Cardiotoxicity is one of the side effects of the anti-cancer drug doxorubicin (DOX) that limits its clinical application. Betaine (BT) is a natural agent with promising useful effects against inflammation and oxidative stress (OS). We assessed the effects of BT on DOX-induced cardiotoxicity in mice. Forty-two male NMRI mice were assigned to six groups: I: control; II: BT (200 mg/kg; orally, alone); III: DOX (2.5 mg/kg; six injections (ip)) for two weeks; IV, V, VI: BT (50 mg/kg, 100 mg/kg, and 200 mg/kg; orally, once a day for two weeks, respectively) plus DOX administration. The cardiac enzymes like cardiac troponin-I (cTn-I), lactate dehydrogenase (LDH), and creatine kinase-MB (CK-MB) were assessed in serum. Oxidative/inflammatory markers like nitric oxide (NO), malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), reduced glutathione level (GSH), and glutathione peroxidase (GPx) activities were determined in cardiac tissue. The expressions of NOD-like receptor protein 3 (NLRP3), caspase-1, interleukin (IL)-1β, and silent information regulator 1 (SIRT1) proteins were also evaluated in cardiac tissue. The results indicated that DOX significantly increased LDH, CK-MB, cTn-I, MDA, and NO levels and also the caspase-1, NLRP3, and IL-1β expression. Furthermore, DOX caused a significant reduction in the GSH levels and SOD, CAT, GPX activities, and the expression of SIRT1 protein in heart tissue. However, BT significantly improved all studied parameters. The findings were confirmed by histopathological assessments of the heart. BT can protect against DOX-induced cardiotoxicity by suppressing the activation of NLRP3 and OS by stimulating the SIRT1 pathway.

Arsenic, an environmental pollutant and poisonous metalloid, has adverse effects on different body organs, including the kidneys. Betaine is a natural nutrient that has many beneficial health effects. This research was conducted to examine the impact of betaine on nephrotoxicity caused by inorganic arsenic (NaAsO2) in mice. Mice were separated into following groups: control, NaAsO2 (50 ppm), NaAsO2 (50 ppm) + betaine (500 mg/kg), and betaine (500 mg/kg). Mice were received NaAsO2 via drinking water for 8 consecutive weeks and betaine was given to the animals via gavage once daily in the 7th and 8th weeks of the study. Upon completion of the study, the mice were euthanized and samples of serum and kidney were obtained for further evaluations. Administration of NaAsO2 increased the levels of blood urea nitrogen and creatinine in the serum. It enhanced the amounts of renal malondialdehyde and decreased the total thiol levels, as well as the activity of antioxidant enzymes (catalase, superoxide dismutase, and glutathione peroxidase). Furthermore, it enhanced the levels of renal inflammatory indicators (tumor necrosis factor-alpha and nitric oxide). Western blot results exhibited an increase in the protein expression of nuclear factor kappa B (NF-κB), and phosphorylated NF-κB in NaAsO2-treated mice. Histopathological results also confirmed kidney damage caused by NaAsO2. However, treatment with betaine improved NaAsO2-related kidney injuries in mice. The results of this work indicated that betaine can attenuate kidney damage caused by NaAsO2 by inhibiting oxidative stress and inflammation.

Cardiotoxicity is a well-established adverse effect of several drugs across multiple therapeutic indications. It is particularly prevalent following anticancer therapy. In order to evaluate the changes in cellular metabolism associated with methotrexate cardiotoxicity, we treated Wistar rats with a single high dose of methotrexate (HDMTX), and after five days, the animals were sacrificed. We then analyzed the cardiotoxicity parameters in serum like Cardiac enzymes(CK-MB, Troponin T, ALP), Inflammatory markers (TNF-α and IL-6), oxidative stress markers (NO, NOX-2), histopathology and cardiac tissue with the goal of identifying a metabolic signature of cardiotoxicity using discovery-based metabolomics. The biochemical parameters for cardiac enzymes, oxidative stress and inflammatory markers showed a significant increase in all three categories in rats treated with HDMTX. These findings were mirrored in the histopathological analysis confirming cardiotoxicity due to HDMTX. The results showed a total of 95 metabolites that were found to be significantly (p < 0.05) modulated: either up- or downregulated in the HDMTX-treated group when compared with the control group. Using integrated pathway analysis we found these metabolites were associated with many important cardiac tissue metabolic pathways, such as the malate aspartate shuttle, taurine and hypotaurine metabolism, betaine metabolism, spermidine biosynthesis, and homocysteine degradation. Among them, L-arginine, homocysteine, and betaine were significantly upregulated, suggesting their possible association with cardiac tissue injury. Overall, we provided evidence for using untargeted metabolomics to identify novel metabolites associated with HDMTX cardiac toxicity.

Choline is an essential nutrient, with high requirements during fetal and postnatal growth. Tissue concentrations of total choline are tightly regulated, requiring an increase in its pool size proportional to growth. Phosphatidylcholine and sphingomyelin, containing a choline headgroup, are constitutive membrane phospholipids, accounting for >85% of total choline, indicating that choline requirements are particularly high during growth. Daily phosphatidylcholine secretion via bile for lipid digestion and very low-density lipoproteins for plasma transport of arachidonic and docosahexaenoic acid to other organs exceed 50% of its hepatic pool. Moreover, phosphatidylcholine is required for converting pro-apoptotic ceramides to sphingomyelin, while choline is the source of betaine as a methyl donor for creatine synthesis, DNA methylation/repair and kidney function. Interrupted choline supply, as during current total parenteral nutrition (TPN), causes a rapid drop in plasma choline concentration and accumulating deficit. The American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) defined choline as critical to all infants requiring TPN, claiming its inclusion in parenteral feeding regimes. We performed a systematic literature search in Pubmed with the terms \"choline\" and \"parenteral nutrition\", resulting in 47 relevant publications. Their results, together with cross-references, are discussed. While studies on parenteral choline administration in neonates and older children are lacking, preclinical and observational studies, as well as small randomized controlled trials in adults, suggest choline deficiency as a major contributor to acute and chronic TPN-associated liver disease, and the safety and efficacy of parenteral choline administration for its prevention. Hence, we call for choline formulations suitable to be added to TPN solutions and clinical trials to study their efficacy, particularly in growing children including preterm infants.

Betaine improves growth performance and health in monogastric animals under both thermoneutral and heat stress conditions, but results in ruminants have been more equivocal. This meta-analysis investigated the effects of betaine supplementation on productive performance, milk production and composition, and carcass traits of ruminants due to betaine supplementation. A comprehensive search for published studies investigating the effect of betaine was performed using Google Scholar, ScienceDirect, PubMed, and Scopus databases. Effect size analysis, random effects models, I2 statistics, and meta-regression analysis were utilized to assess differences in production parameters. Dietary betaine supplementation increased milk yield (+1.0 kg/d (weighted mean differences presented in this abstract), p < 0.001), dry matter intake (+0.15 kg/d, p < 0.001), and milk lactose (+0.05%, p = 0.010) in dairy cows housed under thermoneutral conditions. In the few studies conducted on small ruminants, there was an increase in milk yield in response to dietary betaine (0.45 kg/d, p = 0.040). Under heat stress conditions or grazing pasture during summer, dietary betaine increased milk yield (+1.0 kg/d, p < 0.001) and dry matter intake (+0.21 kg/d, p = 0.020). Dietary betaine increased final liveweight (+2.33 kg, p = 0.050) and back fat thickness (+0.74 cm, p < 0.001) in beef cattle. Dietary betaine increased final liveweight (0.14 kg, p = 0.010), daily gain (+0.019 kg/d, p < 0.001), and carcass weight (+0.80 kg, p < 0.001) but not backfat in small ruminants. These meta-analyses showed that dietary betaine increases liveweight in small ruminants and beef cattle and increases feed intake and milk yield in dairy cattle.

Macrophage inhibitory factor (MIF) is a multipotent cytokine, involved in the inflammatory response to infections or injuries. This study investigates the role of MIF in liver fibrosis and the modulating effect of betaine on MIF in thioacetamide (TAA)-induced liver fibrosis. The wild-type and knockout MIF-/- C57BL/6 mice were divided into the following groups: control; Bet group, which received betaine; MIF-/-; MIF-/-+Bet; TAA group, which received TAA; TAA+Bet; MIF-/-+TAA; and MIF-/-+TAA+Bet group. After eight weeks of treatment, liver tissue was collected for further analysis. The results revealed that TAA-treated MIF-deficient mice had elevated levels of hepatic TGF-β1 and PDGF-BB, as well as MMP-2, MMP-9, and TIMP-1 compared to TAA-treated wild-type mice. However, the administration of betaine to TAA-treated MIF-deficient mice reduced hepatic TGF-β1 and PDGF-BB levels and also the relative activities of MMP-2, MMP-9 and TIMP-1, albeit less effectively than in TAA-treated mice without MIF deficiency. Furthermore, the antifibrogenic effect of MIF was demonstrated by an increase in MMP2/TIMP1 and MMP9/TIMP1 ratios. The changes in the hepatic levels of fibrogenic factors were confirmed by a histological examination of liver tissue. Overall, the dual nature of MIF highlights its involvement in the progression of liver fibrosis. Its prooxidant and proinflammatory effects may exacerbate tissue damage and inflammation initially, but its antifibrogenic activity suggests a potential protective role against fibrosis development. The study showed that betaine modulates the antifibrogenic effects of MIF in TAA-induced liver fibrosis, by decreasing TGF-β1, PDGF-BB, MMP-2, MMP-9, TIMP-1, and the deposition of ECM (Coll1 and Coll3) in the liver.

BACKGROUND: The intestine of young ruminants is in the developmental stage and has weaker resistance to the changes of external environment. Improving intestinal health is vital to promoting growth of young ruminants. This study investigated effects of guanidino acetic acid (GAA) and rumen-protected betaine (RPB) supplementation on growth, dietary nutrient digestion and GAA metabolism in the small intestine of sheep.
METHODS: Eighteen healthy Kazakh rams (27.46 ± 0.10 kg of body weight and 3-month old) were categorized into control, test group I and test group II, which were fed a basal diet, 1500 mg/kg GAA and 1500 mg/kg GAA + 600 mg/kg RPB, respectively.
RESULTS: Compared with control group, test group II had increased (p < 0.05) average daily gain, plasma creatine level, ether extract (EE) and phosphorus digestibility on day 30. On day 60, the EE apparent digestibility, jugular venous plasma GAA, GAA content in the duodenal mucosa and GAA content in the jejunal and ileal mucosa of test group II were higher (p < 0.05) than other groups. Transcriptome analysis revealed that the differentially expressed genes (DEGs) involved in the duodenal pathways of oxidative phosphorylation and non-alcoholic fatty liver disease were significantly altered in test group II versus test group I (p < 0.05). Moreover, in the jejunum, the MAPK signalling pathway, complement and coagulation cascade and B-cell receptor signalling pathway were significantly enriched, with ATPase, solute carrier transporter protein, DHFR, SI, GCK, ACACA and FASN being the significantly DEGs (p < 0.05).
CONCLUSIONS: Dietary supplementation of RPB on top of GAA in sheep diets may promote sheep growth and development by improving the body\'s energy, amino acid, glucose and lipid metabolism capacity.

Natural deep eutectic solvents (NADESs) comprised of osmolytes are of interest as potential biomolecular (cryo)protectants. However, the way these solvents influence the structure and dynamics of biomolecules as well as the role of water remains poorly understood. We carried out principal component analysis of various secondary structure elements of ubiquitin in water and a betaine : glycerol : water (1 : 2 : ζ; ζ = 0, 1, 2, 5, 10, 20, 45) NADES, from molecular dynamics trajectories, to gain insight into the protein dynamics as it undergoes a transition from a highly viscous anhydrous to an aqueous environment. A crossover of the protein\'s essential dynamics at ζ ∼ 5, induced by solvent-shell coupled fluctuations, is observed, indicating that ubiquitin might (re)fold in the NADES upon water addition at ζ > ∼5. Further, in contrast to water, the anhydrous NADES preserves ubiquitin\'s essential modes at high temperatures explaining the protein\'s seemingly enhanced thermal stability.

Cowpea is a leguminous plant belonging to the fabaceae family cultivated in the North and Northeast regions of Brazil, with productive potential. Among the abiotic factors, water deficiency is one of the main environmental limitations that influence agricultural production in the world. The objective of this work was to study the relative water content and osmoregulators of cowpea plants subjected to water stress. The experiment was carried out in a greenhouse at the Universidade Federal Rural da Amazônia (UFRA, Belém, PA), cowpea plants BR-17 Gurguéia Vigna unguiculata (L.) Walp were used. The experimental design was completely randomized (DIC) in a 2 × 2 factorial scheme, two water conditions (control and water deficit) and two times of stress (four and six days of water suspension), with 7 replications, totaling 28 experimental units. The water deficit affected plants, causing a reduction in relative water content (69.98%), starch (12.84% in leaves and 23.48% in roots) and carbohydrates (84.34%), and an increase in glycine-betaine, sucrose (114.11% in leaves and 18.71% in roots) and proline (358.86%) at time 2. The relative water content was negatively affected by water conditions, with a decrease in relation to the interaction of the aerial part and the root system. Therefore, greater metabolic responses were noted in plants that were subjected to stress treatment at time 2 (6 days).

One-carbon metabolism (OCM) is a complex and interconnected network that undergoes drastic changes during pregnancy. In this study, we investigated the longitudinal distribution of OCM-related metabolites in maternal and cord blood and explored their relationships. Additionally, we conducted cross-sectional analyses to examine the interrelationships among these metabolites. This study included 146 healthy pregnant women who participated in the Chiba Study of Mother and Child Health. Maternal blood samples were collected during early pregnancy, late pregnancy, and delivery, along with cord blood samples. We analyzed 18 OCM-related metabolites in serum using stable isotope dilution liquid chromatography/tandem mass spectrometry. We found that serum S-adenosylmethionine (SAM) concentrations in maternal blood remained stable throughout pregnancy. Conversely, S-adenosylhomocysteine (SAH) concentrations increased, and the total homocysteine/total cysteine ratio significantly increased with advancing gestational age. The betaine/dimethylglycine ratio was negatively correlated with total homocysteine in maternal blood for all sampling periods, and this correlation strengthened with advances in gestational age. Most OCM-related metabolites measured in this study showed significant positive correlations between maternal blood at delivery and cord blood. These findings suggest that maternal OCM status may impact fetal development and indicate the need for comprehensive and longitudinal evaluations of OCM during pregnancy.