Targeting Mitochondrial Protein Expression as a Future Approach for Cancer Therapy

Extensive metabolic remodeling is a fundamental feature of cancer cells. Although early reports attributed such remodeling to a loss of mitochondrial functions, it is now clear that mitochondria play central roles in cancer development and progression, from energy production to synthesis of macromolecules, from redox modulation to regulation of cell death. Biosynthetic pathways are also heavily affected by the metabolic rewiring, with protein synthesis dysregulation at the hearth of cellular transformation. Accumulating evidence in multiple organisms shows that the metabolic functions of mitochondria are tightly connected to protein synthesis, being assembly and activity of respiratory complexes highly dependent on de novo synthesis of their components. In turn, protein synthesis within the organelle is tightly connected with the cytosolic process. This implies an entire network of interactions and fine-tuned regulations that build up a completely under-estimated level of complexity. We are now only preliminarily beginning to reconstitute such regulatory level in human cells, and to perceive its role in diseases. Indeed, disruption or alterations of these connections trigger conditions of proteotoxic and energetic stress that could be potentially exploited for therapeutic purposes. In this review, we summarize the available literature on the coordinated regulation of mitochondrial and cytosolic mRNA translation, and their effects on the integrity of the mitochondrial proteome and functions. Finally, we highlight the potential held by this topic for future research directions and for the development of innovative therapeutic approaches

Detonation nanodiamonds tailor the structural oeder of PEDOT chains in conductive coating layers of hybrid nanoparticles

Solid layers of PEDOT–detonation nanodiamond based nanoparticles with an exceptional structural order were produced by means of a template-free polymerization technique. As an efficient multifunctional filler, the nanocrystalline diamond has been shown to possess a high catalytic activity on the monomer polymerization rate as well as to play a fundamental role as a 3D arrangement-directing agent of the PEDOT chains at the micro- and nano-scale. SEM, TEM and TED analyses highlighted the mutual organization between PEDOT oligomers and nanodiamond grains, and the produced hierarchical effects on the arrangement of the backbones of the final polymer. Optical and Raman spectroscopy, used together with XRD diffraction to study the molecular structure and crystallographic features of the hybrid materials, pointed out that the adopted synthetic strategy enables highly conjugated and doped hybrid systems to be generated. The spatial distribution of the filler inside the polymeric matrix and the mutual connectivity of nanodiamond crystals and PEDOT segments are found to strongly improve the functional properties of the host polymer. Mechanical characterizations by advanced AFM-based techniques revealed that both indentation modulus and hardness of PEDOT/nanodiamond materials are 3 times higher than the pure PEDOT polymer, while electrical characterizations by a 4-probe method gave sheet resistance values of 1 106 U sq 1 for the nanocomposite particle

Crucial role of androgen receptor in vascular H2S biosynthesis induced by testosterone.

BACKGROUND AND PURPOSE: Hydrogen sulphide (H2S) is a gaseous mediator strongly involved in cardiovascular homeostasis, where it provokes vasodilation. Having previously shown that H2S contributes to testosterone (T) induced vasorelaxation, here we aim to uncover the mechanisms underlying this effect. EXPERIMENTAL APPROACH: H2S biosynthesis was evaluated in rat isolated aorta rings following androgen receptor (AR) stimulation. Co-immunoprecipitation and surface plasmon resonance analysis have been performed to investigate mechanisms involved in AR activation. KEY RESULTS: H2S biosynthesis is associated to activation of AR by testosterone or androgen agonist mesterolone and blocked by AR antagonist nilutamide. This event is linked to AR-multicomplex-derived heath shock protein 90 (hsp90), since its specific inhibitor geldanamycin strongly reduced T-induced H2S production. Neither progesterone nor 17-β-oestradiol actions did account for H2S release. Furthermore, we found that cystathionine gamma lyase (CSE), the main vascular H2S-synthesizing enzyme, is physically associated to AR/hsp90 complex and the generation of such a ternary system represents a key event leading to CSE activation. Finally, H2S levels in human blood collected from male healthy volunteers were higher than those observed in female samples. CONCLUSIONS AND IMPLICATIONS: Here, we demonstrated that selective activation of the AR is essential for H2S biosynthesis within vascular tissue and this event is based on formation of a ternary complex among CSE, AR and hsp90. This novel molecular mechanism operating in vascular district, corroborated by higher H2S level in males, suggested that L-cysteine/CSE/H2S pathway may be preferentially activated in males leading to a gender-related H2S biosynthesis

Constraints on the quantum gravity scale from kappa - Minkowski spacetime

We compare two versions of deformed dispersion relations (energy vs momenta and momenta vs energy) and the corresponding time delay up to the second order accuracy in the quantum gravity scale (deformation parameter). A general framework describing modified dispersion relations and time delay with respect to different noncommutative kappa -Minkowski spacetime realizations is firstly proposed here and it covers all the cases introduced in the literature. It is shown that some of the realizations provide certain bounds on quadratic corrections, i.e. on quantum gravity scale, but it is not excluded in our framework that quantum gravity scale is the Planck scale. We also show how the coefficients in the dispersion relations can be obtained through a multiparameter fit of the gamma ray burst (GRB) data.Comment: 9 pages, final published version, revised abstract, introduction and conclusion, to make it clear to general reade

Translational control in the stress adaptive response of cancer cells: a novel role for the heat shock protein TRAP1

TNF receptor-associated protein 1 (TRAP1), the main mitochondrial member of the heat shock protein (HSP) 90 family, is induced in most tumor types and is involved in the regulation of proteostasis in the mitochondria of tumor cells through the control of folding and stability of selective proteins, such as Cyclophilin D and Sorcin. Notably, we have recently demonstrated that TRAP1 also interacts with the regulatory protein particle TBP7 in the endoplasmic reticulum (ER), where it is involved in a further extra-mitochondrial quality control of nuclear-encoded mitochondrial proteins through the regulation of their ubiquitination/degradation. Here we show that TRAP1 is involved in the translational control of cancer cells through an attenuation of global protein synthesis, as evidenced by an inverse correlation between TRAP1 expression and ubiquitination/degradation of nascent stress-protective client proteins. This study demonstrates for the first time that TRAP1 is associated with ribosomes and with several translation factors in colon carcinoma cells and, remarkably, is found co-upregulated with some components of the translational apparatus (eIF4A, eIF4E, eEF1A and eEF1G) in human colorectal cancers, with potential new opportunities for therapeutic intervention in humans. Moreover, TRAP1 regulates the rate of protein synthesis through the eIF2α pathway either under basal conditions or under stress, favoring the activation of GCN2 and PERK kinases, with consequent phosphorylation of eIF2α and attenuation of cap-dependent translation. This enhances the synthesis of selective stress-responsive proteins, such as the transcription factor ATF4 and its downstream effectors BiP/Grp78, and the cystine antiporter system xCT, thereby providing protection against ER stress, oxidative damage and nutrient deprivation. Accordingly, TRAP1 silencing sensitizes cells to apoptosis induced by novel antitumoral drugs that inhibit cap-dependent translation, such as ribavirin or 4EGI-1, and reduces the ability of cells to migrate through the pores of transwell filters. These new findings target the TRAP1 network in the development of novel anti-cancer strategies

TRAP1-dependent regulation of p70S6K is involved in the attenuation of protein synthesis and cell migration: Relevance in human colorectal tumors

TNF receptor-associated protein 1 (TRAP1) is an HSP90 chaperone involved in stress protection and apoptosis in mitochondrial and extramitochondrial compartments. Remarkably, aberrant deregulation of TRAP1 function has been observed in several cancer types with potential new opportunities for therapeutic intervention in humans. Although previous studies by our group identified novel roles of TRAP1 in quality control of mitochondria-destined proteins through the attenuation of protein synthesis, molecular mechanisms are still largely unknown. To shed further light on the signaling pathways regulated by TRAP1 in the attenuation of protein synthesis, this study demonstrates that the entire pathway of cap-mediated translation is activated in cells following TRAP1 interference: consistently, expression and consequent phosphorylation of p70S6K and RSK1, two translation activating kinases, are increased upon TRAP1 silencing. Furthermore, we show that these regulatory functions affect the response to translational stress and cell migration in wound healing assays, processes involving both kinases. Notably, the regulatory mechanisms controlled by TRAP1 are conserved in colorectal cancer tissues, since an inverse correlation between TRAP1 and p70S6K expression is found in tumor tissues, thereby supporting the relevant role of TRAP1 translational regulation in vivo. Taken as a whole, these new findings candidate TRAP1 network for new anti-cancer strategies aimed at targeting the translational/quality control machinery of tumor cells

Biocompatibility and antibiofilm properties of calcium silicate-based cements: An in vitro evaluation and report of two clinical cases

Calcium silicate-based cements have reached excellent levels of performance in endodon-tics, providing predictable and successful results. To better assess the properties of these bioactive materials, the present study aimed to compare the biocompatibility and antibiofilm properties of ProRoot MTA and Biodentine. Human osteogenic sarcoma (Saos-2) cells were cultured on ProRoot MTA and Biodentine samples or in the presence of both cement extracts. Cell viability assay, meas-urement of reactive oxygen species (ROS), immunofluorescence analysis, as well as morphological evaluations were conducted. Moreover, Streptococcus mutans was used to assess the biofilm forming ability on ProRoot MTA and Biodentine disks. Finally, both cements were applied in vivo to treat immature permanent teeth affected by reversible pulpitis. Results: Cell viability assay demonstrated that Saos-2 cells had a dose-and time-dependent cytotoxicity to both analyzed cements, although cells exposed to ProRoot MTA showed a better cell vitality than those exposed to Biodentine (p < 0.001). Both cements demonstrated ROS production while this was greater in the case of Biodentine than ProRoot MTA (p < 0.001). Immunofluorescence images of the cytoskeleton and focal adhesions showed no differences in Saos-2 cells grown in the presence of ProRoot MTA eluate; whereas in the Biodentine groups, cells showed a morphology and focal adhesions more similar to that of the control sample, as the eluate concentration decreased. Morphological analysis revealed that Saos-2 cells were more flattened and exhibited better spreading when attached to ProRoot MTA disks than to Biodentine ones. The antibiofilm properties showed a time-dependent powerful inhibition of S. mutans superficial colonization and an antibiofilm effect of both cements. Clinically, complete root formation of the treated elements was achieved using the two studied cements, showing stable results over time. ProRoot MTA and Biodentine was demonstrated to be biocompatible and to possess antibiofilm properties. Their clinical application in vital pulp therapy provided successful outcomes after 2 years of follow-up

Aberrant crosstalk between insulin signaling and mTOR in young Down syndrome individuals revealed by neuronal-derived extracellular vesicles

Introduction: Intellectual disability, accelerated aging, and early-onset Alzheimer-like neurodegeneration are key brain pathological features of Down syndrome (DS). Although growing research aims at the identification of molecular pathways underlying the aging trajectory of DS population, data on infants and adolescents with DS are missing. Methods: Neuronal-derived extracellular vesicles (nEVs) were isolated form healthy donors (HDs, n&nbsp;=&nbsp;17) and DS children (n&nbsp;=&nbsp;18) from 2 to 17 years of age and nEV content was interrogated for markers of insulin/mTOR pathways. Results: nEVs isolated from DS children were characterized by a significant increase in pIRS1Ser636, a marker of insulin resistance, and the hyperactivation of the Akt/mTOR/p70S6K axis downstream from IRS1, likely driven by the higher inhibition of Phosphatase and tensin homolog (PTEN). High levels of pGSK3βSer9 were also found. Conclusions: The alteration of the insulin-signaling/mTOR pathways represents an early event in DS brain and likely contributes to the cerebral dysfunction and intellectual disability observed in this unique population

How can we possibly resolve the planet's nitrogen dilemma?

Nitrogen is the most crucial element in the production of nutritious feeds and foods. The production of reactive nitrogen by means of fossil fuel has thus far been able to guarantee the protein supply for the world population. Yet, the production and massive use of fertilizer nitrogen constitute a major threat in terms of environmental health and sustainability. It is crucial to promote consumer acceptance and awareness towards proteins produced by highly effective microorganisms, and their potential to replace proteins obtained with poor nitrogen efficiencies from plants and animals. The fact that reactive fertilizer nitrogen, produced by the Haber Bosch process, consumes a significant amount of fossil fuel worldwide is of concern. Moreover, recently, the prices of fossil fuels have increased the cost of reactive nitrogen by a factor of 3 to 5 times, while international policies are fostering the transition towards a more sustainable agro-ecology by reducing mineral fertilizers inputs and increasing organic farming. The combination of these pressures and challenges opens opportunities to use the reactive nitrogen nutrient more carefully. Time has come to effectively recover used nitrogen from secondary resources and to upgrade it to a legal status of fertilizer. Organic nitrogen is a slow-release fertilizer, it has a factor of 2.5 or higher economic value per unit nitrogen as fertilizer and thus adequate technologies to produce it, for instance by implementing photobiological processes, are promising. Finally, it appears wise to start the integration in our overall feed and food supply chains of the exceptional potential of biological nitrogen fixation. Nitrogen produced by the nitrogenase enzyme, either in the soil or in novel biotechnology reactor systems, deserves to have a ‘renaissance’ in the context of planetary governance in general and the increasing number of people who desire to be fed in a sustainable way in particular

Aberrant Crosstalk between Insulin Signaling and mTOR in Young Down Syndrome Individuals Revealed by Neuronal-Derived Extracellular Vesicles

INTRODUCTION: Intellectual disability, accelerated aging, and early-onset Alzheimer-like neurodegeneration are key brain pathological features of Down syndrome (DS). Although growing research aims at the identification of molecular pathways underlying the aging trajectory of DS population, data on infants and adolescents with DS are missing. METHODS: Neuronal-derived extracellular vesicles (nEVs) were isolated form healthy donors (HDs, n = 17) and DS children (n = 18) from 2 to 17 years of age and nEV content was interrogated for markers of insulin/mTOR pathways. RESULTS: nEVs isolated from DS children were characterized by a significant increase in pIRS1Ser636, a marker of insulin resistance, and the hyperactivation of the Akt/mTOR/p70S6K axis downstream from IRS1, likely driven by the higher inhibition of Phosphatase and tensin homolog (PTEN). High levels of pGSK3βSer9 were also found. CONCLUSIONS: The alteration of the insulin-signaling/mTOR pathways represents an early event in DS brain and likely contributes to the cerebral dysfunction and intellectual disability observed in this unique population