 expression positively influences the targeting of nuclear-encoded COX Va and Vb to the mitochondria of cancer cells. In addition, evidence is presented in support of a protein–protein interaction between COX Va and Bcl-2, involving the BH2 domain of Bcl-2. Interestingly, episodes of serum withdrawal, glucose deprivation or hypoxia aimed at inducing early oxidative stress triggered Bcl-2-overexpressing cells to preserve mitochondrial levels of COX Va while depressing COX Vb, whereas the reverse was observed in mock-transfected cells. The unique manner in which Bcl-2 adjusted COX subunits during these physiological stress triggers had a profound impact on the resultant decrease in COX activity and maintenance of mitochondrial ROS levels, thus delineating a novel mechanism for the homeostatic role of Bcl-2 in the redox biology and metabolism of cancer cells.

Mitochondrial respiration, the key process behind cellular energy production, is critical for cell proliferation, growth and survival. However, the regulation of mitochondrial respiratory function in tumor cells is not well understood. In this study, we propose a model whereby tumor cells possess the capacity to fine-tune the balance between energy demands and mitochondrial reactive oxygen species (ROS) status, to maintain a milieu optimal for survival. This is achieved through the moderation of mitochondrial respiration, depending on the ROS context within the organelle, with the main players being Bcl-2 and cytochrome c oxidase (COX). We report a higher level of COX activity, oxygen consumption and mitochondrial respiration in tumor cells overexpressing Bcl-2. Transient overexpression, gene silencing and pharmacological inhibition of Bcl-2 corroborate these findings. Interestingly, Bcl-2 is also able to regulate mitochondrial respiration and COX activity in the face of mounting ROS levels, triggered by mitochondrial complex inhibitors. In this respect, it is plausible to suggest that Bcl-2 may be able to create an environment, most suited for survival by adjusting mitochondrial respiration accordingly to meet energy requirements, without incurring an overwhelming, detrimental increase in intracellular ROS.

This study demonstrates the remarkable improvement in structural, optical and dielectric properties of flexible sheets of polymer-based zinc oxide nanocomposites (PB-ZnO-NCs) synthesized by co-precipitation method. The X-ray diffraction patterns show the development of ZnO (100), ZnO (002), ZnO (101) and ZnO (102) diffraction peaks. The variation in peak intensities and crystallite sizes are associated with increasing wt.% of ZnO nanofillers. The FTIR analysis confirms the presence of vibrational modes of PVDF, ZnO and O-H groups and shows strong bonding between PVDF and ZnO, when ZnO is more than 20wt.%. The SEM microstructural analysis of polymer is appeared just like microfibers which is changed into cloudy microstructure when 10 wt.% ZnO nanofillers are mixed, however, the surface morphology strongly depends on increasing wt.% of ZnO nanofillers. The small shift in absorption edges and increasing values of absorption for PVDF and ZnO depend on the increasing wt.% of ZnO nanofillers. The values of energy band gap are found in the range from 5.69-5.47 eV and 3.65-3.38 eV for PVDF and ZnO respectively. Dielectric measurements demonstrate a sharp increase in dielectric permittivity with relatively low loss factor. The static value of dielectric constant at 100 Hz is found to be 13.88 for sample having 50 wt.% ZnO nanofillers which is 4.2 times greater than PVDF and shows relatively low value of loss factor. The observed AC conductivity of synthesized PB-ZnO-NCs having 50 wt.% ZnO and 50 wt.% PVDF is found to be 2.16×10 -5  S/m which is 3.2 times larger than PVDF at 1×10 6 Hz. Results indicate that a chain of polymer matrix arises due to defects and capsulated microstructures, increased with increasing wt.% of ZnO nanofillers which make the NCs more flexible, strengthen and conductive.

Mitochondria have important functions in mammalian cells as the energy powerhouse and integrators of the mitochondrial pathway of apoptosis. The adenine nucleotide translocase (ANT) is a family of proteins involved in cell death pathways that perform distinctly opposite functions to regulate cell fate decisions. On the one hand, ANT catalyzes the adenosine triphosphate export from the mitochondrial matrix to the intermembrane space with the concomitant import of ADP from the intermembrane space to the matrix. On the other hand, during periods of stress, ANT could function as a lethal pore and trigger the process of mitochondrial membrane permeabilization, which leads irreversibly to cell death. In human, ANT is encoded by four homologous genes, whose expression is not only tissue specific, but also varies according to the pathophysiological state of the cell. Recent evidence revealed a differential role of the ANT isoforms in apoptosis and a deregulation of their expression in cancer. In this review, we introduce the current knowledge of ANT in apoptosis and cancer cells and propose a novel classification of ANT isoforms.

Although statins are known to inhibit proliferation and induce death in a number of cancer cell types, the mechanisms through which downregulation of the mevalonate (MVA) pathway activates death signaling remain poorly understood. Here we set out to unravel the signaling networks downstream of the MVA pathway that mediate the death-inducing activity of simvastatin. Consistent with previous reports, exogenously added geranylgeranylpyrophosphate, but not farnesylpyrophosphate, prevented simvastatin’s growth-inhibitory effect, thereby suggesting the involvement of geranylgeranylated proteins such as Rho GTPases in the anticancer activity of simvastatin. Indeed, simvastatin treatment led to increased levels of unprenylated Ras homolog gene family, member A (RhoA), Ras-related C3 botulinum toxin substrate 1 (Rac1) and cell division cycle 42 (Cdc42). Intriguingly, instead of inhibiting the functions of Rho GTPases as was expected with loss of prenylation, simvastatin caused a paradoxical increase in the GTP-bound forms of RhoA, Rac1 and Cdc42. Furthermore, simvastatin disrupted the binding of Rho GTPases with the cytosolic inhibitor Rho GDI α , which provides a potential mechanism for GTP loading of the cytosolic Rho GTPases. We also show that the unprenylated RhoA- and Rac1-GTP retained at least part of their functional activities, as evidenced by the increase in intracellular superoxide production and JNK activation in response to simvastatin. Notably, blocking superoxide production attenuated JNK activation as well as cell death induced by simvastatin. Finally, we provide evidence for the involvement of the B-cell lymphoma protein 2 family, Bcl-2-interacting mediator (Bim), in a JNK-dependent manner, in the apoptosis-inducing activity of simvastatin. Taken together, our data highlight the critical role of non-canonical regulation of Rho GTPases and involvement of downstream superoxide-mediated activation of JNK pathway in the anticancer activity of simvastatin, which would have potential clinical implications.

The silica zinc oxide nanoparticles filled poly-vinylidene-fluoride (PVDF)-based nanocomposite flexible sheets (NC FSs) are synthesized by co-precipitation method. The X-ray diffraction patterns reveal the development of various diffraction planes related to zinc oxide (ZnO) and SiO2 phases. The crystallinity of ZnO phase is decreased with increasing weight percent (wt.%) of silica nanofillers (NFs). The scanning electron microscope microstructure of synthesized PVDF-based NCs FSs is changed with increasing wt.% of silica NFs. The energy-dispersive X-ray spectroscopy and Fourier-transform infrared spectroscopy analyses confirm the presence of different elements and the formation of chemical bonding between them. In high temperature region, the weight-loss of synthesized PVDF-based NCs FSs is decreased from 89.90% to 49.26% with increasing wt.% of silica NFs. The values of dielectric permittivity, loss-factor, impedance, and AC-conductivity of PVDF-based NC FSs synthesized for maximum amount of silica NFs are found to be 13.7, 0.03, 0.16 MΩ, and 19.9×10−6 S/m, respectively. Results show that the synthesized PVDF-based NC FSs are the potential candidates of light emitting diodes and energy storage devices.

Apoptosis, a form of programmed cell death, enables organisms to maintain tissue homeostasis through deletion of extraneous cells and also serves as a means to eliminate potentially harmful cells. Numerous stress signals have been shown to engage the intrinsic pathway of apoptosis, with the release from mitochondria of proapoptotic factors such as cytochrome c and the subsequent formation of a cytosolic complex between apoptotic protease-activating factor-1 (Apaf-1) and procaspase-9, known as the apoptosome. Recent studies have led to the identification of an array of factors that control the formation and activation of the apoptosome under physiological conditions. Moreover, deregulation of apoptosome function has been documented in various forms of human cancer, and may play a role in both carcinogenesis and chemoresistance. We discuss how the apoptosome is regulated in normal and disease states, and how targeting of apoptosome-dependent, post-mitochondrial stages of apoptosis may serve as a rational approach to cancer treatment.

Flexible dielectric polymer nanocomposites (NCs) with high dielectric permittivity and low loss factor have numerous applications in light emitting and storage devices. In this research work, polymer based NCs in the form of flexible sheets containing 5% ZnO and 15, 20% SiO 2 nano-fillers, are synthesized by using co-precipitation method. X-ray diffraction analysis reveals the development of various diffraction planes related to ZnO and SiO 2 phases confirms the synthesis of polycrystalline PB–ZnO–SiO 2 NCs flexible sheets corresponding to various compositions. Morphology and compositional analysis show the uniform distribution of nanoparticles in polymer matrix with estimated elemental contents in each composition. Dielectric measurements demonstrate a sharp increase in dielectric permittivity with relatively low dissipation factor in synthesized compositions having ZnO and SiO 2 nano-fillers. The static value of dielectric constant at 100 Hz is found to be 10.79 for sample having 20% SiO 2 nano-fillers that is 3.4 times greater than pure PVA and it shows relatively low value of dissipation factor. The observed AC conductivity of synthesized NCs flexible sheets having 5% ZnO, 20% SiO 2 nano-fillers is 2.15 × 10 –5  S/m that is 3.3 times greater than pure PVA at 1 × 10 6  Hz. Complex impedance spectroscopy further confirms, these materials as promising candidates for better capacitive performance.