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Introduction: Alanyl-glutamine (Ala-Gln) is a compound known for its protective effects in various tissue injuries. However, its role in asthma-related lung injuries remains underexplored. This study investigates the mechanisms by which Ala-Gln modulates sDPP4-induced airway epithelial-mesenchymal transition and ovalbumin (OVA)-induced asthma in a mouse model. Methods: An asthma model was established in female C57BL/6 J mice by using OVA. CD4+ T cells and bronchial epithelial cells (BECs) were isolated from the spleen and bronchi of the mice, respectively. Interventions included recombinant sCD26/sDPP4 protein, Ala-Gln, and EX527 (a SIRT1 inhibitor). Flow cytometry was used to assess Th17 and Treg cell populations. Mice were treated with Ala-Gln, EX527, and budesonide (BUD). Histopathological changes in lung tissues were evaluated using hematoxylin-eosin and Masson staining. White blood cell counts were measured with a hematology analyzer. The expression levels of DPP4, IL-17, SIRT1, SMAD2/3, N-cadherin, E-cadherin, MMP9, and α-SMA proteins were analyzed. Results: Treatment with recombinant sCD26/sDPP4 resulted in decreased E-cadherin expression in BECs and increased levels of α-SMA, MMP9, and N-cadherin, effects that were mitigated by Ala-Gln. Ala-Gln also prevented the reduction in SIRT1 expression in BECs and the increase in Th17 cell differentiation induced by recombinant sCD26/sDPP4. EX527 administration alongside Ala-Gln reversed these changes and enhanced the phosphorylation of SMAD2/3 through SIRT1 signaling. BUD alone reduced inflammation and fibrosis in bronchial tissue and lowered the Th17/Treg ratio in peribronchial lymph nodes. The therapeutic effect of BUD was further improved with concurrent Ala-Gln treatment. Conclusion: Ala-Gln can inhibit BEC fibrosis and Th17 cell differentiation mediated by recombinant sCD26/sDPP4 through the SIRT1 pathway. Combined with BUD, Ala-Gln enhanced therapeutic efficacy in OVA-induced asthma in mice, which could offer improved outcomes for asthmatic patients with elevated DPP4 levels. [ABSTRACT FROM AUTHOR]

Simple Summary: Alanyl-glutamine dipeptide carries utmost importance for the poultry industry due to its potential for enhancing various aspects of health and performance in laying birds. Glutamine is an important energy source for highly prolific immune cells and intestinal epithelial cells, and it plays a role in protein degradation, cell defense, cell repair, and is a precursor of glutathione. By improving growth, nutrient digestibility, digestive enzyme activity, immunity and antioxidant status, it can lead to the development of more productive and stress tolerant laying birds which can ultimately benefit poultry producers and consumers by reducing feed costs, mortality rates and improving egg production. Alanyl-glutamine (Aln-Gln), a highly soluble and stable Glutamine-dipeptide, is known to improve the performance of poultry birds. This study aimed to investigate the effect of Aln-Gln during the rearing period on growth performance, nutrient digestibility, digestive enzyme activity, immunity, antioxidant status and relative gene expression of Hy-Line brown hens. A total of 480 healthy day-old Hy-line brown chicks with similar body weights were randomly divided into four dietary groups (8 replicates/group and 15 birds/replicate). Groups A, B, C and D were fed diets containing 0%, 0.1%, 0.2% and 0.3% Aln-Gln, respectively, for 6 weeks. The body weight (BW) and average daily gain (ADG) were higher in hens fed test diets compared with the control (p < 0.05). The feed conversion ratio (FCR) was better in test groups as compared to the control group (p < 0.05). The ADFI showed no significant difference between the groups. Dietary treatments had no effect on dry matter (DM), organic matter (OM) and crude fiber (CF) digestibility. The Aln-Gln also improved gross energy (GE) and crude protein (CP) digestibility (p < 0.05). It has also increased IgG levels in groups C and D. IgM levels were similar to the control in B, C and D. The Aln-Gln increased IL-1 in B and C, IL-2 in C and D, and IL-6 in all test groups (p < 0.05). The supplementation of Aln-Gln had no effect on serum antioxidant indices like CAT, MDA, GSH-PX, GSH, and SOD in 42-day-old growing hens. Aln-Gln supplementation had no significant effect (p > 0.05) on the activity of amylase and lipase, however, a significant improvement (p < 0.05) in the activities of trypsin and chymotrypsin was observed in the test groups. Supplemented Aln-Gln levels in the birds' diets led to an increase in the expression of genes related to growth factors (IGF-1, IGFBP-5), immune markers (IL-1, IL-2, IL-6) and antioxidant status (GSH-Px1), as compared to control group. Aln-Gln supplementation in Hy-Line brown hens during their growing period improved growth, nutrient digestibility, immunity and digestive enzymes activity. These findings suggest that Aln-Gln is a promising dietary additive for enhancing poultry performance. [ABSTRACT FROM AUTHOR]

Alanyl-glutamine (Aln-Gln), a highly soluble and stable Glutamine-dipeptide, is known to improve the performance of poultry birds. This study aimed to investigate the effect of Aln-Gln during the rearing period on growth performance, nutrient digestibility, digestive enzyme activity, immunity, antioxidant status and relative gene expression of Hy-Line brown hens. A total of 480 healthy day-old Hy-line brown chicks with similar body weights were randomly divided into four dietary groups (8 replicates/group and 15 birds/replicate). Groups A, B, C and D were fed diets containing 0%, 0.1%, 0.2% and 0.3% Aln-Gln, respectively, for 6 weeks. The body weight (BW) and average daily gain (ADG) were higher in hens fed test diets compared with the control (p < 0.05). The feed conversion ratio (FCR) was better in test groups as compared to the control group (p < 0.05). The ADFI showed no significant difference between the groups. Dietary treatments had no effect on dry matter (DM), organic matter (OM) and crude fiber (CF) digestibility. The Aln-Gln also improved gross energy (GE) and crude protein (CP) digestibility (p < 0.05). It has also increased IgG levels in groups C and D. IgM levels were similar to the control in B, C and D. The Aln-Gln increased IL-1 in B and C, IL-2 in C and D, and IL-6 in all test groups (p < 0.05). The supplementation of Aln-Gln had no effect on serum antioxidant indices like CAT, MDA, GSH-PX, GSH, and SOD in 42-day-old growing hens. Aln-Gln supplementation had no significant effect (p > 0.05) on the activity of amylase and lipase, however, a significant improvement (p < 0.05) in the activities of trypsin and chymotrypsin was observed in the test groups. Supplemented Aln-Gln levels in the birds’ diets led to an increase in the expression of genes related to growth factors (IGF-1, IGFBP-5), immune markers (IL-1, IL-2, IL-6) and antioxidant status (GSH-Px1), as compared to control group. Aln-Gln supplementation in Hy-Line brown hens during their growing period improved growth, nutrient digestibility, immunity and digestive enzymes activity. These findings suggest that Aln-Gln is a promising dietary additive for enhancing poultry performance.

The experiment focused on the study aimed to investigate the effects of adding alanyl-glutamine (Ala-Gln) to the feed on the growth, serum biochemical parameters, and the mRNA expression levels of stress-related genes in largemouth bass (Micropterus salmoides) under dual stress conditions of density and flow rate. The fish were divided into three groups: control group, dual stress group and dual stress with 0.9 % Ala-Gln addition group, and underwent a 60 day aquaculture experiment. The data showed that final weight, average weight gain rate, specific growth rate and feed efficiency of largemouth bass significantly decreased under dual stress (P

Non-alcoholic fatty liver disease (NAFLD) manifests as a persistent liver ailment marked by the excessive buildup of lipids within the hepatic organ accompanied by inflammatory responses and oxidative stress. Alanyl-glutamine (AG), a dipeptide comprising alanine and glutamine, is commonly employed as a nutritional supplement in clinical settings. This research aims to evaluate the impact of AG on NAFLD triggered by a high-fat diet (HFD), while concurrently delving into the potential mechanisms underlying its effects. The results presented herein demonstrate a notable reduction in the elevated body weight, liver mass, and liver index induced by a HFD upon AG administration. These alterations coincide with the amelioration of liver injury and the attenuation of hepatic histological advancement. Furthermore, AG treatment manifests a discernible diminution in oil-red-O-stained regions and triglyceride (TG) levels within the liver. Noteworthy alterations encompass lowered plasma total cholesterol (TC) and low-density lipoprotein cholesterol (LDLC) concentrations, coupled with elevated high-density lipoprotein cholesterol (HDLC) concentrations. The mitigation of hepatic lipid accumulation resultant from AG administration is aligned with the downregulation of ACC1, SCD1, PPAR-γ, and CD36 expression, in conjunction with the upregulation of FXR and SHP expression. Concomitantly, AG administration leads to a reduction in the accumulation of F4/80-positive macrophages within the liver, likely attributable to the downregulated expression of MCP-1. Furthermore, AG treatment yields a decline in hepatic MDA levels and a concurrent increase in the activities of SOD and GPX. A pivotal observation underscores the effect of AG in rectifying the imbalance of gut microbiota in HFD-fed mice. Consequently, this study sheds light on the protective attributes of AG against HFD-induced NAFLD through the modulation of gut microbiota composition. [ABSTRACT FROM AUTHOR]

To investigate the effects of dietary tributyrin (TB) and alanyl-glutamine (AGn) on the intestinal health of largemouth bass (Micropterus salmoides) fed with highlevel soybean meal (SM) diet, six isonitrogenous (41.36%) and isolipidic (10.25%) diets were formulated and fed to largemouth bass (initial body weight 25.5 ± 0.5g) for 8 weeks. The two control diets contained 34.8% peanut meal (PM) and 41.3% SM, while the other four experimental diets supplemented TB at 0.1% (TB0.1), 0.2% (TB0.2) and AGn at 1% (AGn1), 2% (AGn2) in SM, respectively. The results showed that there were no significant differences in weight gain, survival rate, and hepatosomatic index among all groups (P>0.05), while feed coefficient rate in AGn1, AGn2 and TB0.2 groups was significantly lower than that in SM group (P< 0.05). Compared with the PM group, the intestinal inflammation of largemouth bass in SM group were obvious, accompanied by the damage of intestinal structure, the decrease of digestive enzyme activity, and the upregulation of proinflammatory cytokines. Compared with the SM group, the activities of intestinal trypsin, lipase and foregut amylase in TB and AGn groups increased significantly (P<0.05), and the gene expression levels of acetyl-CoA carboxylase (ACC), caspase-3, caspase-8, caspase-9, tumor necrosis factor alpha (TNF-a), and interleukin-1 beta (IL-1b) were down-regulated, while the gene expression levels of target of rapamycin (TOR) and eIF4E-binding protein (4E-BP) were up-regulated in all experimental groups (P<0.05). It can be concluded that supplementation of 1%-2% AGn and 0.1%-0.2% TB can alleviate enteritis caused by high-level soybean meal, and the recommend level is 2% AGn and 0.2% TB. [ABSTRACT FROM AUTHOR]

To investigate the effects of dietary tributyrin (TB) and alanyl-glutamine (AGn) on the intestinal health of largemouth bass (Micropterus salmoides) fed with high-level soybean meal (SM) diet, six isonitrogenous (41.36%) and isolipidic (10.25%) diets were formulated and fed to largemouth bass (initial body weight 25.5 ± 0.5g) for 8 weeks. The two control diets contained 34.8% peanut meal (PM) and 41.3% SM, while the other four experimental diets supplemented TB at 0.1% (TB0.1), 0.2% (TB0.2) and AGn at 1% (AGn1), 2% (AGn2) in SM, respectively. The results showed that there were no significant differences in weight gain, survival rate, and hepatosomatic index among all groups (P>0.05), while feed coefficient rate in AGn1, AGn2 and TB0.2 groups was significantly lower than that in SM group (P< 0.05). Compared with the PM group, the intestinal inflammation of largemouth bass in SM group were obvious, accompanied by the damage of intestinal structure, the decrease of digestive enzyme activity, and the up-regulation of proinflammatory cytokines. Compared with the SM group, the activities of intestinal trypsin, lipase and foregut amylase in TB and AGn groups increased significantly (P

Nonalcoholic steatohepatitis (NASH) is a common chronic liver disease with increasing prevalence rates over years and is associated with hepatic lipid accumulation, liver injury, oxidative stress, hepatic inflammation, and liver fibrosis and lack of approved pharmacological therapy. Alanyl-glutamine (Ala-Gln) is a recognized gut-trophic nutrient that has multiple pharmacological effects in the prevention of inflammation- and oxidative-stress-associated diseases. Nevertheless, whether Ala-Gln has a protective effect on NASH still lacks evidence. The aim of this study is to explore the influence of Ala-Gln on NASH and its underlying mechanisms. Here, C57BL/6 mice were fed a methionine- and choline-deficient (MCD) diet to establish the model of NASH, and Ala-Gln at doses of 500 and 1500 mg/kg were intraperitoneally administered to mice along with a MCD diet. The results showed that Ala-Gln treatment significantly attenuated MCD-induced hepatic pathological changes, lowered NAFLD activity score, and reduced plasma alanine transaminase (ALT), aspartate transaminase (AST) and lactate dehydrogenase (LDH) levels. Ala-Gln dramatically alleviated lipid accumulation in liver through modulating the expression levels of fatty acid translocase (FAT/CD36) and farnesoid X receptor (FXR). In addition, Ala-Gln exerted an anti-oxidant effect by elevating the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPX). Moreover, Ala-Gln exhibited an anti-inflammatory effect via decreasing the accumulation of activated macrophages and suppressing the production of proinflammatory mediators. Notably, Ala-Gln suppressed the development of liver fibrosis in MCD-diet-fed mice, which may be due to the inhibition of hepatic stellate cells activation. In conclusion, these findings revealed that Ala-Gln prevents the progression of NASH through the modulation of oxidative stress and inflammation and provided the proof that Ala-Gln might be an effective pharmacological agent to treat NASH. [ABSTRACT FROM AUTHOR]

Acute liver injury is a worldwide problem with a high rate of morbidity and mortality, and effective pharmacological therapies are still urgently needed. Alanyl-glutamine (Ala-Gln), a dipeptide formed from L-alanine and L-glutamine, is known as a protective compound that is involved in various tissue injuries, but there are limited reports regarding the effects of Ala-Gln in acute liver injury. This present study aimed to investigate the protective effects of Ala-Gln in lipopolysaccharide (LPS)-induced acute liver injury in mice, with a focus on inflammatory responses and oxidative stress. The acute liver injury induced using LPS (50 μg/kg) and D-galactosamine (D-Gal) (400 mg/kg) stimulation in mice was significantly attenuated after Ala-Gln treatment (500 and 1500 mg/kg), as evidenced by reduced plasma alanine transaminase (ALT) (p < 0.01, p < 0.001), aspartate transaminase (AST) (p < 0.05, p < 0.001), and lactate dehydrogenase (LDH) (p < 0.01, p < 0.001) levels, and accompanied by improved histopathological changes. In addition, LPS/D-Gal-induced hepatic apoptosis was also alleviated by Ala-Gln administration, as shown by a greatly decreased ratio of TUNEL-positive hepatocytes, from approximately 10% to 2%, and markedly reduced protein levels of cleaved caspase-3 (p < 0.05, p < 0.001) in liver. Moreover, we found that LPS/D-Gal-triggered oxidative stress was suppressed after Ala-Gln treatment, the effect of which might be dependent on the elevation of SOD and GPX activities, and on GSH levels in liver. Interestingly, we observed that Ala-Gln clearly inhibited LPS/D-Gal exposure-induced macrophage accumulation and the production of proinflammatory factors in the liver. Furthermore, Ala-Gln greatly regulated autophagy in the liver in LPS/D-Gal-treated mice. Using RAW264.7 cells, we confirmed the anti-inflammatory role of Ala-Gln-targeting macrophages. [ABSTRACT FROM AUTHOR]

Acute liver injury is a worldwide problem with a high rate of morbidity and mortality, and effective pharmacological therapies are still urgently needed. Alanyl-glutamine (Ala-Gln), a dipeptide formed from L-alanine and L-glutamine, is known as a protective compound that is involved in various tissue injuries, but there are limited reports regarding the effects of Ala-Gln in acute liver injury. This present study aimed to investigate the protective effects of Ala-Gln in lipopolysaccharide (LPS)-induced acute liver injury in mice, with a focus on inflammatory responses and oxidative stress. The acute liver injury induced using LPS (50 μg/kg) and D-galactosamine (D-Gal) (400 mg/kg) stimulation in mice was significantly attenuated after Ala-Gln treatment (500 and 1500 mg/kg), as evidenced by reduced plasma alanine transaminase (ALT) (p < 0.01, p < 0.001), aspartate transaminase (AST) (p < 0.05, p < 0.001), and lactate dehydrogenase (LDH) (p < 0.01, p < 0.001) levels, and accompanied by improved histopathological changes. In addition, LPS/D-Gal-induced hepatic apoptosis was also alleviated by Ala-Gln administration, as shown by a greatly decreased ratio of TUNEL-positive hepatocytes, from approximately 10% to 2%, and markedly reduced protein levels of cleaved caspase-3 (p < 0.05, p < 0.001) in liver. Moreover, we found that LPS/D-Gal-triggered oxidative stress was suppressed after Ala-Gln treatment, the effect of which might be dependent on the elevation of SOD and GPX activities, and on GSH levels in liver. Interestingly, we observed that Ala-Gln clearly inhibited LPS/D-Gal exposure-induced macrophage accumulation and the production of proinflammatory factors in the liver. Furthermore, Ala-Gln greatly regulated autophagy in the liver in LPS/D-Gal-treated mice. Using RAW264.7 cells, we confirmed the anti-inflammatory role of Ala-Gln-targeting macrophages.

Alanyl-glutamine (Ala-Gln), a highly soluble and stable glutamine dipeptide, is known to improve gut integrity and function. The aim of this study was to evaluate whether dietary Ala-Gln supplementation could improve growth performance, intestinal development and digestive-absorption function in weaned piglets. A total of 100 purebred Yorkshire piglets weaned at 21 days of age were assigned randomly to four dietary treatment groups and fed a basal diet (control group) or a basal diet containing 0.15%, 0.30% and 0.45% Ala-Gln, respectively. Compared with the control group, piglets fed the Ala-Gln diets had higher average daily gain and lower feed : gain and diarrhea rate (P < 0.05). Moreover, dietary Ala-Gln supplementation increased villous height and villous height : crypt depth ratio in duodenum and jejunum (P < 0.05), as well as the activities of maltase and lysozyme in jejunum mucosa (P < 0.05). In addition, a decrease in serum diamine oxidase activity and crypt depth in duodenum and jejunum was observed in piglets fed the Ala-Gln diets (P < 0.05). Serum cytosolic phospholipase A2 (cPLA2) concentration and gene expression of cPLA2, Na+-dependent glucose transporter 1, glucose transporter 2 and peptide transporter 1 in jejunum were increased by feeding Ala-Gln diets relative to control diet (P < 0.05). These results indicated that feeding Ala-Gln diet has beneficial effects on the growth performance of weaned piglets, which associated with maintaining intestinal morphology and digestive-absorption function.

Objective(s): Skin flap necrosis is the most common postoperative side effect in reconstructive surgeries. Glutamine (GLN) has been shown to accelerate wound healing process. The purpose of this study was to evaluate the effects of GLN either in free form or in the dipeptide form along with L- alanyl (Ala-GLN) on random skin flaps survival in rats.Materials and Methods: Dorsal skin flaps with caudal bases (8 ×2 cm) were established in 24 adult male Wistar rats. Then, the animals were randomly assigned into 3 groups (n=8). Control, GLN (0.75 g/kg) and Ala-GLN (0.75 g/kg). All groups administrated orally 24 and 6 hr before flap elevation and continued repeatedly daily until 7 days postoperation. The flap survival rate and vascular density using histological analysis were evaluated. Vascular endothelial growth factor (VEGF) by immunohistochemical method was determined.Results: Seven days after surgery, the mean surviving area in the GLN and Ala-GLN groups were significantly greater than in the untreated control group (P

Objective The study was to investigate the effects of alanyl-glutamine (Ala-Gln) and glutamine (Gln) supplementation on the intestinal mucosa barrier in piglets. Methods A total of 180 barrows with initial weight 10.01±0.03 kg were randomly allocated to three treatments, and each treatment consisted of three pens and twenty pigs per pen. The piglets of three groups were fed with control diet [0.62% alanine (Ala)], Ala-Gln diet (0.5% Ala-Gln), Gln diet (0.34% Gln and 0.21% Ala), respectively. Results The results showed that in comparison with control diet, dietary Ala-Gln supplementation increased the height of villi in duodenum and jejunum (p

Alanyl-glutamine (Ala-Gln), a highly soluble and stable glutamine dipeptide, is known to improve gut integrity and function. The aim of this study was to evaluate whether dietary Ala-Gln supplementation could improve growth performance, intestinal development and digestive-absorption function in weaned piglets. A total of 100 purebred Yorkshire piglets weaned at 21 days of age were assigned randomly to four dietary treatment groups and fed a basal diet (control group) or a basal diet containing 0.15%, 0.30% and 0.45% Ala-Gln, respectively. Compared with the control group, piglets fed the Ala-Gln diets had higher average daily gain and lower feed : gain and diarrhea rate (P < 0.05). Moreover, dietary Ala-Gln supplementation increased villous height and villous height : crypt depth ratio in duodenum and jejunum (P < 0.05), as well as the activities of maltase and lysozyme in jejunum mucosa (P < 0.05). In addition, a decrease in serum diamine oxidase activity and crypt depth in duodenum and jejunum was observed in piglets fed the Ala-Gln diets (P < 0.05). Serum cytosolic phospholipase A2 (cPLA2) concentration and gene expression of cPLA2, Na+-dependent glucose transporter 1, glucose transporter 2 and peptide transporter 1 in jejunum were increased by feeding Ala-Gln diets relative to control diet (P < 0.05). These results indicated that feeding Ala-Gln diet has beneficial effects on the growth performance of weaned piglets, which associated with maintaining intestinal morphology and digestive-absorption function. [ABSTRACT FROM AUTHOR]

Objective: To study the therapeutic effect of alanyl-glutamine plus plasma exchange in treating severe organophosphate poisoning. Methods: 83 patients with severe organophosphate poisoning who were treated in our department from Jan.2013 to Jan. 2017 were enrolled in this study and randomly divided into the observation group (42 cases) and the control group (41 cases). Both groups were treated with conventional therapy and plasma exchange treatment, and the observation group were additionally treated with alanyl-glutamine. The observation period was 7 days. The therapeutic effect, incidence of complications, gastrointestinal barrier function and biochemical markers before and after treatment were evaluated and compared between two groups. Results: The period of unconsciousness of observation group was significantly shorter than that of the control group, and the cholinesterase(ChE) recovery was significantly earlier than that of the control group (P＜0.05). The incidence of liver dysfunction and hemorrhage of gastrointestinal tract of observation group were significantly lower than those of the control group (P<0.05). At 7 days after treatment, the plasma levels of DAO, D-lactate, TP, AST, ALT, Cr in both group were significantly lower than those before treatment, while the plasma level of Gln displayed contrary trend. In addition, the plasma levels of DAO, D-lactate, AST, ALT and Cr of observation group were significantly up-regulated comparted with the control group(P＜0.05), while up-regulation of the plasma level of AST, ALT, Cr were observed in observation group compared with those of the control group(P<0.05). Conclusion: Alanyl-glutamine plus plasma exchange can improve the recovery of patients with severeorganophosphate poisoning by reducing the incidence of complications of the digestive system and protecting the gastrointestinal mucosa. [ABSTRACT FROM AUTHOR]

Understanding and targeting the molecular basis of peritoneal solute and protein transport is essential to improve peritoneal dialysis (PD) efficacy and patient outcome. Supplementation of PD fluids (PDF) with alanyl-glutamine (AlaGln) increased small solute transport and reduced peritoneal protein loss in a recent clinical trial. Transepithelial resistance and 10 kDa and 70 kDa dextran transport were measured in primary human endothelial cells (HUVEC) exposed to conventional acidic, glucose degradation products (GDP) containing PDF (CPDF) and to low GDP containing PDF (LPDF) with and without AlaGln. Zonula occludens-1 (ZO-1) and claudin-5 were quantified by Western blot and immunofluorescence and in mice exposed to saline and CPDF for 7 weeks by digital imaging analyses. Spatial clustering of ZO-1 molecules was assessed by single molecule localization microscopy. AlaGln increased transepithelial resistance, and in CPDF exposed HUVEC decreased dextran transport rates and preserved claudin-5 and ZO-1 abundance. Endothelial clustering of membrane bound ZO-1 was higher in CPDF supplemented with AlaGln. In mice, arteriolar endothelial claudin-5 was reduced in CPDF, but restored with AlaGln, while mesothelial claudin-5 abundance was unchanged. AlaGln supplementation seals the peritoneal endothelial barrier, and when supplemented to conventional PD fluid increases claudin-5 and ZO-1 abundance and clustering of ZO-1 in the endothelial cell membrane.

Apolipoprotein E (APOE=gene, apoE=protein) is a known factor regulating the inflammatory response that may have regenerative effects during tissue recovery from injury. We investigated whether apoE deficiency reduces the healing effect of alanyl-glutamine (Ala-Gln) treatment, a recognized gut-trophic nutrient, during tissue recovery after 5-FU-induced intestinal mucositis. APOE-knockout (APOE-/-) and wild-type (APOE+/+) C57BL6J male and female mice (N=86) were given either Ala-Gln (100 mM) or phosphate buffered saline (PBS) by gavage 3 days before and 5 days after a 5-fluorouracil (5-FU) challenge (450 mg/kg, via intraperitoneal injection). Mouse body weight was monitored daily. The 5-FU cytotoxic effect was evaluated by leukometry. Intestinal villus height, villus/crypt ratio, and villin expression were monitored to assess recovery of the intestinal absorptive surface area. Crypt length, mitotic, apoptotic, and necrotic crypt indexes, and quantitative real-time PCR for insulin-like growth factor-1 (IGF-1) and B-cell lymphoma 2 (Bcl-2) intestinal mRNA transcripts were used to evaluate intestinal epithelial cell turnover. 5-FU challenge caused significant weight loss and leukopenia (P

Objective(s): Skin flap necrosis is the most common postoperative side effect in reconstructive surgeries. Glutamine (GLN) has been shown to accelerate wound healing process. The purpose of this study was to evaluate the effects of GLN either in free form or in the dipeptide form along with L- alanyl (Ala-GLN) on random skin flaps survival in rats. Materials and Methods: Dorsal skin flaps with caudal bases (8 ×2 cm) were established in 24 adult male Wistar rats. Then, the animals were randomly assigned into 3 groups (n=8). Control, GLN (0.75 g/kg) and Ala-GLN (0.75 g/kg). All groups administrated orally 24 and 6 hr before flap elevation and continued repeatedly daily until 7 days postoperation. The flap survival rate and vascular density using histological analysis were evaluated. Vascular endothelial growth factor (VEGF) by immunohistochemical method was determined. Results: Seven days after surgery, the mean surviving area in the GLN and Ala-GLN groups were significantly greater than in the untreated control group (P<0.001). Furthermore, in comparison with the control group, the number of blood vessels and VEGF-positive cells in treated groups with GLN and Ala-GLN were significantly higher. However, no significant differences were observed between treated groups with GLN and Ala-GLN. Conclusion: The findings from this study indicate that oral administration of GLN in free form or in the dipeptide (Ala-GLN) could promote neovascularization and improve skin flap survival in rats. [ABSTRACT FROM AUTHOR]

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Background: Although there are many clinical studies in which the beneficial effect of glutamine formulation on mucositis induced by chemo/radiotherapy was evaluated, the results are sometimes conflicting with the report of clinical deterioration. Then, we hypothesized that chemotherapy may increase the incidence of hyperammonemia without comparable change of major parameters of hepatic/renal disorder. Methods: To verify our hypothesis, we examined the increase in blood ammonia level with 1-h intravenous infusion of alanyl-glutamine on day 1–4 after cisplatin (CDDP) administration in rats and assessed the correlation with hepatic/renal parameters. Results: Hepatic parameters (glutamate-oxaloacetic transaminase [GOT] and glutamic-pyruvic transaminase [GPT]) with CDDP did not change until day 3 and only GOT increased on day 4. Renal parameters (plasma creatinine, blood urea nitrogen) with CDDP continuously increased up to day 4. Alanyl-glutamine infusion significantly elevated blood ammonia level of CDDP rats with the peak on day 3, although the same dose did not change that of control rats. Conclusion: These results indicates that CDDP enhances the increase in blood ammonia level by glutamine supplementation without correlating with primary parameters for hepatic/renal dysfunction. [ABSTRACT FROM AUTHOR]

Introduction of the so-called biocompatible peritoneal dialysis (PD) fluids was based on a large body of experimental evidence and various clinical trials suggesting important clinical benefits. Of these, until now, only preservation of residual renal function-likely due to lower glucose degradation product load and, in case of icodextrin, improved fluid and blood pressure control-have consistently been proven, whereas the impact on important clinical endpoints such as infectious complications, preservation of PD membrane transport function, and patient outcome, are still debated. In view of the high morbidity and mortality rates of PD patients, novel approaches are warranted and comprise the search for alternative osmotic agents and enrichment of PD fluids with specific pharmacologic agents, such as alanyl-glutamine, potentially counteracting local but also systemic sequelae of uremia and PD. [ABSTRACT FROM AUTHOR]

At present, the timing of glutamine administration remains controversial. The aim of the present study was to confirm the early protective mechanisms of alanyl‑glutamine (Ala‑Gln) against lipopolysaccharide (LPS)‑induced lung injury, as well as to detect the best time for Ala‑Gln usage. A total of 60 adult Wistar rats were randomly divided into 6 groups: The control group (C), the LPS‑induced shock group (LPS), the pre‑Ala‑Gln treated group (A1) and the pre‑Gln treated group (G1), which separately received 4.5% Dipeptiven and 3% glutamine just before LPS administration; the post‑Ala‑Gln treated group (A2) and the post‑Gln treated group (G2), which was respectively infused with 4.5% Dipeptiven and 3% glutamine at 1 h following LPS. Survival rates were observed at 6 h following the LPS injection. Blood samples were drawn for analysis of cytokine levels 1 h prior to (T0) and 6 h following (T1) LPS injection. All rats were killed at T1 and the pulmonary samples were collected. Plasma concentrations of tumor necrosis factor‑α, interleukin (IL)‑1β and IL‑8 at T0 and T1, apoptosis in lung epithelial cells and the expression of heat shock protein (HSP)70 were detected. The lung wet/dry weight ratio (W/D) and the content of protein in the bronchoalveolar lavage fluid (BALF) were also determined. Survival rates at 6 h following (T1) LPS administration were both 100% in groups A1 and G2, but 70% in A2 and G2 groups. The W/D, the content of protein in BALF and cytokine levels were significantly lower in groups A1 and G1 than that in group LPS (P<0.05) at T1. The apoptosis index of both alveolar and bronchial epithelial cells was obviously lower in A1 and G1 groups than that in the LPS group (P<0.05). Gray gradients of HSP70 in the A1 and G1 groups were dramatically higher than those of group LPS (P<0.05). In conclusion, pre‑administration of Ala‑Gln just before LPS can effectively protect the lung by enhancing HSP70 expression, but delayed administration cannot protect LPS‑induced lung injury. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effects of ulinastatin (ULi) combined with alanyl glutamine (Ala-Gln) on inflammatory reactions and pulmonary functions in patients with cardiopulmonary bypass (CPB) valve replacement surgery. Methods: 54 cases who had taken the CPB valve replacement surgery in our hospital from June 2013 to November 2016 were selected and randomly divided into two groups. The patients in the control group were treated with conventional method, while the patients in the observation group were treated with Ala-Gln and ULi. Then the serum levels of inflammatory factors and the pulmonary surfactant protein A (SP-A), the lung function indexed and mechanical ventilation time between the two groups were observed and compared. Results: Compared with T0 the serum levels of IL-6, IL-8, TNF-α and SP-A in the two groups at T2，T3, T4 and T5 increased (P<0.01); Compared with the control group at the same time, the serum inflammatory factors and SP-A levels at T2，T3，T4 and T5 in the observation group were lower (P<0.01); Compared with T0, the RI and A-aDO2 in the two groups at T2，T3，T4 and T5 increased (P<0.01); Compared with the control group at the same time, the RI and A-aDO2 values at T2, T3, T4 and T5 in the observation group were lower (P<0.01); Compared with T0, the Cst in the two groups at T1 increased (P<0.01); The mechanical ventilation time in the observation group was significantly lower than that of the control group (P<0.01). Conclusion: ULi combined with Ala-Gln intervention on CPB valve replacement patients can effectively control the inflammatory reactions and protect the pulmonary functions, which is worthy of clinical application. [ABSTRACT FROM AUTHOR]

To investigate the effects of dietary tributyrin (TB) and alanyl-glutamine (AGn) on the intestinal health of largemouth bass ( Micropterus salmoides ) fed with high-level soybean meal (SM) diet, six isonitrogenous (41.36%) and isolipidic (10.25%) diets were formulated and fed to largemouth bass (initial body weight 25.5 ± 0.5g) for 8 weeks. The two control diets contained 34.8% peanut meal (PM) and 41.3% SM, while the other four experimental diets supplemented TB at 0.1% (TB0.1), 0.2% (TB0.2) and AGn at 1% (AGn1), 2% (AGn2) in SM, respectively. The results showed that there were no significant differences in weight gain, survival rate, and hepatosomatic index among all groups ( P >0.05), while feed coefficient rate in AGn1, AGn2 and TB0.2 groups was significantly lower than that in SM group ( P < 0.05). Compared with the PM group, the intestinal inflammation of largemouth bass in SM group were obvious, accompanied by the damage of intestinal structure, the decrease of digestive enzyme activity, and the up-regulation of proinflammatory cytokines. Compared with the SM group, the activities of intestinal trypsin, lipase and foregut amylase in TB and AGn groups increased significantly ( P <0.05), and the gene expression levels of acetyl-CoA carboxylase (ACC), caspase-3, caspase-8, caspase-9, tumor necrosis factor alpha (TNF-α), and interleukin-1 beta (IL-1β) were down-regulated, while the gene expression levels of target of rapamycin (TOR) and eIF4E-binding protein (4E-BP) were up-regulated in all experimental groups ( P <0.05). It can be concluded that supplementation of 1%-2% AGn and 0.1%-0.2% TB can alleviate enteritis caused by high-level soybean meal, and the recommend level is 2% AGn and 0.2% TB., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhao, Yang, Qiu, Zhang, Xu and Wang.)

In this work, we aimed to investigate the effects of long-term supplementations with l-glutamine or l-alanyl- l-glutamine in the high-fat diet (HFD)-fed B6.129SF2/J mouse model over insulin sensitivity response and signaling, oxidative stress markers, metabolism and HSP70 expression. Mice were fed in a standard low-fat diet (STA) or a HFD for 20 weeks. In the 21th week, mice from the HFD group were allocated in five groups and supplemented for additional 8 weeks with different amino acids: HFD control group ( HFD-Con), HFD + dipeptide l-alanyl- l-glutamine group ( HFD-Dip), HFD + l-alanine group ( HFD-Ala), HFD + l-glutamine group ( HFD-Gln), or the HFD + l-alanine + l-glutamine (in their free forms) group ( HFD-Ala + Gln). HFD induced higher body weight, fat pad, fasted glucose, and total cholesterol in comparison with STA group. Amino acid supplementations did not induce any modifications in these parameters. Although insulin tolerance tests indicated insulin resistance in all HFD groups, amino acid supplementations did not improve insulin sensitivity in the present model. There were also no significant differences in the immunocontents of insulin receptor, Akt, and Toll-like receptor-4. Notably, total 70 kDa heat shock protein (HSP72 + HSP73) contents in the liver was markedly increased in HFD-Con group as compared to STA group, which might suggest that insulin resistance is only in the beginning. Apparently, B6.129SF2/J mice are more resistant to the harmful effects of HFD through a mechanism that may include gut adaptation, reducing the absorption of nutrients, including amino acids, which may explain the lack of improvements in our intervention. [ABSTRACT FROM AUTHOR]

The presence of glutamine (Gln) in in vitro maturation (IVM) and in vitro culture (IVC) medium is a more potent factor for improving porcine oocyte and embryo development than other amino acids. However Gln is inherently unstable and spontaneously breaks down into ammonia, and therefore interferes with proper development. To avoid this adverse effect, Gln was replaced in the present study with its stable dipeptide derivative alanyl-glutamine (Ala-Gln) and the effects of this replacement on porcine IVM and IVC were evaluated. Replacement of Gln with Ala-Gln during IVM did not improve nuclear maturation, however numbers of early cleaved embryos were significantly increased after activation. Blastocyst formation rates were also significantly improved by using Ala-Gln during IVM. Replacement of Gln with Ala-Gln during IVC significantly increased total cell numbers in blastocysts. Blastocyst formation rate was also significantly higher when Ala-Gln was used in both IVM and IVC. In conclusion, the use of Ala-Gln rather than Gln gives better results for development in both porcine IVM and IVC. [ABSTRACT FROM PUBLISHER]

Abstract: Background: Anesthesia and surgery starts a series of stress responses in the body. Subsequently, loss of normal anabolic actions of insulin and development of insulin resistance occur. Resulting hyperglycemia has been considered by an evidence based study as a risk factor for perioperative morbidity and mortality. We tested whether a single preoperative dose of alanyl-glutamine would prevent such responses in addition to maintaining glutathione level; an important factor for maintaining cellular redox potential. Methods: A total of 40 cancer patients were enrolled in this study who received an infusions of 500ml of Normal Saline started an hour before surgery and continued throughout the surgery. The Dipeptiven® group (20 patients): 2ml Dipeptiven®/kg were added to saline, while the control group (20 patients): nothing was added to saline. Blood samples were taken a preoperative sample and two postoperative samples (immediately after immergence from anesthesia and 24h after surgery). These samples were analyzed for plasma glucose, plasma insulin to calculate insulin resistance by HOMA test. Plasma reduced glutathione level was also analyzed in the same time points. Results: We found that insulin resistance and glucose level were less in the tested time points in the Dipeptiven® group of patients when compared with the control group. Furthermore, plasma glutathione level was higher in the Dipeptiven® group than the control group. Conclusion: Preoperative alanyl-glutamine is helpful in amelioration of insulin resistance and improvement of plasma glutathione levels in the early postoperative period. [Copyright &y& Elsevier]

Abstract: T helper (Th) cells play a major role in the pathogenesis of inflammatory bowel disease (IBD). Glutamine (Gln) is known to have immunomodulatory effects in metabolic stressed conditions. This study investigated the effects of post-treatment of alanyl-glutamine (Ala-Gln) on Th cell-associated cytokine expressions and inflammatory reaction in dextran sulfate sodium (DSS)-induced colitis. C57BL/6 mice received distilled water containing 3% DSS for 5days to induce colitis, whereas the normal control (NC) group received distilled water. After induction of colitis, one of the colitis groups (DG) was intraperitoneally injected with an Ala-Gln solution (0.5gGln/kg/d), and the saline DSS group (DS) received an identical volume of saline. After treatment for 3days, mice were sacrificed, and the blood and tissue samples were collected for further analysis. DSS colitis resulted in higher percentages of blood interleukin (IL)-17-secreting Th cells and greater expression of Th cell-associated cytokine messenger RNA (mRNA) in the mesenteric lymph nodes (MLN). Also, luminal immunoglobin (Ig) G, keratinocyte-derived chemokine, and macrophage chemoattractant protein-1 levels were higher in the DS group than the NC group, whereas these parameters did not differ between the DG and NC groups. The DG group had lower blood IL-17A, 17F, MLN IL-17 mRNA and macrophage percentage in the peritoneal lavage fluid than those of the DS group. These results suggest that post-treatment with Ala-Gln suppressed Th17-associated cytokine expressions, reduced macrophage infiltration into the peritoneal cavity and decreased pro-inflammatory cytokine production in the colon, thus may have attenuated inflammatory response in DSS-induced colitis. [Copyright &y& Elsevier]

Background. Clostridium difficile is an anaerobic bacterium that causes antibiotic-associated diarrhea. It produces toxin A and toxin B (TcdB), which cause injury to the gut epithelium. Glutamine is a fundamental fuel for enterocytes, maintaining intestinal mucosal health. Alanyl-glutamine (AQ) is a highly soluble dipeptide derivative of glutamine. We studied whether administration of AQ ameliorates the effects of TcdB in the intestinal cells and improves the outcome of C. difficile infection in mice.Methods. WST-1 proliferation and cell-wounding-migration assays were assessed in IEC-6 cells exposed to TcdB, with or without AQ. Apoptosis and necrosis were assessed using Annexin V and flow cytometry. C57BL/6 mice were infected with VPI 10463 and treated with either vancomycin, AQ, or vancomycin with AQ. Intestinal tissues were collected for histopathologic analysis, apoptosis staining, and determination of myeloperoxidase activity.Results. AQ increased proliferation in intestinal cells exposed to TcdB, improved migration at 24 and 48 hours, and reduced apoptosis in intestinal cells challenged with TcdB. Infected mice treated with vancomycin and AQ had better survival and histopathologic findings than mice treated with vancomycin alone.Conclusions. AQ may reduce intestinal mucosal injury in C. difficile–infected mice by partially reversing the effects of TcdB on enterocyte proliferation, migration, and apoptosis, thereby improving survival from C. difficile infection. [ABSTRACT FROM PUBLISHER]

The article examines the effects of enteral and parenteral glutamine supplementation in patients suffering multiple trauma. The immune and metabolic responses to trauma and injury are explained. The mechanism of glutamine synthesis during stress and critical illness is also explained. The authors note the need for multi-centre and well-designed clinical trials to provide evidence that supports using glutamine supplementation as a therapeutic regimen in multiple trauma patients.

Background. Exposure of mesothelial cells to peritoneal dialysis fluids (PDF) results in cytoprotective cellular stress responses (CSR) that counteract PDF-induced damage. In this study, we tested the hypothesis that the CSR may be inadequate in relevant models of peritoneal dialysis (PD) due to insufficient levels of glutamine, resulting in increased vulnerability against PDF cytotoxicity. We particularly investigated the role of alanyl–glutamine (Ala-Gln) dipeptide on the cytoprotective PDF stress proteome. Methods. Adequacy of CSR was investigated in two human in vitro models (immortalized cell line MeT-5A and mesothelial cells derived from peritoneal effluent of uraemic patients) following exposure to heat-sterilized glucose-based PDF (PD4-Dianeal, Baxter) diluted with medium and, in a comparative proteomics approach, at different levels of glutamine ranging from depletion (0 mM) via physiological (0.7 mM) to pharmacological levels (8 mM administered as Ala-Gln). Results. Despite severe cellular injury, expression of cytoprotective proteins was dampened upon PDF exposure at physiological glutamine levels, indicating an inadequate CSR. Depletion of glutamine aggravated cell injury and further reduced the CSR, whereas addition of Ala-Gln at pharmacological level restored an adequate CSR, decreasing cellular damage in both PDF exposure systems. Ala-Gln specifically stimulated chaperoning activity, and cytoprotective processes were markedly enhanced in the PDF stress proteome. Conclusions. Taken together, this study demonstrates an inadequate CSR of mesothelial cells following PDF exposure associated with low and physiological levels of glutamine, indicating a new and potentially relevant pathomechanism. Supplementation of PDF with pharmacological doses of Ala-Gln restored the cytoprotective stress proteome, resulting in improved resistance of mesothelial cells to exposure to PDF. Future work will study the clinical relevance of CSR-mediated cytoprotection. [ABSTRACT FROM PUBLISHER]

Summary: Background & aims: Increased intestinal permeability of Irritable bowel syndrome (IBS) patients has been recently associated with a decreased level of glutamine synthetase. Neonatal maternal deprivation (NMD) is considered as an IBS-like model. The aim of our study was to investigate whether early nutritional intervention with glutamine may attenuate the deleterious impact of early life stress on gut barrier function in NMD. Methods: 124 rat pups were separated from their dam 3 h daily during postnatal days 2–14, or left undisturbed (NS). Separated rats received by gavage either with alanyl-glutamine (GLN), an isonitrogenous amino acid mix (AA, control) or an equal amount of drinking water (H2O). Production of cytokines was measured by multiplex, expression of COX-2, PPARγ, tight junction proteins and TLR4 by western blot. Intestinal permeability was studied by Lactulose/Mannitol test. Results: Treatment of pups with GLN or AA abolished the decrease in body weight observed in NMD. Treatment with GLN decreased in the colon (i) TLR4 expression at D20, (ii) IL-2 and -10 productions at D60 (iii) protein expression of occludin at D20 compared to AA. GLN also decreased colon expression of COX2 and PPARγ at D60 compared to NS. Colon production of IFNγ is significantly reduced by GLN compared to H2O. No significant change in intestinal permeability was observed. Conclusions: These results showed that an early nutritional intervention with alanyl-glutamine specifically abolished the up-regulation of TLR4 expression in NMD. Glutamine may be evaluated as a potential treatment for IBS patients. [Copyright &y& Elsevier]

Mucositis induced by anti-neoplastic drugs is an important, dose-limiting and costly side effect of cancer therapy. To evaluate the effect of oral glutamine and alanyl-glutamine, a more stable glutamine derivative, on 5-FU-induced oral mucositis in hamsters. Oral mucositis was induced by two intraperitoneal (i.p) administrations of 5-FU on the first and second days of the experiment (60 and 40 mg/kg, respectively) followed by mechanical trauma on the fourth day in male hamsters. Animals received saline, glutamine or alanyl-glutamine suspension (100 mM) 1 h before the injections of 5-FU and daily until sacrifice, on the 10th or 14th day. Macroscopic and histopathological analyses were evaluated and graded. Tissues from the cheek pouches were harvested for measurement of myeloperoxidase activity and glutathione stores. For investigation of serum concentration of glutamine, blood was obtained by heart puncture from anesthetized animals before sacrifice, on day 10. Treatment with glutamine and alanyl-glutamine reduced macroscopic and histological parameters of oral mucositis, and reduced the myeloperoxidase activity on day 14, but not on day 10. The 5-FU-induced oral mucositis significantly decreased the serum glutamine levels as well as the cheek pouch glutathione stores observed on day 10. Glutamine or alanyl-glutamine administration reversed the 5-FU effects, restoring serum glutamine levels and cheek pouch glutathione stores, observed on day 10, but did not prevent oral mucositis on the tenth day. Glutamine or alanyl-glutamine accelerated the mucosal recovery increasing mucosal tissue glutathione stores, reducing inflammatory parameters and speeding reepithelization. [ABSTRACT FROM AUTHOR]

Abstract: Objective: We investigated the effect of supplementation with L-glutamine and L-alanyl-L-glutamine (DIP) on the plasma and tissue glutamine concentrations of exercise-trained rats immediately and 3 hours after a single exercise session until exhaustion. Methods: Thirty-six male rats were divided into six groups, and then subdivided into groups submitted only to the exhaustion test: control (CON-EXA, n = 6), glutamine (GLN-EXA, n = 6) and DIP-EXA (n = 6), or to the exhaustion test followed by a recovery period lasting 3 hours: control (CON-REC, n = 6), glutamine (GLN-REC, n = 6) and DIP-REC (n = 6). The training protocol consisted of bouts of swimming exercise (60 min·day1) for 6 weeks. During the last 21 days, before sacrifice, the glutamine and DIP groups received a daily dose of 1 g·kg1 of glutamine and 1.5 g·kg1 of DIP, respectively. The GLN-REC and DIP-REC groups were also supplemented immediately after the exhaustion test. Concentrations of glutamine, glutamate, glucose and ammonia in plasma and of glutamine, protein and glycogen in liver and muscle were evaluated. Results: The time to exhaustion did not differ between groups. A higher concentration of glutamine in the gastrocnemius and soleus muscles was observed for the DIP-EXA group compared to the CON-EXA and GLN-EXA groups (P < 0.05). The DIP-REC group presented a higher plasma and liver glutamine concentration than the CON-REC group (P < 0.05). Muscle glutamine and protein concentration was higher in both the GLN-REC and DIP-REC groups compared to the CON-REC group (P < 0.05). Conclusions: Chronic supplementation with DIP promoted a higher muscle glutamine concentration than chronic supplementation with glutamine immediately after exercise. However, no significant difference in plasma or tissue glutamine concentrations was observed between acute supplementation with glutamine and DIP during the post-exhaustive exercise recovery period. [Copyright &y& Elsevier]

Objective: In this study, we postulated the beneficial role of oral alanyl-glutamine, a more stable glutamine derivative to decrease 5-fluorouracil (5-FU)–induced mucositis in mice.Methods: We measured different morphologic parameters to assess structural changes over time in the small bowel, including crypt depth, villus height, villus area, mitotic and apoptotic indices at the crypt level using terminal deoxyuridine triphosphate nick end labeling, and hematoxylin–eosin staining of ileal tissue. In addition, we analyzed the effect of different alanyl-glutamine concentrations on animal weight curves after 5-FU treatment.Results: Neither glutamine nor alanyl- glutamine prevented the 5-FU intestinal structural damage or apoptosis in crypt enterocytes at 24 h after 5-FU challenge. However, we found that alanyl-glutamine, but not glutamine, speeds intestinal recovery when compared with 5-FU–treated controls (P < 0.05), predominantly by enhancing mitotic activity and crypt length.Conclusion: Our findings provide important data to support clinical studies of oral alanyl-glutamine in 5-FU–induced mucositis. [Copyright &y& Elsevier]

The objective of the present study was to determine the effect of acute oral supplementation with glutamine (GLN) or the dipeptide L-alanyl-L-glutamine (ALA-GLN) on the kinetic response of plasma GLN concentration, as well as the effect of chronic supplementation on plasma, muscle, and liver GLN levels. Acute supplementation with GLN and ALA-GLN significantly increased plasma GLN concentration compared to basal values. However, plasma GLN concentration 30 minutes after supplementation and the area under the curve were significantly higher in the group acutely supplemented with ALA-GLN than in the GLN-supplemented group (P < 0.01). Chronic supplementation with GLN or ALA-GLN did not alter glutaminemia; however, higher muscle (P < 0.05) and liver (P < 0.01) GLN levels were observed for the ALA-GLN-supplemented group. In conclusion, acute ALA-GLN supplementation promoted a greater increase in glutaminemia, and chronic supplementation increased muscle and liver GLN stores. [Copyright &y& Elsevier]

Abstract Background: Glutamine is the principal fuel used by the small intestine. Although the parental administration of glutamine promotes intestinal mucosal growth, it is controversial whether enteral glutamine is effective against small intestinal damage caused by chemotherapy. To further evaluate the benefits of enteral supplementation, peptide and amino acid transporter functions must be considered. Method: Rats were given cyclophosphamide (CPM) intraperitoneally (300 mg/kg). Expression of the amino acid transporter, B0 and peptide transporter (PepT1) in the jejunal mucosa was initially examined by northern blot analysis. Rats received a bolus oral supplement of an alanine (1.22 g/kg/day) plus glutamine (2.0 g/kg/day) mixture, alanyl-glutamine (2.972 g/kg/day) or saline as a control, for 7 days after CPM administration. Results: Levels of B0 mRNA remained unchanged at both 3 and 7 days after CPM administration. Conversely, PepT1 mRNA increased significantly after CPM administration, and reached 200% of the initial level 7 days later. In rats given alanyl-glutamine, the mucosal wet weight and protein content increased significantly with increasing villus height at 3 and 7 days, compared with the alanine plus glutamine mixture. The plasma glutamine concentration in the alanyl-glutamine group, but not the alanine plus glutamine mixture group, increased significantly compared with that in the saline group. Conclusion: Enteral supplementation with an alanyl-glutamine but not alanine plus glutamine mixture prevents intestinal damage, as demonstrated by increased peptide transport expression and an elevated plasma glutamine concentration after CPM administration. [ABSTRACT FROM AUTHOR]

Objectives: Recurring diarrhea and persistent diarrhea are commonly associated with malnutrition and long-term functional deficits. A beneficial approach would be to develop an alanyl-glutamine (AlaGln)—based oral rehydration and nutrition therapy (ORNT). We investigated the effect of an AlaGln-ORNT solution on electrolyte and water absorption in a rat model of secretory diarrhea induced by cholera toxin.Methods: Phenolsulfonphthalein (50 μg/mL) was used as a non-absorbable marker for calculation of net water and electrolyte transport. Solutions tested were Ringer’s solution, a glutamine-based ORNT (Gln-ORNT) solution, and an AlaGln-ORNT solution. Cholera toxin (1 μg/mL) was injected into lumen of rat small intestinal segments and incubated for 18 h before the initiation of the perfusion.Results: Cholera toxin induced significant secretion of electrolyte and water in the control Ringer’s solution. AlaGln-ORNT and Gln-ORNT solutions reduced the sodium secretory effect of cholera toxin by 128% and 36%, respectively. The net water secretion also was reduced by 95% and 60%, respectively, with the AlaGln-ORNT and Gln-ORTN solutions.Conclusions: These results showed that AlaGln-ORNT solution can enhance water and electrolyte intestinal absorption even better than glutamine or glucose and thus provide a potential novel approach for ORNT to break the vicious cycle of diarrhea and malnutrition. Clinical trials are now needed in children and adults with diarrhea and malnutrition. [ABSTRACT FROM AUTHOR]

Endothelial and epithelial barrier function is crucial for the maintenance of physiological processes. The barrier paracellular permeability depends on the composition and spatial distribution of the cell-to-cell tight junctions (TJ). Here, we provide an experimental workflow that yields several layers of physiological data in the setting of a single endothelial cell monolayer. Human umbilical vein endothelial cells were grown on Transwell filters. Transendothelial electrical resistance (TER) and 10 kDa FITC dextran flux were measured using Alanyl-Glutamine (AlaGln) as a paracellular barrier modulator. Single monolayers were immunolabelled for Zonula Occludens-1 (ZO-1) and Claudin-5 (CLDN5) and used for automated immunofluorescence imaging. Finally, the same monolayers were used for single molecule localization microscopy (SMLM) of ZO-1 and CLDN5 at the nanoscale for spatial clustering analysis. The TER increased and the paracellular dextran flux decreased after the application of AlaGln and these functional changes of the monolayer were mediated by an increase in the ZO-1 and CLDN5 abundance in the cell–cell interface. At the nanoscale level, the functional and protein abundance data were accompanied by non-random increased clustering of CLDN5. Our experimental workflow provides multiple data from a single monolayer and has wide applicability in the setting of paracellular studies in endothelia and epithelia. [ABSTRACT FROM AUTHOR]