Branched-Chain and Aromatic Amino Acids, Type 2 Diabetes, and Cardiometabolic Risk Factors among Puerto Rican Adults.

(1) Background: Branched-chain and aromatic amino acids (BCAAs/AAAs) have been considered as markers of type 2 diabetes (T2D); however, studies on associations between these metabolites and T2D and cardiometabolic traits in Hispanic populations are limited. The aim of this study was to examine the associations between baseline BCAAs (isoleucine, leucine, valine)/AAAs (phenylalanine, tyrosine) and prevalent and incident T2D, as well as baseline and longitudinal (2 year) changes in cardiometabolic traits (measures of glycemia, dyslipidemia, inflammation, and obesity) in two large cohorts of adults of Puerto Rican descent. (2) Methods: We included participants of the Boston Puerto Rican Health Study (BPRHS, n = 670) and San Juan Overweight Adult Longitudinal study (SOALS, n = 999) with available baseline metabolite and covariate data. T2D diagnosis was defined based on American Diabetes Association criteria. Multivariable logistic (for baseline T2D), Poisson (for incident T2D), and linear (for cardiometabolic traits) regression models were used; cohort-specific results were combined in the meta-analysis and adjusted for multiple comparisons. (3) Results: Higher baseline BCAAs were associated with higher odds of prevalent T2D (OR1SD BCAA score = 1.46, 95% CI: 1.34-1.59, p < 0.0001) and higher risk of incident T2D (IRR1SD BCAA score = 1.24, 95% CI: 1.13-1.37, p < 0.0001). In multivariable longitudinal analysis, higher leucine and valine concentrations were associated with 2-year increase in insulin (beta 1SD leucine = 0.37 mcU/mL, 95% CI: 0.11-0.63, p < 0.05; beta 1SD valine = 0.43 mcU/mL, 95% CI: 0.17-0.68, p < 0.01). Tyrosine was a significant predictor of incident T2D (IRR = 1.31, 95% CI: 1.09-1.58, p < 0.05), as well as 2 year increases in HOMA-IR (beta 1SD tyrosine = 0.13, 95% CI: 0.04-0.22, p < 0.05) and insulin concentrations (beta 1SD tyrosine = 0.37 mcU/mL, 95% CI: 0.12-0.61, p < 0.05). (4) Conclusions: Our results confirmed the associations between BCAAs and prevalent and incident T2D, as well as concurrent measures of glycemia, dyslipidemia, and obesity, previously reported in predominantly White and Asian populations. Baseline leucine, valine, and tyrosine were predictors of 2 year increases in insulin, whereas tyrosine was a significant predictor of deteriorating insulin resistance over time. Our study suggests that BCAAs and tyrosine could serve as early markers of future glycemic changes in Puerto Ricans.

Association between Childhood Overweight and Altered Concentrations of Circulating Amino Acids.

(1) Background: Dysregulated serum amino acids (AA) are known to be associated with obesity and risk of Type 2 Diabetes (T2D) in adults, and recent studies support the same notion in the pubertal age. It is, however, unknown whether childhood overweight may already display alterations of circulating AA. (2) Methods: We used liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS)-targeted metabolomics to determine plasma concentrations of AA and AA-related molecules in 36 children aged 7-12 years with normal weight or overweight. Clinical and anthropometric parameters were measured. (3) Results: Overweight in children is associated with an altered AA profile, with increased branched-chain amino acids (BCAA) and decreased glycine levels, with no clinically manifested metabolic conditions. Moreover, z-BMI was positively and negatively correlated with BCAA and glycine levels, respectively, even after adjustment for age and gender. We also found a correlation between the AA profile and clinical parameters such as lipids profile and glycemia. (4) Conclusions: A pattern of low glycine, and increased BCAA is correlated to z-BMI, total cholesterol, and triglycerides in overweight but otherwise healthy children. Our data suggest that, in childhood overweight, AA disturbances may precede other clinical parameters, thus providing an early indicator for the later development of metabolic disease.

Effects of Branched-Chain Amino Acids on the Inflammatory Response Induced by LPS in Caco-2 Cells.

Branched-chain amino acids (BCAA) are essential for maintaining intestinal mucosal integrity. However, only a few studies have explored the role of BCAA in the modulation of intestinal inflammation. In this study, we investigated in vitro effects of BCAA on the inflammatory response induced by lipopolysaccharide (LPS) (1 µg/mL) in Caco-2 cells. Caco-2 cells were assigned to six groups: control without BCAA (CTL0), normal BCAA (CTL; 0.8 mM leucine, 0.8 mM isoleucine, and 0.8 mM valine); leucine (LEU; 2 mM leucine), isoleucine (ISO; 2 mM isoleucine), valine (VAL; 2 mM valine), and high BCAA (LIV; 2 mM leucine, 2 mM isoleucine, and 2 mM valine). BCAA was added to the culture medium 24 h before LPS stimulation. Our results indicated that BCAA supplementation did not impair cell viability. The amino acids leucine and isoleucine attenuated the synthesis of IL-8 and JNK and NF-kB phosphorylation induced by LPS. Furthermore, neither BCAA supplementation nor LPS treatment modulated the activity of glutathione peroxidase or the intracellular reduced glutathione/oxidized glutathione ratio. Therefore, leucine and isoleucine exert anti-inflammatory effects in Caco-2 cells exposed to LPS by modulating JNK and NF-kB phosphorylation and IL-8 production. Further in vivo studies are required to validate these findings and gather valuable information for potential therapeutic or dietary interventions.

Memantine Improves Memory and Neurochemical Damage in a Model of Maple Syrup Urine Disease.

Maple Syrup Urine Disease (MSUD) is a metabolic disease characterized by the accumulation of branched-chain amino acids (BCAA) in different tissues due to a deficit in the branched-chain alpha-ketoacid dehydrogenase complex. The most common symptoms are poor feeding, psychomotor delay, and neurological damage. However, dietary therapy is not effective. Studies have demonstrated that memantine improves neurological damage in neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. Therefore, we hypothesize that memantine, an NMDA receptor antagonist can ameliorate the effects elicited by BCAA in an MSUD animal model. For this, we organized the rats into four groups: control group (1), MSUD group (2), memantine group (3), and MSUD + memantine group (4). Animals were exposed to the MSUD model by the administration of BCAA (15.8 µL/g) (groups 2 and 4) or saline solution (0.9%) (groups 1 and 3) and treated with water or memantine (5 mg/kg) (groups 3 and 4). Our results showed that BCAA administration induced memory alterations, and changes in the levels of acetylcholine in the cerebral cortex. Furthermore, induction of oxidative damage and alterations in antioxidant enzyme activities along with an increase in pro-inflammatory cytokines were verified in the cerebral cortex. Thus, memantine treatment prevented the alterations in memory, acetylcholinesterase activity, 2',7'-Dichlorofluorescein oxidation, thiobarbituric acid reactive substances levels, sulfhydryl content, and inflammation. These findings suggest that memantine can improve the pathomechanisms observed in the MSUD model, and may improve oxidative stress, inflammation, and behavior alterations.

Treatment of maple syrup urine disease: Benefits, risks, and challenges of liver transplantation.

Maple syrup urine disease (MSUD) is caused by a deficiency in the activity of the branched-chain α-ketoacid dehydrogenase (BCKD) complex, promoting the accumulation of the branched-chain amino acids (BCAA) leucine, isoleucine, and valine, as well as their respective α-keto acids. MSUD is an autosomal recessive hereditary metabolic disorder characterized by ketoacidosis, ataxia, coma, and mental and psychomotor retardation. The mechanisms involved in the brain damage caused by MSUD are not fully understood. Early diagnosis and treatment, as well as proper control of metabolic decompensation crises, are crucial for patients' survival and for a better prognosis. The recommended treatment consists of a high-calorie diet with restricted protein intake and specific formulas containing essential amino acids, except those accumulated in MSUD. This treatment will be maintained throughout life, being adjusted according to the patients' nutritional needs and BCAA concentration. Because dietary treatment may not be sufficient to prevent neurological damage in MSUD patients, other therapeutic strategies have been studied, including liver transplantation. With transplantation, it is possible to obtain an increase of about 10% of the normal BCKD in the body, an amount sufficient to maintain amino acid homeostasis and reduce metabolic decompensation crises. However, the experience related to this practice is very limited when considering the shortage of liver for transplantation and the risks related to the surgical procedure and immunosuppression. Thus, the purpose of this review is to survey the benefits, risks, and challenges of liver transplantation in the treatment of MSUD.

Melatonin improves behavioral parameters and oxidative stress in zebrafish submitted to a leucine-induced MSUD protocol.

Maple syrup urine disease (MSUD) is an inherited metabolic disorder caused by a deficiency in branched-chain alpha-ketoacid dehydrogenase complex (BCKAC). The treatment is a standard therapy based on a protein-restricted diet with low branched-chain amino acids (BCAA) content to reduce plasma levels and, consequently, the effects of accumulating their metabolites, mainly in the central nervous system. Although the benefits of dietary therapy for MSUD are undeniable, natural protein restriction may increase the risk of nutritional deficiencies, resulting in a low total antioxidant status that can predispose and contribute to oxidative stress. As MSUD is related to redox and energy imbalance, melatonin can be an important adjuvant treatment. Melatonin directly scavenges the hydroxy radical, peroxyl radical, nitrite anion, and singlet oxygen and indirectly induces antioxidant enzyme production. Therefore, this study assesses the role of melatonin treatment on oxidative stress in brain tissue and behavior parameters of zebrafish (Danio rerio) exposed to two concentrations of leucine-induced MSUD: leucine 2 mM and 5mM; and treated with 100 nM of melatonin. Oxidative stress was assessed through oxidative damage (TBARS, DCF, and sulfhydryl content) and antioxidant enzyme activity (SOD and CAT). Melatonin treatment improved redox imbalance with reduced TBARS levels, increased SOD activity, and normalized CAT activity to baseline. Behavior was analyzed with novel object recognition test. Animals exposed to leucine improved object recognition due to melatonin treatment. With the above, we can suggest that melatonin supplementation can protect neurologic oxidative stress, protecting leucine-induced behavior alterations such as memory impairment.

Branched chain amino acids catabolism as a source of new drug targets in pathogenic protists.

Leucine, isoleucine, and valine, collectively termed Branched Chain Amino Acids (BCAA), are hydrophobic amino acids (AAs) and are essential for most eukaryotes since in these organisms they cannot be biosynthesized and must be supplied by the diet. These AAs are structurally relevant for muscle cells and, of course, important for the protein synthesis process. The metabolism of BCAA and its participation in different biological processes in mammals have been relatively well described. However, for other organisms as pathogenic parasites, the literature is really scarce. Here we review the BCAA catabolism, compile evidence on their relevance for pathogenic eukaryotes with special emphasis on kinetoplastids and highlight unique aspects of this underrated pathway.

Branched-chain amino acids (BCAA) administration increases autophagy and the autophagic pathway in brain tissue of rats submitted to a Maple Syrup Urine Disease (MSUD) protocol.

Maple Syrup Urine Disease (MSUD) is an inborn error of metabolism (EIM) biochemically characterized by the tissue accumulation of branched-chain amino acids (BCAA) and their branched-chain alpha-keto acids. The mechanisms by which BCAA and their branched-chain alpha-keto acids lead to the neurological damage observed in MSUD are poorly understood. Mounting evidence has demonstrated that BCAA induce the overproduction of reactive oxygen species, which may modulate several important signaling pathways necessary for cellular homeostasis maintenance, such as autophagy. Taking this into account, we evaluated the effects of BCAA on the autophagic pathway in brain structures of rats submitted to the administration of these amino acids (animal model of MSUD). Our findings showed that BCAA significantly increased the levels of Beclin-1, ATG7, and ATG5 in the cerebral cortex of rats. In addition, BCAA augmented ATG12 levels in the striatum and ATG5 and LC3 I-II in the hippocampus. Therefore, our work demonstrates that the administration of BCAA increases autophagy and autophagic cell death, possibly mediated by the elevated levels of reactive species generated by BCAA.

Current Medical Treatment for Alcohol-Associated Liver Disease.

Alcohol-associated liver disease is one of the main causes of chronic liver disease. It comprises a clinical-histologic spectrum of presentations, from steatosis, steatohepatitis, to different degrees of fibrosis, including cirrhosis and severe necroinflammatory disease, called alcohol-associated hepatitis. In this focused update, we aim to present specific therapeutic interventions and strategies for the management of alcohol-associated liver disease. Current evidence for management in all spectra of manifestations is derived from general chronic liver disease recommendations, but with a higher emphasis on abstinence and nutritional support. Abstinence should comprise the treatment of alcohol use disorder as well as withdrawal syndrome. Nutritional assessment should also consider the presence of sarcopenia and its clinical manifestation, frailty. The degree of compensation of the disease should be evaluated, and complications, actively sought. The most severe acute form of this disease is alcohol-associated hepatitis, which has high mortality and morbidity. Current treatment is based on corticosteroids that act by reducing immune activation and blocking cytotoxicity and inflammation pathways. Other aspects of treatment include preventing and treating hepatorenal syndrome as well as preventing infections although there is no clear evidence as to the benefit of probiotics and antibiotics in prophylaxis. Novel therapies for alcohol-associated hepatitis include metadoxine, interleukin-22 analogs, and interleukin-1-beta antagonists. Finally, granulocyte colony-stimulating factor, microbiota transplantation, and gut-liver axis modulation have shown promising results. We also discuss palliative care in advanced alcohol-associated liver disease.

Exposure to leucine alters glutamate levels and leads to memory and social impairment in zebrafish.

Maple Syrup Urine Disease (MSUD) is a metabolic disorder characterized by high levels in blood and urine of branched-chain amino acids leucine, isoleucine, and valine and their alpha-ketoacids, by a partial or total blockade in the activity of branched-chain complex alpha-keto acids dehydrogenase. The main symptoms in MSUD occur in the central nervous system, including cognitive deficits, locomotor, poor feeding, seizures, psychomotor delay, and mental retardation, but the mechanisms of neurotoxicity and behavior alteration due to this disease are poorly understood, thus this study aimed at showing the effects of leucine exposure on glutamate levels and behavior in zebrafish. For this, we analyzed the behavior using the social preference test and novel object recognition test, moreover, we analyse the glutamate levels and uptake using scintillation and high-performance liquid chromatography methods. Our results demonstrated a decrease in glutamate levels and uptake, accompanied by memory and social impairment. In conclusion, these results suggest that alterations in glutamate levels can be associated with behavior impairment, however, more studies are necessary to understand the mechanisms for brain damage in MSUD.

Pathophysiology of maple syrup urine disease: Focus on the neurotoxic role of the accumulated branched-chain amino acids and branched-chain α-keto acids.

Maple syrup urine disease (MSUD) is an autosomal recessive neurometabolic disorder caused by severe deficiency of branched-chain α-keto acid dehydrogenase complex activity, which catalyzes the oxidative decarboxylation of the branched-chain α-keto acids (BCKA). The metabolic blockage results in tissue accumulation and high urinary excretion of the branched-chain amino acids (BCAA) leucine, isoleucine and valine, as well as alloisoleucine, and their respective BCKA α-ketoisocaproic (α-KIC), α-ketoisovaleric and α-keto-ß-methylvaleric acids. Affected patients usually manifest acute episodes of encephalopathy associated with seizures, coma and life-threatening cerebral edema in the first weeks of life, which is followed by progressive neurological deterioration with motor delay, ataxia, intellectual disability and psychiatric symptoms. The pathophysiology of the brain damage in MSUD has been mainly focused on brain amino acid imbalance leading to deficient cerebral protein and neurotransmitter synthesis. However, the acute episodes of severe neurological symptoms accompanied by large increases of BCKA/BCAA levels suggest neurotoxic actions of these compounds. In this particular, mounting evidence from humans and animal models support an important role of particularly leucine and α-KIC on the pathogenesis of the brain injury in MSUD. In this review we will present the current knowledge of the major mechanisms presumably involved in MSUD neuropathology and highlight the neurotoxic properties of the BCAA and BCKA, disturbing brain bioenergetics and redox homeostasis, besides inducing neuroinflammation. We suggest that these pathomechanisms may contribute to the neurological sequelae of MSUD patients and hopefully allow the design of novel therapeutic strategies, including antioxidant and bioenergetics stimulating drugs targeting the mitochondria.

Coadministration of tianeptine alters behavioral parameters and levels of neurotrophins in a chronic model of Maple Syrup Urine disease.

Maple Syrup Urine Disease (MSUD) is caused by the deficiency in the activity of the branched-chain α-ketoacid dehydrogenase complex (BCKDC), resulting in the accumulation of the branched-chain amino acids (BCAA) leucine, isoleucine, and valine, and their respective branched-chain α-keto acids. Patients with MSUD are at high risk of developing chronic neuropsychiatric disorders; however, the pathophysiology of brain damage in these patients remains unclear. We hypothesize that MSUD can cause depressive symptoms in patients. To test our hypothesis, Wistar rats were submitted to the BCAA and tianeptine (antidepressant) administration for 21 days, starting seven days postnatal. Depression-like symptoms were assessed by testing for anhedonia and forced swimming after treatments. After the last test, the brain structures were dissected for the evaluation of neutrophins. We demonstrate that chronic BCAA administration induced depressive-like behavior, increased BDNF levels, and decreased NGF levels, suggesting a relationship between BCAA toxicity and brain damage, as observed in patients with MSUD. However, the administration of tianeptine was effective in preventing behavioral changes and restoring neurotrophins levels.

Exposure to leucine induces oxidative stress in the brain of zebrafish.

Maple Syrup Urine Disease (MSUD) is an autosomal recessive inherited disorder caused by a deficiency in the activity of the branched-chain alpha-ketoacid dehydrogenase complex leading to the accumulation of branched-chain amino acids (BCAA) leucine, isoleucine, and valine and their respective branched-chain α-ketoacids and corresponding hydroxy acids. Considering that Danio rerio, known as zebrafish, has been widely used as an experimental model in several research areas because it has favorable characteristics that complement other experimental models, this study aimed to evaluate oxidative stress parameters in zebrafish exposed to high levels of leucine (2 mM and 5 mM), in a model similar of MSUD. Twenty-four hours after exposure, the animals were euthanized, and the brain content dissected for analysis of oxidative stress parameters: thiobarbituric acid reactive substances (TBARS), 2',7'-dichlorofluorescein oxidation assay (DCF); content of sulfhydryl, and superoxide dismutase (SOD) and catalase (CAT) activities. Animals exposed to 2 mM and 5 mM leucine showed an increase in the measurement of TBARS and decreased sulfhydryl content. There were no significant changes in DCF oxidation. In addition, animals exposed to 2 mM and 5 mM leucine were found to have decreased SOD activity and increased CAT activity. Based on these results, exposure of zebrafish to high doses of leucine can act as a promising animal model for MSUD, providing a better understanding of the toxicity profile of leucine exposure and its use in future investigations and strategies related to the pathophysiology of MSUD.

The role of the electron-transfer flavoprotein: ubiquinone oxidoreductase following carbohydrate starvation in Arabidopsis cell cultures.

KEY MESSAGE: The functional absence of the electron-transfer flavoprotein: ubiquinone oxidoreductase (ETFQO) directly impacts electrons donation to the mitochondrial electron transport chain under carbohydrate-limiting conditions without major impacts on the respiration of cell cultures. Alternative substrates (e.g., amino acids) can directly feed electrons into the mitochondrial electron transport chain (mETC) via the electron transfer flavoprotein/electron-transfer flavoprotein: ubiquinone oxidoreductase (ETF/ETFQO) complex, which supports plant respiration during stress situations. By using a cell culture system, here we investigated the responses of Arabidopsis thaliana mutants deficient in the expression of ETFQO (etfqo-1) following carbon limitation and supplied with amino acids. Our results demonstrate that isovaleryl-CoA dehydrogenase (IVDH) activity was induced during carbon limitation only in wild-type and that these changes occurred concomit with enhanced protein content. By contrast, neither the activity nor the total amount of IVDH was altered in etfqo-1 mutants. We also demonstrate that the activities of mitochondrial complexes in etfqo-1 mutants, display a similar pattern as in wild-type cells. Our findings suggest that the defect of ETFQO protein culminates with an impaired functioning of the IVDH, since no induction of IVDH activity was observed. However, the functional absence of the ETFQO seems not to cause major impacts on plant respiration under carbon limiting conditions, most likely due to other alternative electron entry pathways.

Whey Protein Supplementation Is Superior to Leucine-Matched Collagen Peptides to Increase Muscle Thickness During a 10-Week Resistance Training Program in Untrained Young Adults.

The purpose of this study was to investigate the effects of supplementation of whey protein (WP) versus leucine-matched collagen peptides (CP) on muscle thickness MT and performance after a resistance training (RT) program in young adults. Twenty-two healthy untrained participants were randomly assigned to either a WP (n = 11) or leucine-matched CP (n = 11) group and then submitted to a supervised 10-week RT program (3 days/week). The groups were supplemented with an equivalent amount of WP (35 g, containing 3.0 g of leucine) and CP (35 g, containing 1.0 g of leucine and 2.0 g of free leucine) during the intervention period (after each workout and in the evening on nontraining days). MT of the vastus lateralis and biceps brachii, isokinetic peak torque and mean power output of the elbow flexors, and peak power output of the lower body were assessed before and after the RT program. The WP group experienced a greater (interaction, p < .05) increase in the vastus lateralis (effect size, WP = 0.68 vs. CP = 0.38; % Δ, WP = 8.4 ± 2.5 vs. CP = 5.6 ± 2.6%) and biceps brachii muscle thickness (effect size, WP = 0.61 vs. CP = 0.35; % , WP = 10.1 ± 3.8 vs. CP = 6.0 ± 3.2%), with a similar increase in muscle performance (peak torque, mean power output, and peak power output) between groups (time p < .05). Supplementation with WP was superior to leucine content-matched CP supplementation in increasing muscle size, but not strength and power, after a 10-week RT program in young adults.

Involvement of the fecal amino acid profile in a clinical and anthropometric study of Mexican patients with insulin resistance and type 2 diabetes mellitus.

The amino acids synthesized by the intestinal microbiota have been correlated with metabolic diseases, such as type 2 diabetes mellitus and insulin resistance; both are high incidence conditions in Mexico. However, the knowledge of the relationship of fecal amino acids with the development of both diseases in the Mexican population is scarce. The clinical study was descriptive; the study was carried out in the Antiguo Civil Hospital of Guadalajara. Samples were taken from a total of 48 participants with insulin resistance, diabetes, and a control group (n = 16 each). Anthropometric and biochemical measures were evaluated. HPLC carried out the quantification of fecal amino acids. A strong correlation between alanine and HOMA-IR (r = 0.5416) was found and between phenylalanine and HOMA-IR (r = 0.4258). Other interesting correlations were between alanine and glucose (r = 0.5854) and isoleucine and glucose (r = 0.5008). The diabetic group and the insulin-resistant group had increased fecal values of valine and isoleucine (branched-chain amino acids), which were positively correlated with the progression of both conditions. Likewise, alanine and phenylalanine can help predict the development of the disease in the Mexican population. Registry number: 037/19.

Menopause Per se Is Associated with Coronary Artery Calcium Score: Results from the ELSA-Brasil.

Background: Menopause and aging deteriorate the metabolic profile, but little is known about how they independently contribute to structural changes in coronary arteries. We compared a broad cardiometabolic risk profile of women according to their menopausal status and investigated if menopause per se is associated with presence of coronary artery calcium (CAC) in the ELSA-Brasil. Materials and Methods: All participants, except perimenopausal women, who had menopause <40 years or from non-natural causes or reported use of hormone therapy were included. Sample was stratified according to menopause and age categories (premenopause ≤45 years, premenopause >45 years, and postmenopause); their clinical profile and computed tomography-determined CAC were compared using Kruskal-Wallis and chi squared test for frequencies. Associations of CAC (binary variable) with menopause categories adjusted for traditional and nontraditional covariables were tested using logistic regression. Results: From 2,047 participants 51 ± 9 years of age, 1,175 were premenopausal (702 ≤ 45 years) and 872 were postmenopausal women. Mean values of anthropometric variables, blood pressure, lipid and glucose parameters, branched-chain amino acids (BCAA), and homeosthasis model assessment (HOMA-IR), as well as frequencies of morbidities, were more favorable in premenopausal, particularly in younger ones. In crude analyses, CAC >0 was associated with triglyceride-rich lipoprotein remnants, dense low-density lipoprotein, BCAA, and other variables, but not with HOMA-IR. Menopause was independently associated with CAC >0 (odds ratios 2.37 [95% confidence interval 1.17-4.81]) when compared to the younger premenopausal group. Conclusion: Associations of menopause with CAC, independent of traditional and nontraditional cardiovascular risk factors, suggest that hormonal decline per se may contribute to calcium deposition in coronary arteries.

Nutritional therapy for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer and presents together with cirrhosis in most cases. In addition to commonly recognized risk factors for HCC development, such as hepatitis B virus/hepatitis C virus infection, age and alcohol/tobacco consumption, there are nutritional risk factors also related to HCC development including high intake of saturated fats derived from red meat, type of cooking (generation of heterocyclic amines) and contamination of foods with aflatoxins. On the contrary, protective nutritional factors include diets rich in fiber, fruits and vegetables, n-3 polyunsaturated fatty acids and coffee. While the patient is being evaluated for staging and treatment of HCC, special attention should be paid to nutritional support, including proper nutritional assessment and therapy by a multidisciplinary team. It must be considered that these patients usually develop HCC on top of long-lasting cirrhosis, and therefore they could present with severe malnutrition. Cirrhosis-related complications should be properly addressed and considered for nutritional care. In addition to traditional methods, functional testing, phase angle and computed tomography scan derived skeletal muscle index-L3 are among the most useful tools for nutritional assessment. Nutritional therapy should be centered on providing enough energy and protein to manage the increased requirements of both cirrhosis and cancer. Supplementation with branched-chain amino acids is also recommended as it improves response to treatment, nutritional status and survival, and finally physical exercise must be encouraged and adapted to individual needs.

Serum Metabolite Profile Associated with Sex-Dependent Visceral Adiposity Index and Low Bone Mineral Density in a Mexican Population.

Recent evidence shows that obesity correlates negatively with bone mass. However, traditional anthropometric measures such as body mass index could not discriminate visceral adipose tissue from subcutaneous adipose tissue. The visceral adiposity index (VAI) is a reliable sex-specified indicator of visceral adipose distribution and function. Thus, we aimed to identify metabolomic profiles associated with VAI and low bone mineral density (BMD). A total of 602 individuals from the Health Workers Cohort Study were included. Forty serum metabolites were measured using the targeted metabolomics approach, and multivariate regression models were used to test associations of metabolomic profiles with anthropometric, clinical, and biochemical parameters. The analysis showed a serum amino acid signature composed of glycine, leucine, arginine, valine, and acylcarnitines associated with high VAI and low BMD. In addition, we found a sex-dependent VAI in pathways related to primary bile acid biosynthesis, branched-chain amino acids, and the biosynthesis of pantothenate and coenzyme A (CoA). In conclusion, a metabolic profile differs by VAI and BMD status, and these changes are gender-dependent.

Molecular basis of various forms of maple syrup urine disease in Chilean patients.

BACKGROUND: Maple syrup urine disease (MSUD) is an autosomal recessive inherited metabolic disorder caused by the deficient activity of the branched-chain α-keto acid dehydrogenase (BCKD) enzymatic complex. BCKD is a mitochondrial complex encoded by four genes: BCKDHA, BCKDHB, DBT, and DLD. MSUD is predominantly caused by mutations in the BCKDHA, BCKDHB, and DBT genes which encode the E1α, E1ß, and E2 subunits of the BCKD complex, respectively. The aim of this study was to characterize the genetic basis of MSUD in a cohort of Chilean MSUD patients by identifying point mutations in the BCKDHA, BCKDHB, and DBT genes and to describe their impact on the phenotypic heterogeneity of these patients. METHODS: This manuscript describes a cross-sectional study of 18 MSUD patients carried out using PCR and DNA sequencing. RESULTS: Four novel pathogenic mutations were identified: one in BCKDHA (p.Thr338Ile), two in BCKDHB (p.Gly336Ser e p.Pro240Thr), and one in DBT (p.Gly406Asp). Four additional pathogenic mutations found in this study have been described previously. There were no correlations between the genotype and phenotype of the patients. CONCLUSION: If MSUD is diagnosed earlier, with a newborn screening approach, it might be possible to establish genotype-phenotype relationships more efficiently.