β-hydroxybutyrate accumulates in the rat heart during low-flow ischaemia with implications for functional recovery

Extrahepatic tissues which oxidise ketone bodies also have the capacity to accumulate them under particular conditions. We hypothesised that acetyl-coenzyme A (acetyl-CoA) accumulation and altered redox status during low-flow ischaemia would support ketone body production in the heart. Combining a Langendorff heart model of low-flow ischaemia/reperfusion with liquid chromatography coupled tandem mass spectrometry (LC-MS/MS), we show that β-hydroxybutyrate (β-OHB) accumulated in the ischaemic heart to 23.9 nmol/gww and was secreted into the coronary effluent. Sodium oxamate, a lactate dehydrogenase (LDH) inhibitor, increased ischaemic β-OHB levels 5.3-fold and slowed contractile recovery. Inhibition of β-hydroxy-β-methylglutaryl (HMG)-CoA synthase (HMGCS2) with hymeglusin lowered ischaemic β-OHB accumulation by 40%, despite increased flux through succinyl-CoA-3-oxaloacid CoA transferase (SCOT), resulting in greater contractile recovery. Hymeglusin also protected cardiac mitochondrial respiratory capacity during ischaemia/reperfusion. In conclusion, net ketone generation occurs in the heart under conditions of low-flow ischaemia. The process is driven by flux through both HMGCS2 and SCOT, and impacts on cardiac functional recovery from ischaemia/reperfusion.

The epidemic of COVID-19 prompted widespread use of mRNA vaccinations

COVID-19 challenge resulted in huge expenditure in mRNA-lipid-based nanoparticles (LNPs) manufacturing. Hundreds of billions are produced for human use. This is a significant shift, inconceivable only a year ago. If an LNP platform can traverse thick mucus in patients with respiratory difficulties (such as cystic fibrosis) or target extrahepatic tissues in the future, multi-billion-dose procedures are in place to serve a significant number of patients with unusual genetic diseases (>100,000 individuals). Due to LNPs' versatility in delivering genome editing components, a successful strategy might be easily scaled up and employed to successfully eliminate a rare disease with a single treatment.COVID-19 led to widespread usage of mRNA vaccines. For years, academic and industrial scientists have worked intensely to produce these technologies. Although not enough time to analyze the long-term effects of mRNA vaccines, phase III clinical studies of Pfizer/BioNTech and Moderna vaccines showed around 95 percent efficacy and outstanding safety profiles. The COVID-19 outbreak laid the stage for scaling and overcoming distribution limits that would otherwise have taken decades. RNA treatments and nanomedicine as a field will never be the same again, and will take center stage. The Enlightenment Age of the RNA nanotherapeutics sector is coming to an end, and the area is ready for a full-scale industrial revolution.

Impact of Carotenoid Cleaving Enzymes on Lycopene Accumulation in Transgenic Mice

Objectives To evaluate the role of β-carotene oxygenase 1 (BCO1) and BCO2 on lycopene tissue distribution. Methods Three-week old C57BL/6 male and female mice (wild type [WT], Bco1−/−, Bco2−/−, Bco1−/− × Bco2−/− double knock out [DKO]) were divided into groups based on genotype (n = 16 per group split evenly by sex) and fed a powdered AIN 93G control diet for 2 weeks. After this period, mice were gavaged daily for 2 weeks with 1 mg of lycopene dissolved in cottonseed oil. 12 h-fasted mice were then sacrificed, and liver, serum, heart, kidney, intestine, gonadal adipose, prostate, spleen, and testes were harvested. Tissues were preserved in liquid nitrogen and stored at −80 until analyses. We measured lycopene levels in all samples by using high-performance liquid chromatography. Data analyses were performed using two-way ANOVA, followed by the Sidaks test with a statistical significance threshold of P < 0.05. Results Female mice showed higher lycopene levels in the intestine (P < 0.045) and liver (P < 0.007) irrespective of genotype, while male mice had higher lycopene levels in serum (P < 0.004). Intestine, serum, and kidneys exhibited higher lycopene levels in DKO mice compared to all other genotypes (P < .0001), while having higher lycopene levels in testes (P < 0.0001) compared to Bco2−/− and WT mice and adipose (P < 0.005) only in comparison to Bco2−/− mice. DKO exhibited higher lycopene levels in the spleen compared to Bco1−/− mice (P < 0.02). Lycopene levels in the liver (P < 0.0001) were higher in Bco2−/− mice compared to Bco1 −/− and DKO mice, while Bco1−/− mice had lower hepatic lycopene levels compared to all other genotypes. Conclusions Female mice accumulated higher lycopene levels in most tissues compared to males. These results were consistent when data were corrected by total tissue weight. The data suggest the absence of BCO2 favors carotenoid accumulation in many extrahepatic tissues, an effect that is enhanced in the absence of both carotenoid cleaving enzymes. Funding Sources Internal funding, University of Illinois Urbana Champaign.

Minireview: Effect of the ketogenic diet in excitable tissues

In the last decade Ketogenic Diet (KD) came to light as a potential treatment for a wide range of diseases, from neurological to metabolic disorders, thanks to a beneficial role mainly related to its anti-inflammatory properties. The high-fat, carbohydrate-restricted regimen causes changes in the metabolism leading, through the β-oxidation of fatty acids, to the hepatic production of ketone bodies (KBs), used by many extrahepatic tissues as energy fuels. Once synthetized, KBs move through the systemic circulation and reach all the tissues of the organism, affecting their functions and playing pleiotropic roles acting directly and indirectly on various targets as ion channels and neurotransmitters. Moreover, they can operate as signalling metabolites and epigenetic modulators. Therefore, it is limiting to consider that the clinical condition of each single patient could improve after a KD regimen based on its localized effects; rather it is more complete to think about how KBs might affect the organism as a whole. In this minireview, we tried to summarize the recent knowledge of the effects of KBs on various tissues, with a particular attention to the excitable ones, namely the nervous system, heart and muscles.

Influence of Histidine Administration on Ammonia and Amino Acid Metabolism: A Review

Histidine (HIS) is an essential amino acid investigated for therapy of various diseases, used for tissue protection in transplantation and cardiac surgery, and as a supplement to increase muscle performance. The data presented in the review show that HIS administration may increase ammonia and affect the level of several amino acids. The most common are increased levels of alanine, glutamine, and glutamate and decreased levels of glycine and branched-chain amino acids (BCAA, valine, leucine, and isoleucine). The suggested pathogenic mechanisms include increased flux of HIS through HIS degradation pathway (increases in ammonia and glutamate), increased ammonia detoxification to glutamine and exchange of the BCAA with glutamine via L-transporter system in muscles (increase in glutamine and decrease in BCAA), and tetrahydrofolate depletion (decrease in glycine). Increased alanine concentration is explained by enhanced synthesis in extrahepatic tissues and impaired transamination in the liver. Increased ammonia and glutamine and decreased BCAA levels in HIS-treated subjects indicate that HIS supplementation is inappropriate in patients with liver injury. The studies investigating the possibilities to elevate carnosine (β-alanyl-L-histidine) content in muscles show positive effects of β-alanine and inconsistent effects of HIS supplementation. Several studies demonstrate HIS depletion due to enhanced availability of methionine, glutamine, or β-alanine.