Amelioration of hepatic steatosis by dietary essential amino acid-induced ubiquitination.

Nonalcoholic fatty liver disease (NAFLD) is a global health concern with no approved drugs. High-protein dietary intervention is currently the most effective treatment. However, its underlying mechanism is unknown. Here, using Drosophila oenocytes, the specialized hepatocyte-like cells, we find that dietary essential amino acids ameliorate hepatic steatosis by inducing polyubiquitination of Plin2, a lipid droplet-stabilizing protein. Leucine and isoleucine, two branched-chain essential amino acids, strongly bind to and activate the E3 ubiquitin ligase Ubr1, targeting Plin2 for degradation. We further show that the amino acid-induced Ubr1 activity is necessary to prevent steatosis in mouse livers and cultured human hepatocytes, providing molecular insight into the anti-NAFLD effects of dietary protein/amino acids. Importantly, split-intein-mediated trans-splicing expression of constitutively active UBR2, an Ubr1 family member, significantly ameliorates obesity-induced and high fat diet-induced hepatic steatosis in mice. Together, our results highlight activation of Ubr1 family proteins as a promising strategy in NAFLD treatment.

Effects of an essential amino acid mixture on behavioral and psychological symptoms of dementia and executive function in patients with Alzheimer's disease: A double-blind, randomized, placebo-controlled exploratory clinical trial.

BACKGROUND: The increasing number of dementia patients has become a global social problem. Amino acids are known to be used as precursors of neurotransmitters in the brain. Amino acid mixtures as a supplement may be used as a solution to Alzheimer's symptoms. This exploratory study evaluated the efficacy and safety of a mixture containing nine essential amino acids on behavioral and psychological symptoms of dementia (BPSD) and cognitive function in patients with Alzheimer's disease (AD). DESIGN: We conducted a double-blind, randomized, placebo-controlled trial to evaluate the intervention effects of nine essential amino acid mixture for 28 days. A total of 36 patients with AD were enrolled in Japan. BPSD and cognitive function were evaluated by the Neuropsychiatric Inventory-12 item (NPI-12; the primary endpoint), Mini-Mental State Examination (MMSE), Trail Making Test A (TMT-A), Trail Making Test B (TMT-B), Frontal Assessment Battery (FAB), and Clinical Dementia Rating Scale (CDR). RESULTS: Compared with placebo, the amino acid mixture did not improve NPI-12, MMSE, TMT-A and B or CDR scores. However, the analysis of covariance revealed improved FAB scores in the amino acid mixture group as a secondary endpoint. There were four subjects with adverse events in each group. CONCLUSIONS: Our results did not show a beneficial effect of the mixture containing nine essential amino acids on BPSD as a primary endpoint; however, it may improve executive function in patients with AD.

Supplemented amino acids may enhance the walking recovery of elderly subjects after hip fracture surgery.

The purpose of this study was to investigate whether supplemented essential amino acids (EAAs) could enhance rehabilitation therapy (Rehab) for recovery of walking capacity in subjects after hip fracture surgery (HFS). Eighty-three elderly subjects with HFS (20 ± 11 days after acute trauma) were eligible for the study and randomized to receive Rehab only (Rehab; n = 27), Rehab + placebo (RP; n = 28) or Rehab + EAAs (RE 8 g/day; n = 28). The patients' walking capacity (m) was measured by 6-min walking distance (6MWD) at admission and at discharge (median 66 days after admission). All patient groups were treated with the same Rehab (2 sessions/day × 5 days/week). The results showed that the gain in 6MWD was higher in RE than in Rehab and RP (p = 0.034; p = 0.024). The study shows that EAA supplementation can enhance walking recovery rate in subjects with HFS.

Effects of essential amino acid supplementation and rehabilitation on functioning in hip fracture patients: a pilot randomized controlled trial.

BACKGROUND: Physical exercise and nutrition seem to have a key role in the management of hip fracture patients. AIM: To evaluate the impact of a 2-month rehabilitative protocol combined with dietetic counseling, with or without essential amino acid supplementation, on functioning in hip fracture patients. METHODS: In this pilot randomized controlled study, we recruited patients aged more than 65 years, at 3 months after hip fracture. We randomly assigned the participants into two groups (A and B). Both groups performed a physical exercise rehabilitative programme (five sessions of 40 min/week for 2 weeks, followed by a home-based exercise protocol) and received a dietetic counseling; only group A was supplemented with two sachets of 4 g/day of essential amino acids (Aminotrofic®). We evaluated at baseline and after 2 months of intervention (T1): hand grip strength, Timed Up and Go, and Iowa Level of Assistance scale (ILOA). RESULTS: The 32 hip fracture patients (mean aged 79.03 ± 7.80 years) were allocated into two groups: group A (n = 16) and group B (n = 16). All the participants showed significant differences in all outcomes at T1 (p < 0.017). Sarcopenic patients in group A (n = 10) showed statistically significant differences in all the primary outcomes at T1 (p < 0.017), whereas sarcopenic patients in group B (n = 13) showed a significant reduction of ILOA only. In non-sarcopenic patients, we found no differences at T1 in all outcome measures. DISCUSSION: Hip fractures are a complex multifactorial condition of the elderly that determines devastating effects on functioning and independence. CONCLUSION: A multidisciplinary rehabilitative and nutritional intervention seems to be effective on functioning in hip fracture patients, in particular sarcopenic ones.

Nutrition and physical activity in the prevention and treatment of sarcopenia: systematic review.

This systematic review summarizes the effect of combined exercise and nutrition intervention on muscle mass and muscle function. A total of 37 RCTs were identified. Results indicate that physical exercise has a positive impact on muscle mass and muscle function in subjects aged 65 years and older. However, any interactive effect of dietary supplementation appears to be limited. INTRODUCTION: In 2013, Denison et al. conducted a systematic review including 17 randomized controlled trials (RCTs) to explore the effect of combined exercise and nutrition intervention to improve muscle mass, muscle strength, or physical performance in older people. They concluded that further studies were needed to provide evidence upon which public health and clinical recommendations could be based. The purpose of the present work was to update the prior systematic review and include studies published up to October 2015. METHODS: Using the electronic databases MEDLINE and EMBASE, we identified RCTs which assessed the combined effect of exercise training and nutritional supplementation on muscle strength, muscle mass, or physical performance in subjects aged 60 years and over. Study selection and data extraction were performed by two independent reviewers. RESULTS: The search strategy identified 21 additional RCTs giving a total of 37 RCTs. Studies were heterogeneous in terms of protocols for physical exercise and dietary supplementation (proteins, essential amino acids, creatine, ß-hydroxy-ß-methylbuthyrate, vitamin D, multi-nutrients, or other). In 79% of the studies (27/34 RCTs), muscle mass increased with exercise but an additional effect of nutrition was only found in 8 RCTs (23.5%). Muscle strength increased in 82.8% of the studies (29/35 RCTs) following exercise intervention, and dietary supplementation showed additional benefits in only a small number of studies (8/35 RCTS, 22.8%). Finally, the majority of studies showed an increase of physical performance following exercise intervention (26/28 RCTs, 92.8%) but interaction with nutrition supplementation was only found in 14.3% of these studies (4/28 RCTs). CONCLUSION: Physical exercise has a positive impact on muscle mass and muscle function in healthy subjects aged 60 years and older. The biggest effect of exercise intervention, of any type, has been seen on physical performance (gait speed, chair rising test, balance, SPPB test, etc.). We observed huge variations in regard to the dietary supplementation protocols. Based on the included studies, mainly performed on well-nourished subjects, the interactive effect of dietary supplementation on muscle function appears limited.

Ketoanalogue-Supplemented Vegetarian Very Low-Protein Diet and CKD Progression.

Dietary protein restriction may improve determinants of CKD progression. However, the extent of improvement and effect of ketoanalogue supplementation are unclear. We conducted a prospective, randomized, controlled trial of safety and efficacy of ketoanalogue-supplemented vegetarian very low-protein diet (KD) compared with conventional low-protein diet (LPD). Primary end point was RRT initiation or >50% reduction in initial eGFR. Nondiabetic adults with stable eGFR<30 ml/min per 1.73 m(2), proteinuria <1 g/g urinary creatinine, good nutritional status, and good diet compliance entered a run-in phase on LPD. After 3 months, compliant patients were randomized to KD (0.3 g/kg vegetable proteins and 1 cps/5 kg ketoanalogues per day) or continue LPD (0.6 g/kg per day) for 15 months. Only 14% of screened patients patients were randomized, with no differences between groups. Adjusted numbers needed to treat (NNTs; 95% confidence interval) to avoid composite primary end point in intention to treat and per-protocol analyses in one patient were 4.4 (4.2 to 5.1) and 4.0 (3.9 to 4.4), respectively, for patients with eGFR<30 ml/min per 1.73 m(2) Adjusted NNT (95% confidence interval) to avoid dialysis was 22.4 (21.5 to 25.1) for patients with eGFR<30 ml/min per 1.73 m(2) but decreased to 2.7 (2.6 to 3.1) for patients with eGFR<20 ml/min per 1.73 m(2) in intention to treat analysis. Correction of metabolic abnormalities occurred only with KD. Compliance to diet was good, with no changes in nutritional parameters and no adverse reactions. Thus, this KD seems nutritionally safe and could defer dialysis initiation in some patients with CKD.

The Rise and Fall of Protein Malnutrition in Global Health.

BACKGROUND: From the 1950s to the mid-1970s, United Nations (UN) agencies were focused on protein malnutrition as the major worldwide nutritional problem. The goal of this review is to examine this era of protein malnutrition, the reasons for its demise, and the aftermath. SUMMARY: The UN Protein Advisory Group was established in 1955. International conferences were largely concerned about protein malnutrition in children. By the early 1970s, UN agencies were ringing the alarm about a 'protein gap'. In The Lancet in 1974, Donald McLaren branded these efforts as 'The Great Protein Fiasco', declaring that the 'protein gap' was a fallacy. The following year, John Waterlow, the scientist who led most of the efforts on protein malnutrition, admitted that a 'protein gap' did not exist and that young children in developing countries only needed sufficient energy intake. The emphasis on protein malnutrition waned. It is recently apparent that quality protein and essential amino acids are missing in the diet and may have adverse consequences for child growth and the reduction of child stunting. Key Messages: It may be time to re-include protein and return protein malnutrition in the global health agenda using a balanced approach that includes all protective nutrients.

High anabolic potential of essential amino acid mixtures in advanced nonsmall cell lung cancer.

BACKGROUND: Conventional nutritional supplements are not or only partly successful in inducing protein accretion in advanced cancer, suggesting an attenuated anabolic response. To prevent muscle wasting and its deleterious consequences, generating an anabolic response is crucial. Dietary essential amino acids (EAA) have anabolic properties in other wasting diseases; however, data in advanced cancer are lacking. PATIENTS AND METHODS: In 13 patients with advanced nonsmall-cell lung cancer (NSCLC) (stage III and IV) and 11 healthy age-matched subjects, we measured protein synthesis and breakdown of the whole body, and net protein anabolism (difference between protein synthesis and breakdown) after intake of 14 g of free EAA with high leucine levels (EAA/leucine) versus a balanced amino acid mixture containing both EAA and non-EAA as present in whey protein, according to a randomized, double-blind, crossover design. RESULTS: Protein synthesis and net protein anabolism were higher after intake of the EAA/leucine than the balanced amino acid mixture (P < 0.001), independent of presence of cancer. A highly significant linear relationship between net protein anabolism and the amount of EAA available in the systemic circulation (R(2): 0.85, P < 0.001) was found in both groups. The presence of muscle or recent weight loss, systemic inflammatory response, or length of survival did not influence this relationship. High leucine levels in the EAA/leucine mixture was of no anabolic benefit. CONCLUSIONS: There is no anabolic resistance or attenuated anabolic potential to intake of 14 g of EAA/leucine or balanced amino acid mixture in advanced (mainly stage III) NSCLC. The high anabolic potential of dietary EAA in cancer patients is independent of their nutritional status, systemic inflammatory response or disease trajectory, suggesting a key role of EAA in new nutritional approaches to prevent muscle loss, thereby improving outcome of patients with advanced cancer. CLINICALTRAILSGOV: NCT01172314.

[Analysis of the Effectiveness of Renoprotection of Low-Protein Diet and Ketoanalogues of Amino Acids In Patients With Chronic Kidney Disease].

AIM: Analysis of the effectiveness of renoprotection in patients with chronic kidney disease (CKD), who is observed by general practitioners for up to 72.1 months, keeping traditional LPD or LPD with prescription of ketoanalogues of amino acids (KA/AK). METHODS: 63 patients with CKD stages 3-4, mainly with glomerulonephritis (GN), were divided into 3 groups: 1 gr--31 patients (53.3 ± 3.1 years old; M/F--18/13), LPD with prescription of ketoanalogues of amino acids; 2 gr--22 patients (54.9 3.2 years old; M/F--13/9) traditional LPD without ketoanalogues; 3 gr--10 patients (51.7 ± 4.2 years old; M/F--6/4) with natural course of CKD. Group 4 (control)--30 healthy subjects (52.3 ± 2.2 years old; M/F--16/14). The following parameters were studied: dynamics of the glomerular filtration rate (GFR), systolic blood pressure (SBP), diastolic blood pressure (DBP), hemoglobin levels (Hb), daily proteinuria, and basic parameters of protein, lipid and phosphate- calcium metabolism. RESULTS: The rate of decline in GFR was significantly lower in patients of the first group (-0.78 mL/min/year) than those of the second group (-4.9 ml/min/year). 9.7% of patients of the first group needed the start of renal replacement therapy at the end of the observation, 18.1%--of the second group and 40%--of the third. All patients who received renoprotective therapy, including low-protein diet with KA/AA reached target levels of blood pressure < 140/90 mm Hg. Patients of this group was able to achieve a significant reduction in proteinuria, improvement of lipid metabolism, prevent of reduction of Hb and the development of metabolic disorders of protein and calcium-phosphate metabolism. The second group of patients, following nephroprotection recommendations and LPD without KA/AA, had fewer reductions in BP without reaching the target level, DBP did not change; reduction of proteinuria was less significant than in group 1. There was no negative dynamics of protein and calcium-phosphate metabolism, though significantly increased levels of total cholesterol and LHD were observed. The third group of patients, who did not follow the renoprotection recommendations demonstrated negative dynamics of the studied parameters. CONCLUSION: Renoprotection based on the use KA/AA in patients with CKD stages 3-4 proved to be more effective than without it in slowing the rate of decline in GFR, hypertension correction, proteinuria reduction, maintaining the level of Hb, prevention of disorders of protein and calcium-phosphate metabolism, as well as correction of the lipid metabolism.

The effectiveness of oral essential aminoacids and aminoacids containing dialysate in peritoneal dialysis.

BACKGROUND/AIM: Oral essential amino acids (AAs) containing supplements (EAS) and AA containing dialysate (ACD) are frequently used in peritoneal dialysis (PD) patients with malnutrition. The present study was conducted to investigate two strategies and compare their effects on the malnutrition status of PD patients. MATERIALS AND METHODS: A total of 31 EAS, 14 ACD patients were enrolled in this study. Serum albumin levels were lower than 3.5 g/dL in all subjects. EAS group patients took five pills containing AAs three times a day with meals. In the other, 2.000 cc of 1.1% ACD was given to patients daily during the study. Demographic and laboratory parameters were analyzed and compared at baseline and 6th month. RESULTS: Significant increases in BMI, albumin, and protein in both groups. Mean albumin levels increased significantly by 0.54 g/dL in ACD group (p < 0.005) and 0.49 g/dL in EAS group (p < 0.001) following 6 months. Mean albumin and delta albumin levels did not differ between two groups. CONCLUSION: These strategies may play an important role in increasing albumin levels and improving the nutritional status of PD patients.

Effects of essential amino acid (EAA) and glutamine supplementation on skeletal muscle wasting in acute, subacute, and postacute conditions.

Under optimal physiological conditions, muscle mass maintenance is ensured by dietary protein, which balances the amino acid loss during the post-absorption period and preserves the body's protein homeostasis. Conversely, in critical clinical conditions (acute, subacute or postacute), particularly those related to hypomobility or immobility, combined with malnutrition, and local/systemic inflammation, the loss of muscle mass and strength can be quantitatively significant. A decline of more than 1% in muscle mass and of more than 3% in muscle strength has been registered in subjects with aged 20-37 yr after just five days of bed rest, similarly to those observed during one year of age-related decline in individuals over the age of 50. Loss of muscle mass and strength can have a dramatic effect on subjects' functional capacities, on their systemic metabolic control and on the amino acid reserve function, all of which are fundamental for the maintenance of other organs' and tissues' cell processes. References available indicate that the average 1%-2% reduction per day of muscle mass in patients in the intensive care unit (ICU) could represent an independent predictor of hospital mortality and physical disability in the five years following hospitalization. After just a few days or weeks of administration, supplementation with EAAs and glutamine has shown significant effects in maintaining muscle size and strength, which are typically negatively affected by some acute/subacute or postacute critical conditions (muscle recovery after surgery, oncology patients, ICU treatments), especially in the elderly or in those with pre-existing degenerative diseases. In this review, we focused on the theoretical bases and the most relevant clinical studies of EAA and glutamine supplementation as a single compound, with the aim of clarifying whether their combined use in a blend (EAAs-glutamine) could be potentially synergistic to prevent disease-related muscle wasting and its impact on the duration and quality of patients' clinical course.

The efficacy and safety of leucine-enriched essential amino acids in knee osteoarthritis patients: A randomized controlled trial.

BACKGROUND: Supplementation with leucine-enriched essential amino acids (LEAAs) has shown efficacy in the recovery of muscle injury and activation of muscle synthesis. Muscle function in knee osteoarthritis is a crucial factor for managing pain and preserving ambulatory function. However, the efficacy and safety of LEAAs supplementation in patients with knee osteoarthritis have not been evaluated. METHODS: In this prospective analysis, we evaluated the efficacy and safety of supplementation with 12 g of LEAAs daily for 8 weeks in knee-symptomatic osteoarthritis patients. For assessing the efficacy, clinical pain, calf circumference, and disability were assessed using questionnaires (visual analog scale, Knee Society Score, and 36-item short form survey [SF-36]), laboratory analyses (total protein and albumin), and radiologic study (dual-energy X-ray absorptiometry [DEXA]) for muscle and bone density. To evaluate safety, generalized or localized protein allergic reactions, complete blood count, liver and kidney function, and serum glucose were measured. RESULTS: Sixty-five participants, categorized into the experimental (n = 32) and control (n = 33) groups, were included in this 8-week trial from March 2022 to July 2022. A significantly higher efficacy was observed in the experimental group than in the control group, as indicated by muscle density in the DEXA scan (P = .001) and SF-36 (P < .001). The safety evaluation revealed no related generalized or local protein allergy. Hematological findings, serum glucose, and kidney and liver toxicity were not significantly different between the groups. CONCLUSION: Supplementation with leucine-enriched proteins is safe and efficacious in the improvement of muscle density and quality of life.

Do ketoanalogues still have a role in delaying dialysis initiation in CKD predialysis patients?

Early versus later start of dialysis is still a matter of debate. Low-protein diets have been used for many decades to delay dialysis initiation. Protein-restricted diets (0.3-0.6 g protein/kg/day) supplemented with essential amino acids and ketoanalogues (sVLPD) can be offered, in association with pharmacological treatment, to motivated stage 4-5 chronic kidney disease (CKD) patients not having severe comorbid conditions; they probably represent 30-40% of the concerned population. A satisfactory adherence to such dietary prescription is observed in approximately 50% of the patients. While the results of the studies on the effects of this diet on the rate of progression of renal failure remain inconclusive, they are highly significant when initiation of dialysis is the primary outcome. The correction of uremic symptoms allows for initiation of dialysis treatment at a level of residual renal function lower than that usually recommended. Most of the CKD-associated complications of cardiovascular and metabolic origin, which hamper both lifespan and quality of life, are positively influenced by the diet. Lastly, with regular monitoring jointly assumed by physicians and dietitians, nutritional status is well preserved as confirmed by a very low mortality rate and by the absence of detrimental effect on the long-term outcome of patients once renal replacement therapy is initiated. On account of its feasibility, efficacy and safety, sVLPD deserves a place in the management of selected patients to safely delay the time needed for dialysis.

Role of specific dietary amino acids in clinical conditions.

In a variety of chronic and acute disease states, alterations in protein synthesis, breakdown and protein turnover rates occur that are related to the loss of body protein and skeletal muscle wasting. A key observation is the stimulation of protein breakdown in muscle and the stimulation of protein synthesis in the splanchnic area; mainly liver. An altered splanchnic extraction of amino acids as well as an anabolic resistance to dietary protein, related to stress, disuse and aging play a key role in the pathogenesis of muscle wasting in these conditions. To overcome these factors, specific dietary protein and amino acid diets have been introduced. The main focus of these diets is the quantity and quality of dietary proteins and whether a balanced mixture or solely dietary essential amino acids are required with or without higher intake levels of specific amino acids. Specifically in cancer patients, stimulated muscle protein synthesis has been obtained by increasing the amount of protein in a meal and by providing additional leucine. Also in other chronic diseases such as chronic obstructive pulmonary disease and cystic fibrosis, meals with specific dietary proteins and specific combinations of dietary essential amino acids are able to stimulate anabolism. In acute diseases, a special role for the amino acid arginine and its precursor citrulline as anabolic drivers has been observed. Thus, there is growing evidence that modifying the dietary amino acid composition of a meal will positively influence the net balance between muscle protein synthesis and breakdown, leading to muscle protein anabolism in a variety of chronic and acute disease states. Specific amino acids with anabolic potential are leucine, arginine and citrulline.

The inclusion of a partial meal replacement with or without inulin to a calorie restricted diet contributes to reach recommended intakes of micronutrients and decrease plasma triglycerides: a randomized clinical trial in obese Mexican women.

BACKGROUND: Obesity is a major public health problem in many poor countries where micronutrient deficiencies are prevalent. A partial meal replacement may be an effective strategy to decrease obesity and increase micronutrient intake in such populations. The objective was to evaluate the efficacy of a partial meal replacement with and without inulin on weight reduction, blood lipids and micronutrients intake in obese Mexican women. METHODS: In a randomized controlled clinical trial 144 women (18-50 y) with BMI ≥ 25 kg/m², were allocated into one of the following treatments during 3 months: 1) Two doses/d of a partial meal replacement (PMR), 2) Two doses/d of PMR with inulin (PMR + I) , 3) Two doses/d of 5 g of inulin (INU) and 4) Control group (CON). All groups received a low calorie diet (LCD). Weight, height, hip and waist circumference were measured every 2 weeks and body composition, lipids and glucose concentration and nutrient intake were assessed at baseline and after 3 months. RESULTS: All groups significantly reduced weight, BMI, waist and hip circumference. Differences between groups were only observed in BMI and weight adjusted changes: At 45 days PMR group lost more weight than INU and CON groups by 0.9 and 1.2Kg, respectively. At 60 days, PMR + I and PMR groups lost more weight than in INU by 0.7 and 1Kg, respectively. Subjects in PMR, PMR + I and INU significantly decreased triglycerides. Energy intake was reduced in all groups. Fiber intake increased in PMR + I and INU groups. Some minerals and vitamins intakes were higher in PMR and PMR + I compared with INU and CON groups. CONCLUSION: Inclusion of PMR with and without inulin to a LCD had no additional effect on weight reduction than a LCD alone but reduced triglycerides and improved intake of micronutrients during caloric restriction. PMR could be a good alternative for obese populations with micronutrient deficiencies.

Glutamine relieves the hypermetabolic response and reduces organ damage in severe burn patients: A multicenter, randomized controlled clinical trial.

BACKGROUND: Severe burns can cause a hypermetabolic response and organ damage. Glutamine is a conditionally essential amino acid with various pharmacological effects. In this study, whether glutamine could alleviate the hypermetabolic response and maintain organ function after burn injury was analyzed. METHODS: A multicenter, randomized, single-blind, parallel controlled trial was conducted to evaluate the efficacy of glutamine in decreasing hypermetabolism after burn injury. Physiological and biochemical indexes, such as vital signs, metabolic hormones, metabolic rate, and organ damage, were recorded on the 7th and 14th days after treatment. RESULTS: In total, 55 adult burn patients with a total burn surface area (TBSA) of 30-70% were included in this study and randomly divided into the burn control (B, 28 patients) and burn+glutamine (B+G, 27 patients) groups. Except for the glutamine administration, the groups did not differ in the other treatments and nutrition supplements. The levels of diamine oxidase (DAO), lactulose/mannitol (L/M), ß2-microglobulin, lactate dehydrogenase (LDH), hydroxybutyrate dehydrogenase (HBD) and cardiac troponin l (cTnl) in the B+G group were significantly lower than those in the B group (p < 0.05 or 0.01). The levels of resting energy expenditure (REE), serum catecholamines, glucagon, lactate and Homeostasis model assessment (HOMA) in the B+G group were significantly lower than those in the B group (p < 0.05 or 0.01). No significant difference was found in the length of hospitalization or the mortality rate between the two groups (p > 0.05). CONCLUSIONS: Glutamine moderately alleviates the hypermetabolic response and reduces organ damage after severe burns. Therefore, the early application of glutamine, which is effective and safe, should be used as an active intervention as early as possible.

Sirpiglenastat (DRP-104) Induces Antitumor Efficacy through Direct, Broad Antagonism of Glutamine Metabolism and Stimulation of the Innate and Adaptive Immune Systems.

Glutamine is a conditionally essential amino acid consumed by rapidly proliferating cancer cells, which deprives the same fuel from immune cells and contributes to tumor immune evasion. As such, the broad antagonism of glutamine in tumors and the tumor microenvironment may lead to direct antitumor activity and stimulation of antitumoral immune responses. DRP-104 (sirpiglenastat) was designed as a novel prodrug of the broad-acting glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON). DRP-104 is an inactive form that is preferentially converted to DON within tumors. Metabolomic profiling of tumors treated with DRP-104 revealed widespread changes indicative of the disruption of tumor anabolism and canonical cancer metabolism pathways; including altered glutamine metabolism while several immunosuppressive metabolites were decreased. Gene expression profiling revealed broad immunological modulation, confirmed by flow cytometry indicating that DRP-104 treatment resulted in substantial and broad changes in various immune cell infiltrates, such as increased TIL, T, NK, and NK T cells. Functionally, T cells became more proliferative and less exhausted; tumor-associated macrophages were polarized to the M1 phenotype; MDSCs and protumorigenic proteins were decreased in TME. Finally, DRP-104 demonstrated significant antitumor activity as a monotherapy, which was further enhanced in combination with checkpoint blockade therapies, leading to improved survival and long-term durable cures. In summary, DRP-104 broadly remodels the tumor microenvironment by inducing extensive tumor metabolism effects and enhancing the infiltration and function of multiple immune cells distinct from those obtained by checkpoint inhibitor therapy. This unique mechanism of action supports the ongoing clinical development of DRP-104 alone and in combination with checkpoint inhibitors.

Prevention of Loss of Muscle Mass and Function in Older Adults during COVID-19 Lockdown: Potential Role of Dietary Essential Amino Acids.

As the COVID-19 pandemic became a global emergency, social distancing, quarantine, and limitations in outdoor activities have resulted in an environment of enforced physical inactivity (EPI). A prolonged period of EPI in older individuals accelerates the deterioration of skeletal muscle health, including loss of muscle mass and function, commonly referred to as sarcopenia. Sarcopenia is associated with an increased likelihood of the progression of diabetes, obesity, and/or depression. Well-known approaches to mitigate the symptoms of sarcopenia include participation in resistance exercise training and/or intake of balanced essential amino acids (EAAs) and high-quality (i.e., containing high EEAs) protein. As the pandemic situation discourages physical exercise, nutritional approaches, especially dietary EAA intake, could be a good alternative for counteracting against EPI-promoted loss of muscle mass and function. Therefore, in the present review, we cover (1) the impact of EPI-induced muscle loss and function on health, (2) the therapeutic potential of dietary EAAs for muscle health (e.g., muscle mass and function) in the EPI condition in comparison with protein sources, and finally (3) practical guidelines of dietary EAA intake for optimal anabolic response in EPI.

A randomised feasibility study of EPA and Cox-2 inhibitor (Celebrex) versus EPA, Cox-2 inhibitor (Celebrex), resistance training followed by ingestion of essential amino acids high in leucine in NSCLC cachectic patients--ACCeRT study.

BACKGROUND: Cancer cachexia is a syndrome of progressive weight loss. Non-small cell lung cancer patients experience a high incidence of cachexia of 61%. Research into methods to combat cancer cachexia in various tumour sites has recently progressed to the combination of agents.The combination of the anti-cachectic agent Eicosapentaenoic acid (EPA) and the cyclo-oxygenase-2 (COX-2) inhibitor celecoxib has been tested in a small study with some benefit. The use of progressive resistance training (PRT) followed by the oral ingestion of essential amino acids (EAA), have shown to be anabolic on skeletal muscle and acceptable in older adults and other cancer groups.The aim of this feasibility study is to evaluate whether a multi-targeted approach encompassing a resistance training and nutritional supplementation element is acceptable for lung cancer patients experiencing cancer cachexia. METHODS/DESIGN: Auckland's Cancer Cachexia evaluating Resistance Training (ACCeRT) is an open label, prospective, randomised controlled feasibility study with two parallel arms. All patients will be treated with EPA and the COX-2 inhibitor celecoxib on an outpatient basis at the study site. In the experimental group patients will participate in PRT twice a week, followed by the ingestion of essential amino acids high in leucine. A total of 21 patients are planned to be enrolled. Patients will be randomised using 1:2 ratio with 7 patients enrolled into the control arm, and 14 patients into the treatment arm. The primary endpoint is the acceptability of the above multi-targeted approach, determined by an acceptability questionnaire. DISCUSSION: To our knowledge ACCeRT offers for the first time the opportunity to investigate the effect of stimulating the anabolic skeletal muscle pathway with the use of PRT along with EAA alongside the combination of EPA and celecoxib in this population. TRIAL REGISTRATION: Netherlands Trial Register (NTR): ACTRN12611000870954.

Essential amino acid supplementation decreases liver damage induced by chronic ethanol consumption in rats.

The liver sustains the greatest damage from ethanol (EtOH) abuse. EtOH and its metabolites impair hepatocyte metabolism, causing intracellular accumulation of proteins and lipids and increasing radical oxygen species production. These processes are toxic to the mitochondrial respiratory chain and to mitochondrial DNA. We have recently shown that supplementating the diet of rodents with an essential amino acid-enriched mixture (EAAem) significantly increases mitochondrial mass and number in cardiac and skeletal muscles and improves mitochondrial function in aged animals. Thus, in this study we sought to test whether EAAem supplementation could reduce EtOH-induced liver damage. Groups of adult male Wistar rats were fed a standard diet and water ad libitum (the control group), drinking water with 20 percent EtOH (the EtOH group), or drinking water with 20 percent EtOH and EAAem supplementation (1.5 g/kg/day) (the EtOH+EAAem group) for 2 months. The blood EtOH concentration was measured, and markers for fat (Oil-Red-O), mitochondria (Grp75, Cyt-c-ox), endoplasmic reticulum (Grp78), and inflammation (Heme Oxigenase 1, iNOS, and peroxisomes) were analyzed in the liver of animals in the various experimental groups. EAAem supplementation in EtOH-drinking rats ameliorated EtOH-induced changes in liver structure by limiting steatosis, recruiting more mitochondria and peroxisomes mainly to perivenous hepatocytes, stimulating or restoring antioxidant markers, limiting the expression of inflammatory processes, and reducing ER stress. Taken together, these results suggest that EAAem supplementation may represent a promising strategy to prevent and treat EtOH-induced liver damage.