Our study investigates the biochemical and functional impact of selective histone deacetylase 6 (HDAC6) inhibitors, a promising class of novel therapeutics, in several cancer models. Selective HDAC6 inhibitors (Tubathian A, Tubastatin A, Tubacin and Ricolinostat) and a non‐selective HDAC inhibitor (Vorinostat) were evaluated on cancer cell lines derived from multiple tumour types in both an in vitro and in vivo setting as potential cancer therapeutics. Selective HDAC6 inhibitors resulted in α‐tubulin acetylation with no impact on histone acetylation but failed to show any anti‐cancer properties. Only the use of high concentrations of selective HDAC6 inhibitors resulted in co‐inhibition of other HDAC enzymes and consequently in reduced growth, migratory and/or invasive activity of cancer cells in vitro as well as in vivo. The specificity of HDAC6 inhibition was confirmed using a CRISPR/Cas9 knockout cell line. Our results suggest that selective HDAC6 inhibitors may fall short as potential single agent anti‐cancer drugs and prove that many previous data regarding this promising class of compounds need to be interpreted with great care due to their use in high concentrations resulting in low selectivity and potential off‐target effects.
Scope
Muscle food characteristics (fatty acid profile, heme‐Fe, intrinsic antioxidants) that relate to the formation of (patho)physiological oxidation products during gastrointestinal digestion are investigated.
Methods and Results
Muscles (n = 33) from 18 mammal, poultry, and fish species, of which some are mixed with lard to standardize their fatty acid profile, are digested in vitro. Lipid oxidation is assessed by thiobarbituric reactive substances (TBARS), n‐3 PUFA derivative 4‐hydroxy‐2‐hexenal and propanal, n‐6 PUFA derivative 4‐hydroxy‐2‐nonenal and hexanal, and protein oxidation by carbonylation. Digests of n‐3 PUFA‐rich fish demonstrated the highest n‐3 PUFA oxidation, whereas digests of various poultry and rabbit muscles showed highest n‐6 PUFA oxidation, which correlated significantly with the n‐6/n‐3 PUFA ratio. Without lard addition, lipid oxidation is significantly higher in chicken and pork loin digests versus beef and deer digests, whereas the opposite occurred when these muscles are mixed with lard. Protein carbonylation correlates significantly with levels of TBARS and the sum of hydroxy‐alkenals in digests. The n‐6/n‐3 PUFA ratio correlates well with the 4‐hydroxy‐2‐nonenal/4‐hydroxy‐2‐hexenal ratio in digests.
Conclusions
Muscular fatty acid profiles largely explain type and extent of lipid and protein oxidation during gastrointestinal digestion. Red meat only stimulates oxidation when digested with specific fat sources.
Red meat has been associated with an increased cardiovascular disease (CVD) risk, possibly through gut microbial-derived trimethylamine-N-oxide (TMAO). However, previous reports are conflicting, and influences from the background diet may modulate the impact of meat consumption. This study investigated the effect of red and white meat intake combined with two different background diets on urinary TMAO concentration and its association with the colon microbiome in addition to apparent hepatic TMAO-related activity. For 4 weeks, 32 pigs were fed chicken or red and processed meat combined with a prudent or western background diet. 1 H NMR-based metabolomics analysis was conducted on urine samples and hepatic Mrna expression of TMAO-related genes determined. Lower urinary TMAO concentrations were observed after intake of red and processed meat when consumed with a prudent compared to a western background diet. In addition, correlation analyses between urinary TMAO concentrations and relative abundance of colon bacterial groups suggested an association between TMAO and specific bacterial taxa. Diet did not affect the hepatic Mrna expression of genes related to TMAO formation. The results suggest that meat-induced TMAO formation is regulated by mechanisms other than alterations at the hepatic gene expression level, possibly involving modulations of the gut microbiota.
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