Heptanoate is neuroprotective in vitro but triheptanoin post-treatment did not protect against middle cerebral artery occlusion in rats

Triheptanoin, the medium-chain triglyceride of heptanoate, has been shown to be anticonvulsant and neuroprotective in several neurological disorders. In the gastrointestinal tract, triheptanoin is cleaved to heptanoate, which is then taken up by the blood and most tissues, including liver, heart and brain. Here we evaluated the neuroprotective effects of heptanoate and its effects on mitochondrial oxygen consumption in vitro. We also investigated the neuroprotective effects of triheptanoin compared to long-chain triglycerides when administered after stroke onset in rats. Heptanoate pre-treatment protected cultured neurons against cell death induced by oxygen glucose deprivation and N-methyl-D-aspartate. Incubation of cultured astrocytes with heptanoate for 2 h increased mitochondrial proton leak and also enhanced basal respiration and ATP turnover, suggesting that heptanoate protects against oxidative stress and is used as fuel. However, continuous 72 h infusion of triheptanoin initiated 1 h after middle cerebral artery occlusion in rats did not alter stroke volume at 3 days or neurological deficit at 1 and 3 days relative to long-chain triglyceride control treatment

HBO1 is required for the maintenance of leukaemia stem cells.

Acute myeloid leukaemia (AML) is a heterogeneous disease characterized by transcriptional dysregulation that results in a block in differentiation and increased malignant self-renewal. Various epigenetic therapies aimed at reversing these hallmarks of AML have progressed into clinical trials, but most show only modest efficacy owing to an inability to effectively eradicate leukaemia stem cells (LSCs)1. Here, to specifically identify novel dependencies in LSCs, we screened a bespoke library of small hairpin RNAs that target chromatin regulators in a unique ex vivo mouse model of LSCs. We identify the MYST acetyltransferase HBO1 (also known as KAT7 or MYST2) and several known members of the HBO1 protein complex as critical regulators of LSC maintenance. Using CRISPR domain screening and quantitative mass spectrometry, we identified the histone acetyltransferase domain of HBO1 as being essential in the acetylation of histone H3 at K14. H3 acetylated at K14 (H3K14ac) facilitates the processivity of RNA polymerase II to maintain the high expression of key genes (including Hoxa9 and Hoxa10) that help to sustain the functional properties of LSCs. To leverage this dependency therapeutically, we developed a highly potent small-molecule inhibitor of HBO1 and demonstrate its mode of activity as a competitive analogue of acetyl-CoA. Inhibition of HBO1 phenocopied our genetic data and showed efficacy in a broad range of human cell lines and primary AML cells from patients. These biological, structural and chemical insights into a therapeutic target in AML will enable the clinical translation of these findings

The Anti-Cancer Effect of Quercetin: Molecular Implications in Cancer Metabolism

Cancer is a problem with worldwide importance and is the second leading cause of death globally. Cancer cells reprogram their metabolism to support their uncontrolled expansion by increasing biomass (anabolic metabolism—glycolysis) at the expense of their energy (bioenergetics-mitochondrial function) requirements. In this aspect, metabolic reprogramming stands out as a key biological process in understanding the conversion of a normal cell into a neoplastic precursor. Quercetin is the major representative of the flavonoid subclass of flavonols. Quercetin is ubiquitously present in fruits and vegetables, being one of the most common dietary flavonols in the western diet. The anti-cancer effects of quercetin include its ability to promote the loss of cell viability, apoptosis and autophagy through the modulation of PI3K/Akt/mTOR, Wnt/β-catenin, and MAPK/ERK1/2 pathways. In this review, we discuss the role of quercetin in cancer metabolism, addressing specifically its ability to target molecular pathways involved in glucose metabolism and mitochondrial function

Sulforaphane is anticonvulsant and improves mitochondrial function

The nuclear factor erythroid 2-related factor 2 pathway (Nrf2) has been previously identified to protect the brain against various impacts. Here, we investigated the effect of the Nrf2 activator sulforaphane in various seizure models and hippocampal mitochondrial bioenergetics. We found that daily injections of sulforaphane for 5 days elevated the seizure thresholds to 6 Hz stimulation and fluorothyl-, but not pentylenetetrazole-induced tonic seizures and protected mice against pilocarpine-induced status epilepticus (SE). Also, sulforaphane increased the antioxidant defences within hippocampal formations and blood plasma. In addition, sulforaphane treatment reduced the extent of hippocampal lipid peroxidation 24 h post-SE and protected hippocampal mitochondria against SE-induced reduction in state 2 and uncoupler-stimulated state 3 respiration. SE-mediated partial loss of rotenone-sensitive and complex II-driven respiration was reduced, consistent with the enhanced activities of complexes I and II in sulforaphane-treated SE mice. In mitochondria isolated from both no SE and SE mice, sulforaphane increased state 3 respiration and respiration linked to ATP synthesis, which may contribute to its anticonvulsant and antioxidant effects by providing more ATP for cellular vital and protective functions. However, sulforaphane did not prevent SE-induced hippocampal cell death. In conclusion, sulforaphane and/or Nrf2 activation are viable anticonvulsant strategies, which are antioxidant and enhance mitochondrial function, especially the ability to produce ATP

Apple peel polyphenol extract protects against indomethacin-induced damage in Caco-2 cells by preventing mitochondrial Complex i inhibition

The aim of this work was to investigate the role of mitochondrial dysfunction in the development of oxidative stress and cytotoxicity induced by indomethacin and to evaluate the potential of an apple peel polyphenol extract (APPE) in protecting against these events Indomethacin induced, time-dependently, mitochondria] and oxidative perturbations which led to cell losses An inhibition of complex I activity, shown for first time here, which resulted in a concomitant drop in cellular ATP and an increment in mitochondrial superoxide production, was observed after 10 mm of exposure These early cytotoxicity-triggering events were followed by an increase in the intracellular production of superoxide (20 min), an elevation in the activity of xanthine oxidase which led to an increased lipid peroxidation (30 mm), and a decline in cell viability which manifested after 40 nun These events were selectively prevented using allopurinol, tempol and APPE (a standardized apple peel polyphenol extract) While the oxidative and cell lytic effects of indomethacin were equally prevented by the three agents, only APPE protected against complex I inhibition and its downstream oxidative consequences Since tempol (a SOD mimetic)prevented the elevation xanthine oxidase activity, and allopurinol (a xanthine oxidase inhibitor) totally abolished the increment in lipid peroxidation and loss of cell viability, it appears that a superoxide-dependent increase in xanthine oxidase activity is critical to trigger cytotoxicity Thus, preventing the early increment in superoxide formation that, as a result of inhibiting complex I, takes place within mitochondria would be key toward protecting the cells against the oxidative and cytolytic effects of indomethacin The ability of APPE in preventing the inhibition of complex land the subsequent superoxide-dependent increase in XO activity warrants further studies to evaluate the mechanism involves in the protecting effect of APPE against the indomethacin-associated adverse effects in viv

Aspetti strutturali e congiunturali della domanda vinicola nel Veneto

L'analisi della domanda al consumo di vino è effettuata attraverso l'approccio metodologico Almost Ideal Demand System, idoneo ad offrire una descrizione sintetica delle modalità di scelta al consumo delle singole tipologie vinicole all'interno della regione Veneto

Hemin Prevents Increased Glycolysis in Macrophages upon Activation: Protection by Microbiota-Derived Metabolites of Polyphenols

Meat consumption plays a critical role in the development of several types of cancer. Hemin, a metabolite of myoglobin produced after meat intake, has been demonstrated to be involved in the cancer initiation phase. Macrophages are key components of the innate immunity, which, upon activation, can prevent cancer development by eliminating neoplastic cells. Metabolic reprogramming, characterized by high glycolysis and low oxidative phosphorylation, is critical for macrophage activation. 3,4-dihydroxyphenylacetic acid (3,4DHPAA) and 4-hydroxyphenylacetic acid (4HPAA), both microbiota-derived metabolites of flavonoids, have not been extensively studied although they exert antioxidant properties. The aim of this study was to determine the effect of hemin on the anticancer properties of macrophages and the role of 3,4DHPAA and 4HPAA in metabolic reprogramming and activation of macrophages leading to the elimination of cancer cells. The results showed that hemin inhibited glycolysis, glycolytic, and pentose phosphate pathway (PPP) enzyme activities and hypoxia-inducible factor-1 alpha (HIF-1α) stabilization, which interferes with macrophage activation (evidenced by decreased interferon-γ-inducible protein 10 (IP-10) release) and their ability to eliminate cancer cells (via cytotoxic mediators and phagocytosis). Hemin also reduced the mitochondrial membrane potential (MMP) and mitochondrial mass in macrophages. 3,4DHPAA and 4HPAA, by stimulating glycolysis and PPP, prevented the impairment of the macrophage anticancer activity induced by hemin. In conclusion, 3,4HPAA and 4HPAA administration could represent a promising strategy for preventing the reduction of macrophage activation induced by hemin

Sulforaphane protects against high cholesterol-induced mitochondrial bioenergetics impairments, inflammation, and oxidative stress and preserves pancreatic β-cells function

Cholesterol plays an important role in inducing pancreatic β-cell dysfunction, leading to an impaired insulin secretory response to glucose. This study aimed to determine the protective effects of sulforaphane, a natural isothiocyanate Nrf2-inducer, against cholesterol-induced pancreatic β-cells dysfunction, through molecular and cellular mechanisms involving mitochondrial bioenergetics. Sulforaphane prevented cholesterol-induced alterations in the coupling efficiency of mitochondrial respiration, improving ATP turnover and spare capacity, and averted the impairment of the electron flow at complexes I, II, and IV. Sulforaphane also attenuated the cholesterol-induced activation of the NFB pathway, normalizing the expression of pro- and anti-inflammatory cytokines. In addition, it also inhibited the decrease in sirtuin 1 expression and greatly increased Pgc-1α expression in Min6 cells. Sulforaphane increased the expression of antioxidant enzymes downstream of the Nrf2 pathway and prevented lipid peroxidation induced by cholesterol. The antioxidant and anti-inflammatory properties of sulforaphane and its ability to protect and improve mitochondrial bioenergetic function contribute to its protective action against cholesterol-induced pancreatic β-cell dysfunction. Our data provide a scientifically tested foundation upon which sulforaphane can be developed as nutraceutical to preserve β-cell function and eventually control hyperglycemia