RIFM fragrance ingredient safety assessment, hexyl isovalerate, CAS Registry Number 10032-13-0.

The existing information supports the use of this material as described in this safety assessment. Hexyl isovalerate was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from read-across analog hexyl isobutyrate (CAS # 2349-07-7) show that hexyl isovalerate is not expected to be genotoxic. Data on read-across analog propyl (2S)-2-(1,1-dimethylpropoxy)-propanoate (CAS # 319002-92-1) provide a calculated MOE >100 for the repeated dose toxicity and reproductive toxicity endpoints. Data from read-across analog hexyl 2-methylbutyrate (CAS # 10032-15-2) do not indicate that hexyl isovalerate is a skin sensitizer. The phototoxicity/photoallergenicity endpoints were evaluated based on UV spectra; hexyl isovalerate is not expected to be phototoxic/photoallergenic. The local respiratory toxicity endpoint was evaluated using the TTC for a Cramer Class I material, and the exposure to hexyl isovalerate is below the TTC (1.4 mg/day). The environmental endpoints were evaluated; hexyl isovalerate was found not to be PBT as per the IFRA Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., PEC/PNEC), are <1.

Gut Dysbiosis Dysregulates Central and Systemic Homeostasis via Suboptimal Mitochondrial Function: Assessment, Treatment and Classification Implications.

The gut and mitochondria have emerged as two important hubs at the cutting edge of research across a diverse array of medical conditions, including most psychiatric conditions. This article highlights the interaction of the gut and mitochondria over the course of development, with an emphasis on the consequences for transdiagnostic processes across psychiatry, but with relevance to wider medical conditions. As well as raised levels of circulating lipopolysaccharide (LPS) arising from increased gut permeability, the loss of the short-chain fatty acid, butyrate, is an important mediator of how gut dysbiosis modulates mitochondrial function. Reactive cells, central glia and systemic immune cells are also modulated by the gut, in part via impacts on mitochondrial function in these cells. Gut-driven alterations in the activity of reactive cells over the course of development are proposed to be an important determinant of the transdiagnostic influence of glia and the immune system. Stress, including prenatal stress, also acts via the gut. The suppression of butyrate, coupled to raised LPS, drives oxidative and nitrosative stress signalling that culminates in the activation of acidic sphingomyelinase-induced ceramide. Raised ceramide levels negatively regulate mitochondrial function, both directly and via its negative impact on daytime, arousal-promoting orexin and night-time sleep-promoting pineal gland-derived melatonin. Both orexin and melatonin positively regulate mitochondria oxidative phosphorylation. Consequently, gut-mediated increases in ceramide have impacts on the circadian rhythm and the circadian regulation of mitochondrial function. Butyrate, orexin and melatonin can positively regulate mitochondria via the disinhibition of the pyruvate dehydrogenase complex, leading to increased conversion of pyruvate to acetyl- CoA. Acetyl-CoA is a necessary co-substrate for the initiation of the melatonergic pathway in mitochondria and therefore the beneficial effects of mitochondria melatonin synthesis on mitochondrial function. This has a number of treatment implications across psychiatric and wider medical conditions, including the utilization of sodium butyrate and melatonin. Overall, gut dysbiosis and increased gut permeability have significant impacts on central and systemic homeostasis via the regulation of mitochondrial function, especially in central glia and systemic immune cells.

Biosynthesis of butyric acid by Clostridium tyrobutyricum.

Butyric acid (C3H7COOH) is an important chemical that is widely used in foodstuffs along with in the chemical and pharmaceutical industries. The bioproduction of butyric acid through large-scale fermentation has the potential to be more economical and efficient than petrochemical synthesis. In this paper, the metabolic pathways involved in the production of butyric acid from Clostridium tyrobutyricum using hexose and pentose as substrates are investigated, and approaches to enhance butyric acid production through genetic modification are discussed. Finally, bioreactor modifications (including fibrous bed bioreactor, inner disk-shaped matrix bioreactor, fibrous matrix packed in porous levitated sphere carriers), low-cost feedstocks, and special treatments (including continuous fermentation with cell recycling, extractive fermentation with solvent, using different artificial electron carriers) intended to improve the feasibility of commercial butyric acid bioproduction are summarized.

Genomic assessment in Lactobacillus plantarum links the butyrogenic pathway with glutamine metabolism.

The butyrogenic capability of Lactobacillus (L.) plantarum is highly dependent on the substrate type and so far not assigned to any specific metabolic pathway. Accordingly, we compared three genomes of L. plantarum that showed a strain-specific capability to produce butyric acid in human cells growth media. Based on the genomic analysis, butyric acid production was attributed to the complementary activities of a medium-chain thioesterase and the fatty acid synthase of type two (FASII). However, the genomic islands of discrepancy observed between butyrogenic L. plantarum strains (S2T10D, S11T3E) and the non-butyrogenic strain O2T60C do not encompass genes of FASII, but several cassettes of genes related to sugar metabolism, bacteriocins, prophages and surface proteins. Interestingly, single amino acid substitutions predicted from SNPs analysis have highlighted deleterious mutations in key genes of glutamine metabolism in L. plantarum O2T60C, which corroborated well with the metabolic deficiency suffered by O2T60C in high-glutamine growth media and its consequent incapability to produce butyrate. In parallel, the increase of glutamine content induced the production of butyric acid by L. plantarum S2T10D. The present study reveals a previously undescribed metabolic route for butyric acid production in L. plantarum, and a potential involvement of the glutamine uptake in its regulation.

New hypotheses for the health-protective mechanisms of whole-grain cereals: what is beyond fibre?

Epidemiological studies have clearly shown that whole-grain cereals can protect against obesity, diabetes, CVD and cancers. The specific effects of food structure (increased satiety, reduced transit time and glycaemic response), fibre (improved faecal bulking and satiety, viscosity and SCFA production, and/or reduced glycaemic response) and Mg (better glycaemic homeostasis through increased insulin secretion), together with the antioxidant and anti-carcinogenic properties of numerous bioactive compounds, especially those in the bran and germ (minerals, trace elements, vitamins, carotenoids, polyphenols and alkylresorcinols), are today well-recognised mechanisms in this protection. Recent findings, the exhaustive listing of bioactive compounds found in whole-grain wheat, their content in whole-grain, bran and germ fractions and their estimated bioavailability, have led to new hypotheses. The involvement of polyphenols in cell signalling and gene regulation, and of sulfur compounds, lignin and phytic acid should be considered in antioxidant protection. Whole-grain wheat is also a rich source of methyl donors and lipotropes (methionine, betaine, choline, inositol and folates) that may be involved in cardiovascular and/or hepatic protection, lipid metabolism and DNA methylation. Potential protective effects of bound phenolic acids within the colon, of the B-complex vitamins on the nervous system and mental health, of oligosaccharides as prebiotics, of compounds associated with skeleton health, and of other compounds such as alpha-linolenic acid, policosanol, melatonin, phytosterols and para-aminobenzoic acid also deserve to be studied in more depth. Finally, benefits of nutrigenomics to study complex physiological effects of the 'whole-grain package', and the most promising ways for improving the nutritional quality of cereal products are discussed.

Influence of the antibiotic erythromycin on anaerobic treatment of a pharmaceutical wastewater.

A laboratory-scale anaerobic sequencing batch reactor was used to treat a model substrate mixture representing pharmaceutical wastewater at an organic loading rate of 2.9 g COD/(L d). After reaching stable operation the reactor was first exposed to low (1 mg/L) and, subsequently, to high (200 mg/L) concentrations of the antibiotic erythromycin. The addition of low levels of erythromycin resulted in a significant but limited reduction of biogas production by 5% and the higher level of erythromycin did not impact biogas production further, suggesting that a substantial fraction of the microbial populations in the ASBR were resistant to the antibiotic. Effluent soluble COD could not be accounted for in measured volatile fatty acids, perhaps suggesting the production of soluble microbial products. In batch tests evaluating the specific methanogenic activity, conversion of the model substrate mixture was only slightly affected by the presence of erythromycin. However, the conversion of butyric acid was inhibited when erythromycin was present. After 47 days of exposure to erythromycin, the conversion of butyric acid was inhibited to a lesser extent, suggesting the development of antibiotic resistance in the biomass. Exposure to antibiotics can affect specific substrate degradation pathways, leading to the accumulation of volatile fatty acids, soluble microbial products, and potentially to overall system instabilities.