Depressive disorders are heterogeneous diseases, and the complexity of symptoms has led to the formulation of several aethiopathological hypotheses. This heterogeneity may account for the following ...open issues about antidepressant therapy: (i) antidepressants show a time lag between pharmacological effects, within hours from acute drug administration, and therapeutic effects, within two-four weeks of subchronic treatment; (ii) this latency interval is critical for the patient because of the possible further mood worsening that may result in suicide attempts for the seemingly ineffective therapy and for the apparent adverse effects; (iii) and only 60–70 % of treated patients successfully respond to therapy. In this review, the complexity of the biological theories that try to explain the molecular mechanisms of these diseases is considered, encompassing (i) the classic “monoaminergic hypothesis” alongside the updated hypothesis according to which long-term therapeutical action of antidepressants is mediated by intracellular signal transduction pathways and (ii) the hypothalamic–pituitary-adrenal axis involvement. Although these models have guided research efforts in the field for decades, they have not generated a compelling and conclusive model either for depression pathophysiology or for antidepressant drugs’ action. So, other emerging theories are discussed: (iii) the alterations of neuroplasticity and neurotrophins in selective vulnerable cerebral areas; (iv) the involvement of inflammatory processes; (v) and the alterations in mitochondrial function and neuronal bioenergetics. The focus is put on the molecular and theoretical links between all these hypotheses, which are not mutually exclusive but otherwise tightly correlated, giving an integrated and comprehensive overview of the neurobiology of depressive disorders.
The Southern Westerly Winds (SWW) are the surface expression of geostrophic winds that encircle the southern mid-latitudes. In conjunction with the Southern Ocean, they establish a coupled system ...that not only controls climate in the southern third of the world, but is also closely connected to the position of the Intertropical Convergence Zone and CO
degassing from the deep ocean. Paradoxically, little is known about their behavior since the last ice age and relationships with mid-latitude glacier history and tropical climate variability. Here we present a lake sediment record from Chilean Patagonia (51°S) that reveals fluctuations of the low-level SWW at mid-latitudes, including strong westerlies during the Antarctic Cold Reversal, anomalously low intensity during the early Holocene, which was unfavorable for glacier growth, and strong SWW since ~7.5 ka. We detect nine positive Southern Annular Mode-like events at centennial timescale since ~5.8 ka that alternate with cold/wet intervals favorable for glacier expansions (Neoglaciations) in southern Patagonia. The correspondence of key features of mid-latitude atmospheric circulation with shifts in tropical climate since ~10 ka suggests that coherent climatic shifts in these regions have driven climate change in vast sectors of the Southern Hemisphere at centennial and millennial timescales.
Small-molecule inhibitors targeting growth factor receptors have failed to show efficacy for brain cancers, potentially due to their inability to achieve sufficient drug levels in the CNS. Targeting ...non-oncogene tumor co-dependencies provides an alternative approach, particularly if drugs with high brain penetration can be identified. Here we demonstrate that the highly lethal brain cancer glioblastoma (GBM) is remarkably dependent on cholesterol for survival, rendering these tumors sensitive to Liver X receptor (LXR) agonist-dependent cell death. We show that LXR-623, a clinically viable, highly brain-penetrant LXRα-partial/LXRβ-full agonist selectively kills GBM cells in an LXRβ- and cholesterol-dependent fashion, causing tumor regression and prolonged survival in mouse models. Thus, a metabolic co-dependency provides a pharmacological means to kill growth factor-activated cancers in the CNS.
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•Glioblastoma (GBM) cells rely on exogenous cholesterol for survival•GBM cells suppress cholesterol and liver X receptor (LXR) ligand synthesis•A brain-penetrant LXR agonist kills GBM cells in a cholesterol-dependent fashion
Villa et al. show that glioblastomas (GBM) are reliant on cholesterol uptake and highly sensitive to liver X receptor (LXR) agonist LXR-623, a full LXRβ and partial LXRα agonist. LXR-623 shows brain penetration and causes tumor regression in a GBM mouse model, reducing cholesterol and inducing cell death.
Aerobic glycolysis (the Warburg effect) is a core hallmark of cancer, but the molecular mechanisms underlying it remain unclear. Here, we identify an unexpected central role for mTORC2 in cancer ...metabolic reprogramming where it controls glycolytic metabolism by ultimately regulating the cellular level of c-Myc. We show that mTORC2 promotes inactivating phosphorylation of class IIa histone deacetylases, which leads to the acetylation of FoxO1 and FoxO3, and this in turn releases c-Myc from a suppressive miR-34c-dependent network. These central features of activated mTORC2 signaling, acetylated FoxO, and c-Myc levels are highly intercorrelated in clinical samples and with shorter survival of GBM patients. These results identify a specific, Akt-independent role for mTORC2 in regulating glycolytic metabolism in cancer.
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•mTORC2 is required for the growth of GBM cells in glucose•mTORC2 controls glycolytic metabolism by regulating the cellular level c-Myc•mTORC2 signaling acetylates FoxO1 and FoxO3 to upregulate c-Myc•mTORC2, acetylated FoxO, and c-Myc axis confer shorter survival in patients
Late twentieth-century instrumental records reveal a persistent southward shift of the Southern Westerly Winds during austral summer and autumn associated with a positive trend of the Southern ...Annular Mode (SAM) and contemporaneous with glacial recession, steady increases in atmospheric temperatures and CO2 concentrations at a global scale. However, despite the clear importance of the SAM in the modern/future climate, very little is known regarding its behaviour during pre-Industrial times. Here we present a stratigraphic record from Lago Cipreses (51°S), southwestern Patagonia, that reveals recurrent ~200-year long dry/warm phases over the last three millennia, which we interpret as positive SAM-like states. These correspond in timing with the Industrial revolution, the Mediaeval Climate Anomaly, the Roman and Late Bronze Age Warm Periods and alternate with cold/wet multi-centennial phases in European palaeoclimate records. We conclude that SAM-like changes at centennial timescales in southwestern Patagonia represent in-phase interhemispheric coupling of palaeoclimate over the last 3,000 years through atmospheric teleconnections.
High-load resistance training (HL) may be contraindicated in older adults due to pre-existing health conditions (e.g. osteoarthritis). Low-load blood flow restricted (BFR) resistance training offers ...an alternative to HL with potentially similar strength improvement.
To compare muscle strength, cross-sectional area (CSA), physical function, and quality of life (QOL) following 12-weeks of HL or BFR training in older adults at risk of mobility limitations.
Thirty-six males and females (mean: 75.6years 95% confidence interval: 73.4–78.5, 1.67m 1.64–1.70, 74.3kg 69.8–78.8) were randomly assigned to HL (70% of one repetition maximum 1-RM) or low-load BFR (30% 1-RM coupled with a vascular restriction) exercise for the knee extensors and flexors twice per week for 12weeks. A control (CON) group performed light upper body resistance and flexibility training. Muscle strength, CSA of the quadriceps, 400-m walking speed, Short Physical Performance Battery (SPPB), and QOL were assessed before, midway and after training.
Within 6-weeks of HL training, increases in all strength measures and CSA were evident and the gains were significantly greater than the CON group (P<0.05). The BFR group had strength increases in leg extension and leg press 1-RM tests, but were significantly lower in leg extension isometric maximum voluntary contraction (MVC) and leg extension 1-RM than the HL group (P<0.01). At 12-weeks HL and BFR training did not differ in MVC (P=0.14). Walking speed increased 4% among all training groups (P<0.01) and no changes were observed for overall SPPB score and QOL (P>0.05).
Both training programs resulted in muscle CSA improvements and HL training had more pronounced strength gains than BFR training after 6-weeks and were more similar to BFR after 12-weeks of training. These changes in both groups did not transfer to improvements in QOL, SPPB, and walking speed. Since both programs result in strength and CSA gains, albeit at different rates, future research should consider using a combination of HL and BFR training in older adults with profound muscle weakness and mobility limitations.
•High-load and low-load blood flow restricted resistance training was compared.•Both training programs resulted in similar cross-sectional area of the quadriceps.•Most strength adaptations were apparent within 6-weeks.•Strength was highest after high-load training but not different than blood flow restricted training.•Training did not impact physical function and quality of life in older adults.
Hydrogen sulfide (H2S) has been extensively studied as a signal molecule in the body for the past 30 years. Researchers have conducted studies using both natural and synthetic sources of H2S, known ...as H2S donors, which have different characteristics in terms of how they release H2S. These donors can be inorganic salts or have various organic structures. In recent years, certain types of sulfur compounds found naturally in foods have been characterized as H2S donors and explored for their potential health benefits. These compounds are referred to as "sulfanutraceuticals," a term that combines "nutrition" and "pharmaceutical". It is used to describe products derived from food sources that offer additional health advantages. By introducing the terms "sulfaceuticals" and "sulfanutraceuticals," we categorize sulfur-containing substances based on their origin and their use in both preclinical and clinical research, as well as in dietary supplements.
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Mutations in cancer reprogram amino acid metabolism to drive tumor growth, but the molecular mechanisms are not well understood. Using an unbiased proteomic screen, we identified mTORC2 as a critical ...regulator of amino acid metabolism in cancer via phosphorylation of the cystine-glutamate antiporter xCT. mTORC2 phosphorylates serine 26 at the cytosolic N terminus of xCT, inhibiting its activity. Genetic inhibition of mTORC2, or pharmacologic inhibition of the mammalian target of rapamycin (mTOR) kinase, promotes glutamate secretion, cystine uptake, and incorporation into glutathione, linking growth factor receptor signaling with amino acid uptake and utilization. These results identify an unanticipated mechanism regulating amino acid metabolism in cancer, enabling tumor cells to adapt to changing environmental conditions.
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•The cystine-glutamate antiporter xCT physically interacts with mTORC2•Phosphorylation of serine 26 by mTORC2 inhibits xCT activity•Inhibition of mTORC2 enhances xCT-mediated cystine uptake and glutathione synthesis
Gu et al. identified mTORC2 as an important regulator of glutamate and glutathione metabolism in cancer through phosphorylating the cystine-glutamate antiporter xCT on serine 26.
Converting construction and demolition waste (CDW) into secondary raw materials is one of the priorities of environmental policy and circular economy strategy. This study analysed the variation in ...eco-efficient paste reactivity with OPC replacement ratio (5% to 10%) and hydration time (2 d, 28 d and 90 d). Three types of CDW were explored: two (calcareous and siliceous) consisting of fine (<5 mm) concrete waste and one in laminated glass (<40 mm). Further to the mineralogical phases identified at the aforementioned percentages, the four materials, i.e., the three types of CDW-blended cements and the OPC reference, were similarly reactive. The primary hydration products, C-S-H gels, C4AH13 and C4AcH11, ettringite and portlandite, were the same as observed in OPC hydration. These findings attest to the scientific viability recycling such CDWs as mineral additions in eco-cement manufacture and consequently eliminating the need for stockpiling these materials at recycling/storage plants.
Advances in DNA sequencing technologies have reshaped our understanding of the molecular basis of cancer, providing a precise genomic view of tumors. Complementary biochemical and biophysical ...perspectives of cancer point toward profound shifts in nutrient uptake and utilization that propel tumor growth and major changes in the structure of the plasma membrane of tumor cells. The molecular mechanisms that bridge these fundamental aspects of tumor biology remain poorly understood. Here, we show that the lysophosphatidylcholine acyltransferase LPCAT1 functionally links specific genetic alterations in cancer with aberrant metabolism and plasma membrane remodeling to drive tumor growth. Growth factor receptor-driven cancers are found to depend on LPCAT1 to shape plasma membrane composition through enhanced saturated phosphatidylcholine content that is, in turn, required for the transduction of oncogenic signals. These results point to a genotype-informed strategy that prioritizes lipid remodeling pathways as therapeutic targets for diverse cancers.
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•Persistent EGFR signaling activates membrane lipid remodeling through LPCAT1•LPCAT1 regulates phospholipid saturation and oncogenic growth factor signaling•LPCAT1 is frequently amplified in cancer and associated with poor patient survival•Membrane phospholipid remodeling generates an actionable dependency across cancers
Persistent growth factor receptor signaling and metabolic reprograming are hallmarks of cancer. Bi et al. show that LPCAT1-mediated phospholipid remodeling supports the sustained oncogenic activity of growth factor receptors on plasma membrane of tumor cells, suggesting an actionable dependency in a wide variety of cancers.
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