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Introduction: Since its discovery in the early 1900s, sickle cell disease (SCD) has contributed significantly to the scientific understanding of hemoglobin and hemoglobinopathies. Despite this, now almost a century later, optimal medical management and even curative options remain limited. Encouragingly, in the last decade, there has been a push toward advancing the care for individuals with SCD and a diversifying interest in options to manage this disorder. Areas Covered: Here, we review the current state of disease modifying therapies for SCD including fetal hemoglobin inducers, monoclonal antibodies, anti-inflammatory modulators, and enzyme activators. We also discuss current curative strategies with specific interest in transformative gene therapies. Expert Opinion: SCD is a chronic, progressive disease that despite a century of clinical description, only now is seeing a growth and advance in therapeutic options to improve the lifespan and quality of life for individuals with SCD. We anticipate newly designed and even repurposed therapies that may work as a single agent or combination agents to tackle the progression of SCD. The vast majority of individuals living with SCD are unlikely to receive gene therapy, therefore improved disease management is critical even for those that may ultimately chose to pursue a potentially curative strategy. [ABSTRACT FROM AUTHOR]

Zeel Vishnubhai Patel,1 Priyadarshi Prajjwal,2 Lakshmi Deepak Bethineedi,3 Divyakshi J Patel,4 Kaarvi Khullar,5 Hinal Patel,6 Kanishka Khatri,2 Mohammed Dheyaa Marsool Marsool,7 Srikanth Gadam,8 Soumya Aleti,9 Omniat Amir10 1Internal Medicine, Medical College Baroda, Baroda, Gujarat, India; 2Internal Medicine, Bharati Vidyapeeth University Medical College, Pune, India; 3Internal Medicine, Andhra Medical College, Visakhapatnam, Andhra Pradesh, India; 4Internal Medicine, Smt. NHL Municipal Medical College, Ahmedabad, India; 5Internal Medicine, Maharashtra University of Health Sciences, Government Medical College, Gondia, India; 6Internal Medicine, GMERS Medical College and Hospital Sola, Ahmedabad, India; 7Internal Medicine, University of Baghdad, Al-Kindy College of Medicine, Baghdad, Iraq; 8Internal Medicine, NYC Health+ Hospitals, New York, NYC, USA; 9Internal Medicine, Berkshire Medical Center, Pittsfield, MA, USA; 10Internal Medicine, Al Manhal Academy of Science, SudanCorrespondence: Omniat Amir, Internal Medicine, Al Manhal Academy of Science, Khartoum, 1442, Sudan, Email omniatamir123@gmail.comAbstract: Sickle cell disease (SCD), the most common autosomal recessive genetic disorder, affects the hemoglobin (Hb) chains in human red blood cells. It is caused by mutations in the β-globin genes, leading to the production of hemoglobin S, which results in the formation of sickle-shaped red blood cells (RBCs). These abnormal cells cause hemolysis, endothelial damage, and small vessel occlusion, leading to both acute and long-term complications. According to the World Health Organization’s 2008 estimates, SCD affects approximately 2.28 per 1000 individuals globally. Despite this high prevalence, therapeutic advancements have been slow. For many years, the only FDA-approved medications for managing SCD complications were hydroxyurea and deferiprone. However, recent years have seen the approval of several new therapies, including L-glutamine (2017), voxelotor and crizanlizumab (2019), as well as exagamglogene autotemcel (Casgevy) and lovotibeglogene autotemcel (Lyfgenia) (2023). These treatments have proven effective in managing both the acute and chronic effects of SCD, including hemolytic anemia, chronic pain, stroke, vaso-occlusive crises, and multiple organ damage syndromes. This review explores the mechanisms of action, practical considerations, and side effects of these emerging therapies, drawing from a comprehensive search of databases such as PubMed, Medline, and Cochrane.Keywords: sickle cell disease, L-Glutamine, Voxelotor, Crizanlizumab, Casgevy, Lyfgenia

To evaluate the safety and efficacy of L-glutamine in reducing vaso-occlusive crisis (VOC) and improving cerebral arterial blood flow in children with sickle cell disease (SCD). This is an interventional randomized controlled trial that recruited sixty SCD patients, aged 9.2 ± 3.7 years, who had at least two VOCs during the last 12 months and on a stable dose of hydroxyurea. They were randomly assigned in a 1:1 ratio to receive glutamine (0.3 gm/kg/dose/12h) orally for 24 weeks or the standard of care (SOC). All patients had VOCs in the last year > 3, those on glutamine had a higher number of VOCs and hospitalization for VOC in the last year. There was a decreasing trend in the number, severity, and hospitalization of VOC and a significantly lower cumulative number of VOCs and hospitalizations in the glutamine group than in SOC (p = 0.008, p < 0.001 respectively). Time-averaged mean maximum velocity for the glutamine group had a marginal increase in both middle cerebral arteries, all values remained normal within a normal range, and in both internal carotid arteries, values increased from abnormally low to normal ranges at week 24. Glutamine reduced the number of VOCs and severity and may have a potentially favorable impact on the cerebral arterial flow velocities. [ABSTRACT FROM AUTHOR]

Summary: The mechanisms of action of l‐glutamine for the treatment of sickle cell disease (SCD) are not well understood and there are no validated clinical biomarkers to assess response. We conducted a three‐week, dose‐ascending trial of glutamine and measured the pharmacokinetic (PK) exposure parameters, peak concentration (Cmax) and area under the curve (AUC). We used a panel of biomarkers to investigate the pharmacodynamics (PD) of glutamine and studied PK–PD relationships. There was no plasma accumulation of glutamine, glutamate, arginine or other amino acids over time, but modestly improved arginine bioavailability was observed. In standard analysis by dose levels over time, there were no measurable effects on blood counts, viscosity, ektacytometry or reactive oxygen species (ROS). In PK–PD analysis, however, higher glutamine exposure (Cmax or AUC) was associated with increased whole blood viscosity and cellular dehydration, yet also with higher haemoglobin concentration, increased haematocrit‐to‐viscosity ratio, decreased reticulocyte ROS, improved RBC deformability and decreased point of sickling. This novel PK–PD analysis identified biomarkers reflecting the positive and negative effects of glutamine, helping to elucidate its mechanisms of action in SCD. PK‐optimized dosing to achieve glutamine exposure (AUC or Cmax) that is associated with salutary biological effects should be studied to support its therapeutic use. [ABSTRACT FROM AUTHOR]

Advanced pancreatic cancer is underscored by progressive therapeutic resistance and a dismal 5-year survival rate of 3%. Preclinical data demonstrated glutamine supplementation, not deprivation, elicited antitumor effects against pancreatic ductal adenocarcinoma (PDAC) alone and in combination with gemcitabine in a dose-dependent manner. The GlutaPanc phase I trial is a single-arm, open-label clinical trial investigating the safety of combination L-glutamine, gemcitabine, and nab-paclitaxel in subjects (n = 16) with untreated, locally advanced unresectable or metastatic pancreatic cancer. Following a 7-day lead-in phase with L-glutamine, the dose-finding phase via Bayesian design begins with treatment cycles lasting 28 days until disease progression, intolerance, or withdrawal. The primary objective is to establish the recommended phase II dose (RP2D) of combination L-glutamine, gemcitabine, and nab-paclitaxel. Secondary objectives include safety of the combination across all dose levels and preliminary evidence of antitumor activity. Exploratory objectives include evaluating changes in plasma metabolites across multiple time points and changes in the stool microbiome pre and post L-glutamine supplementation. If this phase I clinical trial demonstrates the feasibility of L-glutamine in combination with nab-paclitaxel and gemcitabine, we would advance the development of this combination as a first-line systemic option in subjects with metastatic pancreatic cancer, a high-risk subgroup desperately in need of additional therapies.

In 2022, sickle cell disease (SCD) continues to affect the lives of millions of people, being one of the most frequently inherited blood disorders worldwide. Recently, several new therapies have been FDA approved for the treatment of SCD. The complexity of the pathophysiology of sickling has given opportunity to the evolution of several modalities of therapies. Nonetheless, the potential for complementary targeting of HbS polymerization, vasocclusion, and other inflammatory pathways remains controversial. None of these drugs can be considered a single curative line of treatment. With the advancement of CRISPR/Cas9 technology, autologous transplant of gene-edited hematopoietic stem cells could possibly provide a cure for most patients with SCD. The advantage of this approach over the conventional stem cell transplantation is that it decreases the need for immuno-suppressive drugs and the risk of graft-versus-host disease. In addition, recent technological advances can reduce the off-target effects, but long-term monitoring is needed to ensure the reliability of these methods in the clinical setting. This review explores the efficacy and safety of combination therapies and contrasting this alternative with the challenges that exist with sickle cell gene therapy using CRISPR. [ABSTRACT FROM AUTHOR]

Bile acid-induced hepatotoxicity is inevitable in Cholestasis pathogenesis and L-Glutamine (L-Gln) has been reported to prevent total parenteral nutrition (TPN)-induced cholestasis in premature neonates. While mechanisms remain unknown, we hypothesize that bile acids impair growth factor (GF) function in hepatocytes which L-glutamine prevents through NAPDH oxidase (NOX) modulation. Glycochenodeoxycholic acid (GCDC, 0–100 µM) when added to primary hepatocyte cultures significantly (p < 0.01) decreased the FBS-induced BrdU incorporation, however inhibition of Fibroblast Growth factor (FGF)- or Hepatocyte growth factor (HGF)-induced DNA synthesis was more pronounced (p < 0.001). L-Gln markedly attenuated GCDC-mediated inhibition of DNA synthesis in both FBS and GF-treated cells. GCDC significantly increased the NADPH oxidase activity and NOX-1 protein expression that were markedly reduced by L-Gln and protein kinase c (PKC) inhibitor, LY-333531. Apocynin (APCN) and diphenyliodonium (DPI) significantly blocked the GCDC-mediated inhibition of GF-induced DNA synthesis. This study demonstrates that bile acid-induced hepatotoxicity involves dysfunction of certain growth factors via protein kinase c (PKC)- mediated NOX modulation which can be corrected, at least partly, by L-glutamine. [ABSTRACT FROM AUTHOR]

Introduction: Glutamine is a non-essential amino acid that is critical for cell growth. However, the differential metabolism of l-glutamine in metastatic versus primary colorectal cancer (CRC) has not been evaluated adequately. Materials and methods: Differential expression of glutamine-related genes was determined in primary versus metastatic CRC. Univariate Cox regression and hierarchical clustering were used to generate a gene signature for prognostication. Untargeted metabolomics and 18O based fluxomics were used to identify differential metabolite levels and energy turnover in the paired primary (SW480) and metastatic (SW620) CRC cells. Western blot and qRT-PCR were used to validate differential gene expression. Subcellular localization of E-cadherin was determined by immunocytochemistry. Lipid droplets were visualized with Nile Red. Results: The GO term “Glutamine metabolism” was significantly enriched in metastatic versus primary tumors. Supporting this, SW620 cells showed decreased membrane localization of E-cadherin and increased motility upon l-Glutamine withdrawal. A glutamine related signature associated with worse prognosis was identified and validated in multiple datasets. A fluxomics assay revealed a slower TCA cycle in SW480 and SW620 cells upon l-Glutamine withdrawal. SW620 cells, however, could maintain high ATP levels. Untargeted metabolomics indicated the preferential metabolism of fatty acids in SW620 but not SW480 cells. Lipids were mainly obtained from the environment rather than by de novo synthesis. Conclusions: Metastatic CRC cells can display aberrant glutamine metabolism. We show for the first time that upon l-glutamine withdrawal, SW620 (but not SW480) cells were metabolically plastic and could metabolize lipids for survival and cellular motility.

Clonal breeding programs of Pinus maximinoi require the establishment of a robust somatic embryogenesis (SE) protocol to produce enough cell lines to accelerate the effective continuous deployment of elite planting stocks to research and commercial compartments. Somatic embryogenesis was induced from immature zygotic embryo explants enclosed in megagametophytes of P. maximinoi collected from two plantations located in different climatic conditions. Cones were collected during the winter months from July to August and the influence of seed family, cone collection date and culture medium formulation, with emphasis on the organic and inorganic nitrogen supply, were studied. Ammonium to nitrate molar ratios of 1:1 and 1:2 in modified Litvay’s medium (mLV) produced the highest numbers of extrusions, while a 1:4 ratio mostly produced unhealthy, non-embryogenic extrusions. The formation of a tissue showing a rapidly-proliferating, spiky morphotype was produced in a medium supplemented with 1.5 g/L of L-glutamine. Morphologically advanced cultures with nodular structures were produced in megagametophytes from both plantations in a 1:2 NH4+:NO3− medium regardless of L-glutamine supplementation levels. The optimal medium for P. maximinoi SE induction contained a 1:2 NH4+:NO3− molar ratio with 1.5 g/L L-glutamine. The synergy between the molar ratio of NH4+:NO3− and L-glutamine resulted in the highest numbers of extrusions. The overall inductive competence window for somatic embryogenic response in P. maximinoi was determined to be from the second week of July to the first week of August for both plantations. The “peak” period was in the fourth week of July 2022. The success of the SE technology in P. maximinoi seed families is determined by the optimal inductive competence window of the immature megagametophytes enclosing zygotic embryos and the chemical composition of the induction medium in terms of the ammonium to nitrate molar ratio and the concentration of the L-glutamine used.Key Message: Interaction between the collection date, genotype of the seed family and nitrogen content of the medium determine the somatic embryogenesis capacity of immature zygotic embryos at the optimal developmental stage. [ABSTRACT FROM AUTHOR]

Illegal extraction of the heart of palm is threatening Euterpe edulis Martius with extinction. Here, we investigated the induction of somatic embryogenesis in segments of E. edulis seedlings as a means of propagating this palm species. Immature seeds were harvested from the wild and germinated in vitro. After 6 months, the seedlings were excised in the middle of the caulicle and cut either transversely into two explants, or longitudinally with the wounded surface face down, up or sideways on the medium, supplemented with picloram 150 µM. Friable calli formed from upward facing explants were transferred to a suspension culture with different concentrations of picloram (15, 25, 35, and 45 µM) and then matured in the presence of abscisic acid (1, 5, 10, and 20 µM). Explants derived from upward facing segments were placed in culture medium containing l-glutamine or hydrolyzed casein (0.0, 0.5, and 1.0 g L−1). Induction in medium with 150 µM picloram was strongest for stems with longitudinal wounds positioned upward and/or sideways; while medium with 15 µM picloram enabled strong growth of friable calli. The highest average number of proembryos (16.33) was obtained with 1.0 g L−1 hydrolyzed casein and differentiation of somatic embryos was greatest with 1 µM abscisic acid. Therefore, somatic embryogenesis of E. edulis is best achieved by placing segments from longitudinally wounded stems face up on medium containing 150 µM picloram, followed by suspension cultivation with 15 µM picloram and maturation with 1 µM abscisic acid. Key message: The type of injury caused to the explant, and the orientation in which it is placed in the culture medium, directly influences the embryogenic response. [ABSTRACT FROM AUTHOR]

Athletes often take sport supplements to reduce fatigue and immune disturbances during or after training. This study evaluated the acute effects of concurrent ingestion of alkaline water and L-glutamine on the salivary immunity and hormone responses of boxers after training. Twelve male boxing athletes were recruited in this study. During regular training, the participants were randomly divided into three groups and asked to consume 400 mL of alkaline water (Group A), 0.15 g/kg body weight of L-glutamine with 400 mL of water (Group G), and 0.15 g/kg of L-glutamine with 400 mL of alkaline water (Group A+G) at the same time each day for three consecutive weeks. Before and immediately after the training, saliva, heart rates, and the rate of perceived exertion were investigated. The activity of α-amylase and concentrations of lactoferrin, immunoglobulin A (IgA), testosterone, and cortisol in saliva were measured. The results showed that the ratio of α-amylase activity/total protein (TP) significantly increased after training in Group A+G but not in Group A or G, whereas the ratios of lactoferrin/TP and IgA/TP were unaffected in all three groups. The concentrations of salivary testosterone after training increased significantly in Group A+G but not in Group A or G, whereas the salivary cortisol concentrations were unaltered in all groups. In conclusion, concurrent ingestion of 400 mL of alkaline water and 0.15 g/kg of L-glutamine before training enhanced the salivary α-amylase activity and testosterone concentration of boxers, which would be beneficial for post-exercise recovery. [ABSTRACT FROM AUTHOR]

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The protection of implant surfaces from biofilm and corrosion is crucial for osteogenesis and tissue engineering. To this end, an L-glutamine-based green corrosion inhibitor with recently established anticancer properties has been applied onto antibacterial Cu(111) surfaces that usually cover the Ti-based implants. Among several configurations, L-glutamine prefers the parallel to the surface orientation with the carbon chain along the [110] direction having the heteroatoms N and O atoms on top of Cu surface atoms, which is important for the creation of a planar two-dimensioned (2d) stable coating. L-glutamine forms well-localized, directional covalent-like bonded states (below −3 eV) with the Cu surface atoms, using mainly its backbone's N1 atom that interestingly also shows electron charge occupation in the single-molecule highest occupied state, denoting its ability as an active center. The Mulliken analysis shows charge transfer from the molecule's N, C and Cu neighboring atoms towards the O atoms revealing the strong bond tendency of L-glutamine and therefore its ability to act as a corrosion inhibitor on the Cu surface. Additional L-glutamine adsorption results in intermolecular covalent bonding between the molecules, proving the ability of this amino acid to form a stable protective 2d organic coating on Cu(111). These results could be used for the design of a multifunctional hybrid (organic–metallic) coating with anticorrosion, anticancer and antibacterial properties suitable for many technological applications. [ABSTRACT FROM AUTHOR]

BackgroundSickle cell disease (SCD) is a rare genetic blood condition affecting millions worldwide. Oxidative stress is a key player in the pathogenesis of SCD and its comorbid consequences. Renal function impairment is a common complication of SCD in both pediatric and adult patients with serious consequences leading to increased risk of mortality. In this observational real-world study, we are reporting the long-term (120 weeks) renal function in 10 patients treated with L-glutamine.MethodsTen patients (4 pediatric and 6 adults), with confirmed diagnoses of SCD (HbSS genotype), were enrolled, these included four patients from Qatar with Arab Indian haplotype and six patients from French Guiana with African haplotype. All patients were treated with L-glutamine oral powder (~0.3 g/kg body weight, Endari®) twice daily for 120 weeks. Clinical events and laboratory parameters (renal function, hemoglobin, reticulocytes, and lactate dehydrogenase [LDH]) were measured at baseline, 48, and 120 weeks.ResultsThe study showed that with L-glutamine treatment there were improvements in renal and hematological parameters with no vaso-occlusive crisis at both 48-and 120-week follow-up time points in all 10 patients. Improvements were seen in the albumin creatinine ratio (ACR) from baseline to 48 weeks (mean [Standard deviation SD] ACR: −4.19 [9.81] mg/g) and 120 weeks (mean [SD] ACR: −12.31 [21.09] mg/g). Mean (SD) increase in hemoglobin concentrations from baseline to 48 weeks and 120 weeks was 0.72 (1) g/dL and 1.41 (0.79) g/dL, respectively. Mean (SD) reticulocyte counts and LDH levels decreased from baseline to 48 weeks (mean [SD] change from baseline to 48 weeks, reticulocyte counts: −40.30 [101.58] × 109 cells/L; LDH levels: −259 [154.93] U/L) and 120 weeks (mean [SD] change from baseline to 120 weeks, reticulocyte counts: −58.30 [128.38] × 109 cells/L; LDH levels: −344.80 [274.63] U/L).ConclusionThis is one of the first studies that assessed the long-term renal outcomes in SCD using L-glutamine. L-glutamine improved the renal function in patients with SCD along with improvements in clinical outcomes and hemolysis, from 48 weeks and sustained through 120 weeks of treatment.

ABSTRACT Enterohemorrhagic Escherichia coli (EHEC) can colonize the gastrointestinal tract and cause bloody diarrhea in children. Previous studies showed that its pathogenesis could be mediated by metabolites from both the host and microbiota. L-Glutamine (Gln) was found to be depleted in intestinal tissues as the main energy source according to previous studies. Hence, we aimed to determine the effects of Gln on EHEC infection and its underlying mode of action. In this study, a Gln-limited signal was found to activate the type 3 secretion system (T3SS), which is crucial for EHEC infection via perturbation of central metabolism. By shifting the phosphorylation of NtrC, a key regulator in bacterial nitrogen metabolism, Gln stimulates ler transcripts in a σS-PchA-dependent manner. Our in vivo experiments further demonstrated that Gln supplementation can reduce EHEC colonization in the gastrointestinal tract by repressing T3SS. Moreover, Gln could further attenuate bacterial infection by boosting host defense, which might be dependent on multiple pathways. Besides, our experiments demonstrated that Gln did not induce Shiga-like toxin (Stx) production or cause impairment of gut flora. In conclusion, our study presented evidence that Gln could act against EHEC infection by reducing bacterial virulence and strengthening host defense. Therefore, Gln serves as a promising therapeutic agent for EHEC infection. IMPORTANCE The type 3 secretion system (T3SS) was obtained in many Gram-negative bacterial pathogens, and it is crucial for their pathogenesis. Environmental signals were found to be involved in the expression regulation of T3SS, which was vital for successful bacterial infection in the host. Here, we discovered that L-glutamine (Gln), the most abundant amino acid in the human body, could repress enterohemorrhagic Escherichia coli (EHEC) T3SS expression via nitrogen metabolism and therefore had potential as an antivirulence agent. Our in vitro and in vivo evidence demonstrated that Gln could decline EHEC infection by attenuating bacterial virulence and enhancing host defense simultaneously. We repurpose Gln as a potential treatment for EHEC infection accordingly.

ABSTRACT Because of the stubborn resistance to antibiotics, treating clinically resistant bacteria is a tricky business. Although considerable attention has been devoted to preventing and treating infections from drug-resistant bacteria, few studies are available on combining metabolites and antibiotics to combat methicillin-resistant Staphylococcus aureus (MRSA). This study found that exogenous L-glutamine potentiated aminoglycoside (gentamicin)-mediated killing efficacy in a dose- and time-dependent manner in MRSA (USA300 cell line) and other Gram-positive-resistant bacteria including MRSA 252, Listeria monocytogenes, and Corynebacterium diphtheriae. L-glutamine promoted the uptake of gentamicin through increasing the membrane permeability and was correlated with disrupted pH gradient. Furthermore, L-glutamine decreased intracellular reactive oxygen species by glutathione, which also increased USA300 sensitivity to gentamicin. We also demonstrated that combined treatment with gentamicin and L-glutamine enhanced the survival of MRSA-infected mice. In conclusion, we developed a promising therapeutic strategy for treating Gram-positive-resistant bacterial infections. IMPORTANCE Methicillin-resistant Staphylococcus aureus (MRSA) infection severely threatens human health due to high morbidity and mortality; it is urgent to develop novel strategies to tackle this problem. Metabolites belong to antibiotic adjuvants which improve the effect of antibiotics. Despite reports of L-glutamine being applied in antibiotic adjuvant for Gram-negative bacteria, how L-glutamine affects antibiotics against Gram-positive-resistant bacteria is still unclear. In this study, L-glutamine increases the antibacterial effect of gentamicin on MRSA, and it links to membrane permeability and pH gradient (ΔpH), resulting in uptake of more gentamicin. Of great interest, reduced reactive oxygen species (ROS) by glutathione was found under L-glutamine treatment; USA300 becomes sensitive again to gentamicin. This study not only offers deep understanding on ΔpH and ROS on bacterial resistance but also provides potential treatment solutions for targeting MRSA infection.

Sickle cell disease (SCD) is heterogeneous in terms of manifestation severity, even more so when in compound heterozygosity with beta-thalassemia. The aim of the present study was to stratify βSβ+ patient blood samples in a severity-dependent manner. Blood from thirty-two patients with HbS/β-thalassemia compound heterozygosity was examined for several parameters (e.g., hemostasis, inflammation, redox equilibrium) against healthy controls. Additionally, SCD patients were a posteriori (a) categorized based on the L-glutamine dose and (b) clustered into high-/low-RDW subgroups. The patient cohort was characterized by anemia, inflammation, and elevated coagulation. Higher-dose administration of L-glutamine was associated with decreased markers of inflammation and oxidation (e.g., intracellular reactive oxygen species) and an altered coagulation profile. The higher-RDW group was characterized by increased hemolysis, elevated markers of inflammation and stress erythropoiesis, and oxidative phenomena (e.g., membrane-bound hemoglobin). Moreover, the levels of hemostasis parameters (e.g., D-Dimers) were greater compared to the lower-RDW subgroup. The administration of higher doses of L-glutamine along with hydroxyurea seems to attenuate several features in SCD patients, probably by enhancing antioxidant power. Moreover, anisocytosis may alter erythrocytes' coagulation processes and hemolytic propensity. This results in the disruption of the redox and pro-/anti-inflammatory equilibria, creating a positive feedback loop by inducing stress erythropoiesis and, thus, the occurrence of a mixed erythrocyte population. [ABSTRACT FROM AUTHOR]

We previously reported that L-glutamine reduces the severity of mucositis caused by chemoradiotherapy in patients with head and neck cancer. However, the impact of glutamine on the anti-tumor effect of chemoradiotherapy remains controversial. This study, which included 40 patients, investigated whether L-glutamine influences survival. Radiation therapy (total: 66 or 70 Gy), cisplatin, and docetaxel were co-administered for a period of 6 weeks. Patients were randomly assigned to receive either glutamine (glutamine group, n = 20) or placebo (placebo group, n = 20) during the entire course of chemoradiotherapy. We compared the overall survival and progression-free survival rates between the two groups. At 5-year follow-up, 16 (80%) and 13 (72%) patients in the glutamine and placebo groups, respectively, survived (with no significant difference in overall survival [glutamine group: 55.2 ± 12.7 months vs. placebo group: 48.3 ± 21.3 months]). A total of 14 (70%) and 12 (67%) patients in the glutamine and placebo groups, respectively, did not experience disease progression (with no significant difference in progression-free survival [glutamine group: 46.7 ± 19.5 months vs. placebo group: 43.6 ± 25.2 months]). These findings indicate that L-glutamine does not influence the survival of patients with locally advanced head and neck cancer receiving chemoradiotherapy. [ABSTRACT FROM AUTHOR]

Sickle cell disease (SCD) is an autosomal recessive monogenic disorder caused by a homozygous mutation in the β-globin gene, which leads to erythrocyte sickling, hemolysis, vaso-occlusion, and sterile inflammation. The administration of oral L-glutamine has been shown to reduce the frequency of pain in SCD patients; however, the long-term effect of L-glutamine in SCD remains to be determined. To understand the long-term effect of L-glutamine administration in the liver we used quantitative liver intravital microscopy and biochemical analysis in humanized SCD mice. We here show that chronic L-glutamine administration reduces hepatic hemoglobin–heme–iron levels but fails to ameliorate ischemic liver injury. Remarkably, we found that this failure in the resolution of hepatobiliary injury and persistent liver fibrosis is associated with the reduced expression of hepatic Kupffer cells post-L-glutamine treatment. These findings establish the importance of investigating the long-term effects of L-glutamine therapy on liver pathophysiology in SCD patients. [ABSTRACT FROM AUTHOR]

Abstract With the rising demand for entry to extremely high altitudes (HAs), rapid adaptability to extremely hypoxic environments is a challenge that we need to explore. Fasting was used to evaluate acute hypoxia tolerance at HA and was proven to be an effective method for improving the survival rate at extreme HA. Our experiments also showed that fasting pretreatment for 72 h significantly increased the 24 h survival rate of rats at 7620 m from 10 to 85% and protected the myocardium cells of rats. Here, we compared the metabolites and gene expression in the myocardium of SD rats pretreated with fasting and nonfasting at normal altitude and extreme HA. Our findings demonstrated that the dynamic contents of detected differential metabolites (DMs) between different rat groups were consistent with the expression of differentially expressed genes (DEGs), and DM clusters also showed strong correlations with DEG clusters. DM clusters related to amino acids and lipids were significantly lower in the fasting groups, and the correlated DEG clusters were enriched in mitotic pathways, including CDK1, CDC7, NUF2, and MCM6, suggesting that fasting can attenuate mitotic processes in cardiac tissues and reduce the synthesis of amino acids and lipids. L-Glutamine-related metabolites were particularly low at extreme HA without pretreatment but were normal in the fasting groups. The DEGs in the cluster related to L-glutamine-related metabolites were enriched for T-cell receptor V(D)J recombination, the Hippo signaling pathway, the Wnt signaling pathway, the cGMP-PKG signaling pathway, and the mTOR signaling pathway and were significantly downregulated, indicating that the content of L-glutamine decreased at extreme HA, while fasting increased it to adapt to the environment. Moreover, abundant fatty acids were detected when rats were exposed to extreme HA without pretreatment. Our study revealed the fasting and hypoxic environment-related factors in SD rats and provided new insights into the genetic and molecular characteristics in the myocardium, which is critical to developing more potential rapid adaptation methods to extreme HA.

Background: Bronchopulmonary dysplasia (BPD) is one of the major complications of prematurity resulting in significant mortality and morbidity. Reactive oxygen species, which are highly reactive molecules that can cause oxidative damage to lung tissue and trigger inflammatory reactions, are associated with pathophysiological changes in many lung diseases, such as BPD. Hydrogen peroxide (H2O2), which is a strong oxidant, is widely used in simulating cellular oxidative damage. Whether glutamine can protect lung cells from oxidant damages is not known. Objectives: To explore the cytotoxic mechanisms of H2O2 on lung cells, including A549 and HEL299 cells, and investigate the effects of L-glutamine in the protection of oxidative damage on the lung cells. Methods: Cytotoxic effects of H2O2 and the protective effects of glutamine against H2O2 on lung cells were accessed by the cell viability assay. The underlying mechanisms for H2O2 damaging lung cells were analyzed by the flow cytometry to quantify changes in mitochondrial membrane potential before and after H2O2 and L-glutamine were added into lung cells. Pulmonary alveolar epithelial cells line, A549, and human embryonic bronchial fibroblast cell line, HEL 299, were grown in the incubator. H2O2 with and without L-glutamine was added in the lung cells, and cell viability was measured by the water-soluble tetrazolium 1 (WST-1) assay and the changes of mitochondrial membrane potential by the flow cytometry. Statistical analysis used is as follows: data comparisons from cell proliferation studies were analyzed by one-way analysis of variance. The quantification data of the mitochondrial potential assay was analyzed by Student’s t tests. A P-value of less than 0.05 was considered statistically significant. Results: A total of 100-μM H2O2 significantly decreased the viability of A549 and HEL299 cells; 8-mM L-glutamine rescued lung cell death caused by the H2O2 toxicity; and 100 μM of mitochondrial membrane potential was significantly elevated in HEL299 cells, except A549 cells in the application of H2O2 and L-glutamine. Conclusion: H2O2-induced cytotoxicity in A549 and HEL299 cells was associated with mitochondria. The different effects of L-glutamine on A549 and HEL299 cells in response to the 100 μM of H2O2-induced cytotoxicity suggest that these two cell lines may have different mechanisms against oxidative stress.

The outbreak of coronavirus disease 2019 (COVID‐19) has caused a worldwide pandemic since 2019. A metabolic disorder is a contributing factor to deaths from COVID‐19. However, the underlying mechanism of metabolic dysfunction in COVID‐19 patients and the potential interventions are not elucidated. Here targeted plasma metabolomic is performed, and the metabolite profiles among healthy controls, and asymptomatic, moderate, and severe COVID‐19 patients are compared. Among the altered metabolites, arachidonic acid and linolenic acid pathway metabolites are profoundly up‐regulated in COVID‐19 patients. Arginine biosynthesis, alanine, aspartate, and glutamate metabolism pathways are significantly disturbed in asymptomatic patients. In the comparison of metabolite variances among the groups, higher levels of l‐citrulline and l‐glutamine are found in asymptomatic carriers and moderate or severe patients at the remission stage. Furthermore, l‐citrulline and l‐glutamine combination therapy is demonstrated to effectively protect mice from coronavirus infection and endotoxin‐induced sepsis, and is observed to efficiently prevent the occurrence of pulmonary fibrosis and central nervous system damage. Collectively, the data reveal the metabolite profile of asymptomatic COVID‐19 patients and propose a potential strategy for COVID‐19 treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Weaning involves the removal of piglets from a sow, and on commercial farms, it usually occurs at between 3 and 5 weeks of age. Newly weaned piglets face physical, social, environmental, management and dietary challenges. Consequently, post-weaning, they often experience reduced feed intake, poor growth and, in some cases, diarrhoea. There are many interventions which can be employed on-farm during the suckling period to ease the transition at weaning for piglets. Strategies such as supervised farrowing, post-farrowing pain relief for sows, the use of nurse sows, cross-fostering, the administration of energy supplements/feed additives to piglets and liquid/dry creep feeding have been investigated. The objective of these strategies is to promote earlier feed exploration, increase early post-weaning feed intake and growth and improve intestinal maturity. This review focuses in particular on pain relief for sows, piglet management at birth, and the provision of supplementary milk/liquid feed and feed additives to suckling piglets. Carefully selected, these strategies have the potential to increase the lifetime growth and health of pigs from large litters. Weaning is a critical period in a pig's life. Piglets are confronted with abrupt changes to their physical and social environment, as well as management and nutritional changes. Weaning has always been associated with a growth check and is frequently accompanied by post-weaning diarrhoea in piglets. However, rapid increases in litter size in the last decade have increased within-litter piglet weight variation, with piglets now generally lighter at weaning, making the challenges associated with weaning even greater. Many interventions can be employed during the suckling period to ease the weaning transition for piglets. Pre-weaning strategies such as supervised farrowing (assistance with suckling and oxytocin provision), the provision of pain relief to sows around farrowing, split-suckling, early oral supplementation with glucose, bovine colostrum, faecal microbiota transplantation, feed additives and solid and liquid creep feeding (milk and liquid feed) have all been investigated. The objective of these strategies is to stimulate earlier maturation of the digestive tract, improve immunity, reduce latency to the first feed post-weaning and increase early post-weaning feed intake and growth. This review focuses in particular on: (1) pain relief provision to sows around farrowing, (2)split-suckling of piglets, (3) pre-weaning provision of supplementary milk and/or liquid feed, (4) other strategies to stimulate earlier enzyme production (e.g., enzyme supplementation), (5) other nutritional strategies to promote improved gut structure and function (e.g., L-glutamine supplementation), and (6) other strategies to modulate gut microbiota (e.g., probiotics and prebiotics). Correctly implementing these strategies can, not only increase post-weaning growth and reduce mortality, but also maximise lifetime growth in pigs. [ABSTRACT FROM AUTHOR]

The CryoPreservation Media (CPM) for mouse sperm using raffinose and skim milk have been improved by adding either monothioglycerol (MTG) or l -glutamine to reduce the oxidative damage during sperm freezing and thawing. The CARD-CPM utilizing l -glutamine, but not MTG, has been widely used to meet the rising demand for cryopreservation of genetically modified mice, as the CARD method also improved sperm capacitation and in vitro fertilization (IVF). However, the viability of sperm frozen in the CARD-CPM is highly variable, indicating a room for improvement. To develop a more dependable technique for mouse sperm cryopreservation, we investigate whether combining MTG and l -glutamine in the CPM (MG-CPM) can produce a synergistic impact on sperm thawing and IVF rate. We found that MG-CPM reduced the incidence of infertility and increased the IVF success rate. Therefore, cryopreservation of mouse sperm in MG-CPM is a reliable method to ensure embryo generation from frozen sperm. [ABSTRACT FROM AUTHOR]

This study investigated the effects of L-glutamine (Gln) supplementation on growth performance, physiological traits, heat shock proteins (HSPs), and gene expression related to muscle and adipose tissue development in Hanwoo steers under heat stress (HS) conditions. Eight Hanwoo steers (initial body weight [BW] 570.7 ± 43.6 kg, months of age 22.3 ± 0.88) were randomly separated into two groups, control and treatment, and supplied with the concentration (1.5% of BW kg/day/head) and rice straw (1.5 kg/day/head). The treatment group were fed the Gln supplementation (0.5% of concentration, as-fed basis) once a day at 08:00 h. Blood samples for the assessment of haematological and biochemical parameters and the separation of peripheral blood mononuclear cells (PBMCs) were collected four times, at 0, 3, 6, and 10 weeks of the experiment. Feed intake was measured daily. BW to analyze growth performance and hair follicle collection to analyze the expression of HSPs were executed four times at 0, 3, 6, and 10 weeks. To analyze gene expression, longissimus dorsi muscle samples were collected by biopsy at the end of the study. As a result, growing performance, including final BW, average daily gain, and gain-to-feed ratio, were not different between the two groups. Leukocytes including lymphocytes and granulocytes, tended to increase in the Gln supplementation group (p = 0.058). There were also no differences in biochemical parameters shown between the two groups, except total protein and albumin, both of which were lower in the Gln supplementation group (p < 0.05). Gene expressions related to muscle and adipose tissue development were not different between the two groups. As temperature–humidity index (THI) increased, HSP70 and HSP90 expression in the hair follicle showed a high correlation. HSP90 in the hair follicle was decreased in the treatment group compared with the control group at 10 weeks (p < 0.05). Collectively, dietary Gln supplementation (0.5% of concentration, as-fed basis) may not be influential enough to affect growth performance and gene expression related to muscle and adipose tissue development in steers. However, Gln supplementation increased the number of immune cells and decreased HSP90 in the hair follicle implying HS reduction in the corresponding group.

With the rising demand for entry to extremely high altitudes (HAs), rapid adaptability to extremely hypoxic environments is a challenge that we need to explore. Fasting was used to evaluate acute hypoxia tolerance at HA and was proven to be an effective method for improving the survival rate at extreme HA. Our experiments also showed that fasting pretreatment for 72 h significantly increased the 24 h survival rate of rats at 7620 m from 10 to 85% and protected the myocardium cells of rats. Here, we compared the metabolites and gene expression in the myocardium of SD rats pretreated with fasting and nonfasting at normal altitude and extreme HA. Our findings demonstrated that the dynamic contents of detected differential metabolites (DMs) between different rat groups were consistent with the expression of differentially expressed genes (DEGs), and DM clusters also showed strong correlations with DEG clusters. DM clusters related to amino acids and lipids were significantly lower in the fasting groups, and the correlated DEG clusters were enriched in mitotic pathways, including CDK1, CDC7, NUF2, and MCM6, suggesting that fasting can attenuate mitotic processes in cardiac tissues and reduce the synthesis of amino acids and lipids. L-Glutamine-related metabolites were particularly low at extreme HA without pretreatment but were normal in the fasting groups. The DEGs in the cluster related to L-glutamine-related metabolites were enriched for T-cell receptor V(D)J recombination, the Hippo signaling pathway, the Wnt signaling pathway, the cGMP-PKG signaling pathway, and the mTOR signaling pathway and were significantly downregulated, indicating that the content of L-glutamine decreased at extreme HA, while fasting increased it to adapt to the environment. Moreover, abundant fatty acids were detected when rats were exposed to extreme HA without pretreatment. Our study revealed the fasting and hypoxic environment-related factors in SD rats and provided new insights into the genetic and molecular characteristics in the myocardium, which is critical to developing more potential rapid adaptation methods to extreme HA. [ABSTRACT FROM AUTHOR]

Objective: The primary goal in the treatment of corrosive esophagitis (CE) is to control inflammation and scar reactions. L-glutamine (Gln) is beneficial for the integrity of the intestinal mucosal epithelium and is an amino acid that promotes mature collagen growth. This study was designed to demonstrate the positive results of Gln on injury in corrosive esophagitis. Method: Thirty Sprague-Dawley rats were used in the study. They were divided into 3 groups. CE was formed by dripping 20% sodium hydroxide into the distal esophagus in both groups except the control group (n=10). First group (n=9) was left untreated, while the other group (n=9) was fed orally with the addition of 1 g/kg Gln once a day for 21 days. All rats were sacrificed after 3 weeks. Esophagus of treated and other group rats were examined under light microscope to evaluate collagen deposition, histological damage score and stenosis index. Results: Excess submucosal collagen, muscularis mucosal damage, inflammation and ulceration, which are among the histological damage score parameters, were significantly higher in the untreated group than in the Gln group (p=0.005, p=0.015, p=0.001, respectively). The stenosis index was significantly different (p=0.013). The group treated with Gln had inflammation but no ulceration and necrosis. Conclusion: Our experimental animal study suggests that Gln in nutrition reduces damage in the esophageal mucosa, slows down or partially stops the cellular destruction process that causes stenosis.

Cationic lysosomotropic molecules such as ammonium salts and chloroquine inhibit influenza A virus (IAV) infection in cell culture by counteracting endosomal acidification and hampering viral-endosomal fusion. Here, we studied the effects of storage of L-glutamine-supplemented cell culture media on accumulation of ammonium and inhibition of IAV infection. The storage-related inhibitory effect was observed for DMEM and OptiMEM media but not for RPMI medium, and was more pronounced for IAV with pH-stable hemagglutinin. Our results highlight the importance to consider potential presence of virus-inhibiting lysosomotropic agents and/or their production in culture media with negative effect on influenza virus infection. • Improper cell culture medium handling releases ammonium via decomposition of L-glutamine. • Using old or pre-warmed cell culture medium reduces infectivity of influenza A viruses with stable hemagglutinin. • The buffer substance HEPES preserves influenza A virus infectivity. [ABSTRACT FROM AUTHOR]

The protection of implant surfaces from biofilm and corrosion is crucial for osteogenesis and tissue engineering. To this end, an L-glutamine-based green corrosion inhibitor with recently established anticancer properties has been applied onto antibacterial Cu(111) surfaces that usually cover the Ti-based implants. Among several configurations, L-glutamine prefers the parallel to the surface orientation with the carbon chain along the [110] direction having the heteroatoms N and O atoms on top of Cu surface atoms, which is important for the creation of a planar two-dimensioned (2d) stable coating. L-glutamine forms well-localized, directional covalent-like bonded states (below −3 eV) with the Cu surface atoms, using mainly its backbone’s N1 atom that interestingly also shows electron charge occupation in the single-molecule highest occupied state, denoting its ability as an active center. The Mulliken analysis shows charge transfer from the molecule’s N, C and Cu neighboring atoms towards the O atoms revealing the strong bond tendency of L-glutamine and therefore its ability to act as a corrosion inhibitor on the Cu surface. Additional L-glutamine adsorption results in intermolecular covalent bonding between the molecules, proving the ability of this amino acid to form a stable protective 2d organic coating on Cu(111). These results could be used for the design of a multifunctional hybrid (organic–metallic) coating with anticorrosion, anticancer and antibacterial properties suitable for many technological applications.

Objective Two follow-up studies (exp. 1 and 2) were conducted to determine the effects of L-glutamine (L-Gln) supplementation on degradation and rumen fermentation characteristics in vitro. Methods First, rumen liquor from three cannulated cows was used to test L-Gln (50 mM) degradation rate and ammonia-N production at 6, 12, 24, 36, and 48 h after incubation (exp. 1). Second, rumen liquor from two cannulated steers was used to assess the effects of five levels of L-Gln including 0% (control), 0.5%, 1%, 2%, and 3% at 0, 3, 6, 12, 24, 36, and 48 h after incubation on fermentation characteristics, gas production, and degradability of nutrients (exp. 2). Results In exp. 1, L-Gln degradation rate and ammonia-N concentrations increased over time (p

Sickle cell disease (SCD) is a hematological disorder that primarily affects individuals of African descent from sub-Saharan Africa and along the mediterranean. The main complications leading to hospitalizations include vaso-occlusive crises (VOCs) and acute chest syndrome (ACS). Therefore, the main objective of this paper was to identify and evaluate evidence-based management and prevention of VOCs in patients with SCD. A literature search of PubMed, Medline Cochrane and Google Scholar database (January 1985 to April 2020) was performed using the following search terms "vaso-occlusive crises", "sickle cell disease", "hydroxyurea", "L-glutamine", "voxelotor", "crizanlizumab", "treatment" and "prevention" as well as a combination of these terms. All English-language interventional studies assessing the efficacy and safety of VOC outcomes were evaluated. Literature was excluded if published in a language other than English or if it was a review article. A total of 69 articles were identified and there were 7 articles that met the search criteria. Majority of the studies focused on mean and median annual rates of VOCs as primary outcomes while median time to first sickle cell crises, median rates of hospitalizations etc were evaluated as secondary outcomes. After reviewing the literature, many patients with VOCs will still benefit from hydroxyurea therapy since long term efficacy data and cost is still a concern for the newer agents including L-glutamine, voxelotor and crizanlizumab. Other factors such as cost or compliance may also be taken into consideration when making recommendations for therapy. [ABSTRACT FROM AUTHOR]

We evaluated the effects of supplementation of L‐alanine and L‐glutamine on blood glucose levels and biochemical parameters in alloxan‐induced diabetic rat. Forty‐nine animals were distributed into seven equal groups. Except for the non‐diabetic control, diabetes was induced in all groups by intravenous alloxan injection followed by daily supplementation with amino acids for 14 days. Weight and blood glucose were monitored during supplementation, while biochemical parameters such as liver and renal functions, lipid profile, and antioxidant markers were evaluated post‐intervention. A significant increase (p <.05) in weight and decrease in blood glucose were observed in the amino acid(s) treated groups. The supplementation with both amino acids restored important tissue antioxidants, liver and kidney functions and rescued islets cells degeneration. Histopathological examinations of important tissues showed the restoration of alloxan‐induced physiopathological changes by the amino acids. Thus, these amino acids might serve as nutraceuticals for the management and treatment of diabetes. Practical Applications: The discovery and production of antidiabetic bioactive compounds are often challenging, and the existing antidiabetic drugs are expensive. Amino acids are key regulators of glucose metabolism, insulin secretion, and insulin sensitivity; thus, they can play a crucial role in alleviating diabetes. Here, we present findings that strongly suggest the potential of pure amino acids (L‐alanine and L‐glutamine) for the management and treatment of diabetes. We show that these amino acids, when supplemented singly or coadministered can lower blood glucose levels and restore several other biochemical parameters implicated in diabetes. Hence, these cheap amino acids may be consumed as nutraceuticals or food supplements by diabetics for the treatment/management of diabetes. Foods rich in these amino acids may also be consumed as part of the diet of diabetic patients. [ABSTRACT FROM AUTHOR]

Sickle cell disease (SCD) is heterogeneous in terms of manifestation severity, even more so when in compound heterozygosity with beta-thalassemia. The aim of the present study was to stratify βSβ+ patient blood samples in a severity-dependent manner. Blood from thirty-two patients with HbS/β-thalassemia compound heterozygosity was examined for several parameters (e.g., hemostasis, inflammation, redox equilibrium) against healthy controls. Additionally, SCD patients were a posteriori (a) categorized based on the L-glutamine dose and (b) clustered into high-/low-RDW subgroups. The patient cohort was characterized by anemia, inflammation, and elevated coagulation. Higher-dose administration of L-glutamine was associated with decreased markers of inflammation and oxidation (e.g., intracellular reactive oxygen species) and an altered coagulation profile. The higher-RDW group was characterized by increased hemolysis, elevated markers of inflammation and stress erythropoiesis, and oxidative phenomena (e.g., membrane-bound hemoglobin). Moreover, the levels of hemostasis parameters (e.g., D-Dimers) were greater compared to the lower-RDW subgroup. The administration of higher doses of L-glutamine along with hydroxyurea seems to attenuate several features in SCD patients, probably by enhancing antioxidant power. Moreover, anisocytosis may alter erythrocytes’ coagulation processes and hemolytic propensity. This results in the disruption of the redox and pro-/anti-inflammatory equilibria, creating a positive feedback loop by inducing stress erythropoiesis and, thus, the occurrence of a mixed erythrocyte population.

Background: A low level of L-glutamine, a precursor of nicotinamide adenine dinucleotide (NAD) in red blood cells (RBCs), is identified as an underlying mechanism for the potential decrement of the NAD redox and the incidence of pain crisis in sickle cell anemia (SCA). The aim of this study is to assess the impact of oral Lglutamine therapy on pain crisis reduction in patients with SCA and sickle β°-thalassemia. Materials and Methods: In this pilot clinical trial, 15 patients with SCA and sickle β°-thalassemia with the mean age of 17.2 ± 6.07 were examined to evaluate the efficacy of L-glutamine therapy in pain crises. All the subjects received oral L-glutamine (0.3 gr/kg of body weight) every day for 8 weeks. With respect to the effects of L-glutamine on pain crisis, the subjects were in contact with the physicians at least once or more per week. Blood samples were taken at different follow-up times to evaluate the laboratory characteristics of the patients. Results: Pain crises occurred for 1-3 times (mean: 1.29 ± 1.05) during 12 months before the L-glutamine therapy. With no significant change, the patients had lower numbers of painful crises (mean: 0.80 ± 0.58) at the end of a 4-week period compared to the period before the L-glutamine therapy (P = 0.466). Fewer pain crises with a mean of 0.33 ± 0.51 occurred during 8 weeks of L-glutamine therapy than in the pre-treatment period (P = 0.038). Conclusion: The results of the present study showed that oral L-glutamine can mitigate a pain crisis and improve the sickle RBCs and reticulocyte count in SCA. This suggests that L-glutamine therapy can increase the antioxidant potential of sickle RBCs. [ABSTRACT FROM AUTHOR]

Sickle-cell disease (SCD) is an inherited hemoglobinopathy, causing lifelong complications such as painful vaso-occlusive episodes, acute chest syndrome, stroke, chronic anemia, and end-organ damage, with negative effects on quality of life and life expectancy. Within the last five years, three new treatments have been approved: L-glutamine in 2017 and crizanlizumab and voxelotor in 2019. We conducted a literature search of these three medications, and of the 31 articles meeting inclusion criteria, 6 studied L-glutamine, 9 crizanlizumab, and 16 voxelotor. Treatment with L-glutamine was associated with decrease in pain crises, hospitalizations, and time to first and second crises, with a decrease in RBC transfusion rate. Barriers to filling and taking L-glutamine included insurance denial, high deductible, and intolerability, especially abdominal pain. Crizanlizumab was associated with a reduction in pain crises and time to first crisis, with reduction in need for opioid use. Adverse effects of crizanlizumab include headache, nausea, insurance difficulty, and infusion reactions. Voxelotor was associated with increased hemoglobin and decreased markers of hemolysis. Barriers for voxelotor use included insurance denial and side effects such as headache, rash, and diarrhea. These three medications represent exciting new therapies and are generally well-tolerated though price and insurance approval remain potential barriers to access. Other studies are ongoing, particularly in the pediatric population, and more real-world studies are needed. The objective of this article is to evaluate post-approval studies of crizanlizumab, voxelotor, and L-glutamine in SCD, with a focus on real-world efficacy, side effects, and prescribing data. [ABSTRACT FROM AUTHOR]

Exogenous Gln as a single N source has been shown to exert similar roles to the inorganic N in poplar 'Nanlin895′ in terms of growth performance, yet the underlying molecular mechanism remains unclear. Herein, transcriptome analyses of both shoots (L) and roots (R) of poplar 'Nanlin895' fertilized with Gln (G) or the inorganic N (control, C) were performed. Compared with the control, 3109 differentially expressed genes (DEGs) and 5071 DEGs were detected in the GL and GR libraries, respectively. In the shoots, Gln treatment resulted in downregulation of a large number of ribosomal genes but significant induction of many starch and sucrose metabolism genes, demonstrating that poplars tend to distribute more energy to sugar metabolism rather than ribosome biosynthesis when fertilized with Gln-N. By contrast, in the roots, most of the DEGs were annotated to carbon metabolism, glycolysis/gluconeogenesis and phenylpropanoid biosynthesis, suggesting that apart from N metabolism, exogenous Gln has an important role in regulating the redistribution of carbon resources and secondary metabolites. Therefore, it can be proposed that the promotion impact of Gln on poplar growth and photosynthesis may result from the improvement of both carbon and N allocation, accompanied by an efficient energy switch for growth and stress responses. [ABSTRACT FROM AUTHOR]

Glutamine supplementation has been reported to affect blood pressure (BP). However, its role in the progression of hypertension induced by high salt diet (HSD) has not been elucidated. Male normotensive Wistar rats were exposed to high salt diet and treated with different doses of glutamine supplementation. Rats aged 6 weeks were assigned to five groups: (1) Normal-salt diet (0.3% NaCl, NSD); (2) High-salt diet (8% NaCl, HSD); (3) High-salt + low-dose diet (8% NaCl, 0.5 g of L-glutamine/kg body weight, HSLGD); (4) High-salt + middle-dose diet (8% NaCl, 1.5 g of L-glutamine/kg body weight, HSMGD); and (5) High-salt + high-dose diet (8% NaCl, 2.5 g of L-glutamine/kg body weight, HSHGD). After supplementing different doses of glutamine to male Wistar 6-week-old rats fed with HSD for 7 weeks, we found no difference in body weight among groups. Importantly, we showed that dietary L-glutamine supplementation could prevent the development of hypertension in a dose-dependent manner [dramatically lowering systolic blood pressure (SBP) and slightly reducing diastolic blood pressure (DBP) of hypertensive rats, while the differences of DBP between groups did not reach statistical significance]. Our data further elucidated that dietary glutamine supplementation mildly alleviated the degree of left ventricular hypertrophy, including interventricular septal thickness (IVST) and left ventricular posterior wall thickness (LVPWT) in hypertensive rats. Together, our results offer evidence that the dietary uptake of glutamine may be associated with attenuating the development of high salt-induced hypertension and slightly alleviating the degree of left ventricular hypertrophy in hypertensive rats. Therefore, glutamine supplementation may act as a prospective dietary intervention for the treatment of hypertension.

Abstract Background Taurine depletion occurs in patients with end-stage chronic kidney disease (CKD). In contrast, in the absence of CKD, plasma taurine is reported to increase following dietary L-glutamine supplementation. This study tested the hypothesis that taurine biosynthesis decreases in a rat CKD model, but is rectified by L-glutamine supplementation. Methods CKD was induced by partial nephrectomy in male Sprague-Dawley rats, followed 2 weeks later by 2 weeks of 12% w/w L-glutamine supplemented diet (designated NxT) or control diet (NxC). Sham-operated control rats (S) received control diet. Results Taurine concentration in plasma, liver and skeletal muscle was not depleted, but steady-state urinary taurine excretion (a measure of whole-body taurine biosynthesis) was strongly suppressed (28.3 ± 8.7 in NxC rats versus 78.5 ± 7.6 μmol/24 h in S, P

Sickle cell disease (SCD) is an autosomal recessive monogenic disorder caused by a homozygous mutation in the β-globin gene, which leads to erythrocyte sickling, hemolysis, vaso-occlusion, and sterile inflammation. The administration of oral L-glutamine has been shown to reduce the frequency of pain in SCD patients; however, the long-term effect of L-glutamine in SCD remains to be determined. To understand the long-term effect of L-glutamine administration in the liver we used quantitative liver intravital microscopy and biochemical analysis in humanized SCD mice. We here show that chronic L-glutamine administration reduces hepatic hemoglobin–heme–iron levels but fails to ameliorate ischemic liver injury. Remarkably, we found that this failure in the resolution of hepatobiliary injury and persistent liver fibrosis is associated with the reduced expression of hepatic Kupffer cells post-L-glutamine treatment. These findings establish the importance of investigating the long-term effects of L-glutamine therapy on liver pathophysiology in SCD patients.

Many cancers utilize l-glutamine as a major energy source. Often cited in the literature as “l-glutamine addiction”, this well-characterized pathway involves hydrolysis of l-glutamine by a glutaminase to l-glutamate, followed by oxidative deamination, or transamination, to α-ketoglutarate, which enters the tricarboxylic acid cycle. However, mammalian tissues/cancers possess a rarely mentioned, alternative pathway (the glutaminase II pathway): l-glutamine is transaminated to α-ketoglutaramate (KGM), followed by ω-amidase (ωA)-catalyzed hydrolysis of KGM to α-ketoglutarate. The name glutaminase II may be confused with the glutaminase 2 (GLS2) isozyme. Thus, we recently renamed the glutaminase II pathway the “glutamine transaminase—ω-amidase (GTωA)” pathway. Herein, we summarize the metabolic importance of the GTωA pathway, including its role in closing the methionine salvage pathway, and as a source of anaplerotic α-ketoglutarate. An advantage of the GTωA pathway is that there is no net change in redox status, permitting α-ketoglutarate production during hypoxia, diminishing cellular energy demands. We suggest that the ability to coordinate control of both pathways bestows a metabolic advantage to cancer cells. Finally, we discuss possible benefits of GTωA pathway inhibitors, not only as aids to studying the normal biological roles of the pathway but also as possible useful anticancer agents.

Introduction: Patients with sickle cell disease (SCD) suffer from recurrent and unpredictable episodes of acute pain due to vaso-occlusive crisis (VOC) which may require hospitalization and they also develop chronic persistent pain. Since pain usually begins in infancy and continues throughout life, preventing the genesis of pain is comparatively higher than treating the pain once it has been evoked VOC represents the cause of almost 95% of hospitalizations for patients with SCD. L-glutamine is an amino acid needed for the synthesis of the pyridines for nucleotides, including nicotinamide adenine dinucleotide (NAD) and glutathione, in addition to glutamate, and becomes essential during oxidative stress exposure. The NADH: [NAD+ + NADH] (redox) ratio in sickle red blood cells (RBCs) is lower than in normal RBCs which is related to oxidative stress, so L-glutamine availability is important in SCD. Although the FDA-approved it for preventing acute complications in SCD, still has many gaps in our understanding of its therapeutic implications. Aim: To evaluate the safety and efficacy of L-glutamine in reducing the number of VOCs in patients with SCD. Methods: This is an investigator-initiated single-center phase 4 interventional randomized controlled trial at Ain Shams Pediatric Hematology Unit. Sixty SCD participants, their mean age was 9.2 ± 3.7 years, they were 35 males and 25 females, were randomly assigned in a 1:1 ratio to receive glutamine at a dose of 0.3 gm/kg/dose twice daily orally (up to a maximum of 15 g/dose) for 24 weeks or the standard of care (SOC) without glutamine intake. Results: Thirty-seven (62%) had HbSS with 38% had other sickle cell variants. All participants were receiving HU therapy and were on stable dose during the last three months prior to enrollment. Almost half of the patients (48%) were on chelation therapy with deferasirox. Thirty SCD patients were recruited in each group either received glutamine or SOC, both groups were comparable as regards demographic data. All patients in both arms had VOCs in the last year more than two. For the primary endpoint, there was a decreasing trend in the number, severity, and hospitalization of VOC in the glutamine arm and there was a significantly lower cumulative number of VOCs in the glutamine group (38.9%) than SOC (52.8%) (p = 0.008) and lower cumulative number of hospitalizations (p < 0.001). Conclusion: Glutamine reduced the number of VOCs and hospitalizations for VOC in our cohort with SCD. [ABSTRACT FROM AUTHOR]

Oxidative stress is a major contributor to the pathophysiology of sickle cell disease (SCD) including hemolysis and vaso-occlusive crisis (VOC). L-glutamine is a conditionally essential amino acid with important roles, including the synthesis of antioxidants, such as reduced glutathione and the cofactors NAD(H) and NADP(H), as well as nitric oxide. Given the increased levels of oxidative stress and lower (NADH):(NAD +  + NADH) ratio in sickle erythrocytes that adversely affects the blood rheology compared to normal red blood cells, L-glutamine was investigated for its therapeutic potential to reduce VOC. While L-glutamine was approved by the United States (US) Food and Drug Administration to treat SCD, its impact on the redox environment in sickle erythrocytes is not fully understood. The mechanism through which L-glutamine reduces VOC in SCD is also not clear. In this paper, we will summarize the results of the Phase 3 study that led to the approval of L-glutamine for treating SCD and discuss its assumed mechanisms of action. We will examine the role of L-glutamine in health and propose how the extra-erythrocytic functions of L-glutamine might contribute to its beneficial effects in SCD. Further research into the role of L-glutamine on extra-erythrocyte functions might help the development of an improved formulation with more efficacy. [ABSTRACT FROM AUTHOR]

Background/Aim: Hydration and hydroxyurea (HU) can modify sickle cell disease (SCD) severity. Optimal nutrition and L-glutamine (Gln) may provide further amelioration. Patients and Methods: Reviews of medical records and nutrition surveys were used to investigate severity of pediatric patients with SCD in relation to nutrition, growth, hematologic parameters, and diseasemodifying agents. Results: Among 25 females and 25 males (9.1±7 years), beta-globin genotypes were: HbSS/Sβ0, 60%; HbSC, 32%; HbSβ+, 8%. The mean number of annual pain crises (APC) was 0.97±1.1. APCs increased ≥2-fold as HbF dropped to <10% with age. Proper hydration and nutrition correlated with younger ages and fewer APCs. Height and weight Z-scores were ≤-1SD in 20% of 35 surveyed patients (12±7.8 years), who had more APCs (2.5±2.5 vs. 1±1.3, p=0.03). Prealbumin levels were overall low. Twenty-two of 28 patients on HU reported ≥90% adherence - with higher mean corpuscular volume (92±9.6 vs. 74±10 f/l, p<0.01). Seventy percent of Gln prescriptions were filled. Compliance over 23 months was ≥70% in 12 patients, including 2 on chronic transfusion. Of 10 evaluable patients, 6 (8.8±2.2 years) had fewer APCs with Gln (mean 0.2 vs. 0.9, p=0.016), with increasing prealbumin levels (14.1 to 15.8 mg/dl, p=0.1). Conclusion: Younger, and well-nourished, well-hydrated patients have a milder clinic course. Disease severity was the worse in undernourished teenagers with suboptimal compliance. L-Glutamine with prealbumin monitoring should be considered for further evaluation in pediatric SCD. [ABSTRACT FROM AUTHOR]