FGF trapping inhibits multiple myeloma growth through c-Myc degradation-induced mitochondrial oxidative stress

Multiple myeloma (MM), the second most common hematological malignancy, frequently relapses because of chemotherapeutic resistance. Fibroblast growth factors (FGFs) act as pro-angiogenic and mitogenic cytokines in MM. Here, we demonstrate that the autocrine FGF/FGFR axis is essential for MM cell survival and progression by protecting MM cells from oxidative stress-induced apoptosis. In keeping with the hypothesis that the intracellular redox status can be a target for cancer therapy, FGF/FGFR blockade by FGF trapping or tyrosine kinase inhibitor impaired the growth and dissemination of MM cells by inducing mitochondrial oxidative stress, DNA damage and apoptotic cell death that were prevented by the antioxidant vitamin E or mitochondrial catalase overexpression. In addition, mitochondrial oxidative stress occurred as a consequence of proteasomal degradation of the c-Myc oncoprotein that led to glutathione depletion. Accordingly, expression of a proteasome-non-degradable c-Myc protein mutant was sufficient to avoid glutathione depletion and rescue the pro-apoptotic effects due to FGF blockade. These findings were confirmed on Bortezomib-resistant MM cells as well as on bone marrow-derived primary MM cells from newly diagnosed and relapsed/refractory patients, including plasma cells bearing the t(4;14) translocation obtained from high-risk MM patients. Altogether, these findings dissect the mechanism by which the FGF/FGFR system plays a non-redundant role in MM cell survival and disease progression, and indicate that FGF targeting may represent a therapeutic approach for MM patients with poor prognosis and advanced disease stage

Effect of extrusion and autoclaving on the biological potential of proteins and naturally-occurring peptides from common beans: Antioxidant and vasorelaxant properties

Aiming to understand the impact of hardening on the biological potential of bean protein and peptides, we evaluated the antioxidant and vasorelaxant properties of common beans after and before hardening. It was also evaluated the effect of extrusion and autoclaving in the biological potential of hardened beans. In general, hardening caused a reduction from 13.5 to 39.6% on the antioxidant activity of the peptide-rich fractions. On the other hand, hardening did not strongly interfere with the vascular reactivity in thoracic aorta rings, being observed maximal relation varying from 801% to 84.7%. The thermal treatment caused a general increase in the antioxidant and vasorelaxant potential of these fractions, being observed EC50 values ranging from 0.22 mg mL -1 to 0.26 mg mL -1. We can conclude that hardening did not seem to affect definitively the bioactivity of the obtained peptide-rich fractions. Finally, this study allows suggesting practical applications of extrusion as a thermal process in the production of functional food ingredients, and as ready-to-eat products presenting nutraceutical potential. In addition, autoclaving can be used as a pre-treatment of the hardened grains aiming to use them as whole grains with potentialized benefits for human health

Cutting-Edge Search for Safer Opioid Pain Relief: Retrospective Review of Salvinorin A and Its Analogs

Over the years, pain has contributed to low life quality, poor health, and economic loss. Opioids are very effective analgesic drugs for treating mild, moderate, or severe pain. Therapeutic application of opioids has been limited by short and long-term side effects. These side effects and opioid-overuse crisis has intensified interest in the search for new molecular targets and drugs. The present review focuses on salvinorin A and its analogs with the aim of exploring their structural and pharmacological profiles as clues for the development of safer analgesics. Ethnopharmacological reports and growing preclinical data have demonstrated the antinociceptive effect of salvinorin A and some of its analogs. The pharmacology of analogs modified at C-2 dominates the literature when compared to the ones from other positions. The distinctive binding affinity of these analogs seems to correlate with their chemical structure and in vivo antinociceptive effects. The high susceptibility of salvinorin A to chemical modification makes it an important pharmacological tool for cellular probing and developing analogs with promising analgesic effects. Additional research is still needed to draw reliable conclusions on the therapeutic potential of salvinorin A and its analogs

Inorganic carbon physiology underpins macroalgal responses to elevated CO2

Beneficial effects of CO2 on photosynthetic organisms will be a key driver of ecosystem change under ocean acidification. Predicting the responses of macroalgal species to ocean acidification is complex, but we demonstrate that the response of assemblages to elevated CO2 are correlated with inorganic carbon physiology. We assessed abundance patterns and a proxy for CO2:HCO3- use (\u3b413C values) of macroalgae along a gradient of CO2 at a volcanic seep, and examined how shifts in species abundance at other Mediterranean seeps are related to macroalgal inorganic carbon physiology. Five macroalgal species capable of using both HCO3- and CO2 had greater CO2 use as concentrations increased. These species (and one unable to use HCO3-) increased in abundance with elevated CO2 whereas obligate calcifying species, and non-calcareous macroalgae whose CO2 use did not increase consistently with concentration, declined in abundance. Physiological groupings provide a mechanistic understanding that will aid us in determining which species will benefit from ocean acidification and why

Effects of oil and global environmental drivers on two keystone marine invertebrates

Ocean warming (OW) and acidification (OA) are key features of global change and are predicted to have negative consequences for marine species and ecosystems. At a smaller scale increasing oil and gas activities at northern high latitudes could lead to greater risk of petroleum pollution, potentially exacerbating the effects of such global stressors. However, knowledge of combined effects is limited. This study employed a scenario-based, collapsed design to investigate the impact of one local acute stressor (North Sea crude oil) and two chronic global drivers (pH for OA and temperature for OW), alone or in combination on aspects of the biology of larval stages of two key invertebrates: the northern shrimp (Pandalus borealis) and the green sea urchin (Strongylocentrotus droebachiensis). Both local and global drivers had negative effects on survival, development and growth of the larval stages. These effects were species- and stage-dependent. No statistical interactions were observed between local and global drivers and the combined effects of the two drivers were approximately equal to the sum of their separate effects. This study highlights the importance of adjusting regulation associated with oil spill prevention to maximize the resilience of marine organisms to predicted future global conditions

Catalysing sustainable fuel and chemical synthesis

Concerns over the economics of proven fossil fuel reserves, in concert with government and public acceptance of the anthropogenic origin of rising CO2 emissions and associated climate change from such combustible carbon, are driving academic and commercial research into new sustainable routes to fuel and chemicals. The quest for such sustainable resources to meet the demands of a rapidly rising global population represents one of this century’s grand challenges. Here, we discuss catalytic solutions to the clean synthesis of biodiesel, the most readily implemented and low cost, alternative source of transportation fuels, and oxygenated organic molecules for the manufacture of fine and speciality chemicals to meet future societal demands