Glutamine Concentrations Research Articles

Accelerated biological aging, mediating amino acids, and risk of incident type 2 diabetes: a prospective cohort study.

Aging plays an important role in type 2 diabetes mellitus (T2DM). But the association between accelerated biological age and T2DM, and the mechanisms underlying this association remains unclear. Thus, this study aimed to examine the associations of biological aging with T2DM, and explore the potential mediation effect of amino acids. This prospective cohort study included 95,773 participants in the UK Biobank who were free of diabetes at baseline. Biological age was measured from clinical traits using PhenoAgeAccel. Cox proportional hazard models were used to estimate the hazard ritios (HRs) and 95% confidence intervals (CIs), and mediation analysis was used to explore the mediation effect of amino acids. During a median follow-up of 14.02 years, 6,347 incident T2DM cases were recorded. After multivariable adjustment for sociodemographic characteristics, lifestyle factors, and other risk factors of T2DM, participants with older biological age were at increased risk of incident T2DM (30% increase per standard deviation of PhenoAgeAccel, 95% CI: 28.0-33.0%). Additionally, higher branched chain amino acids (BCAAs) including isoleucine and leucine, aromatic amino acids (AAAs) including phenylalanine and tyrosine, were associated with increased PhenoAgeAccel and risk of incident T2DM; while glutamine and glycine were inversely associated. Alanine, glutamine, glycine, phenylalanine, tyrosine, isoleucine, leucine, and total concentration of branched-chain amnio acids could partially explain the associations between PhenoAgeAccel and T2DM. Accelerated biological aging was associated with increased risk of incident T2DM independent of chronological age and may be a risk factor of T2DM, partially mediated by several amino acids.

Hyperglycemia-depleted glutamine contributes to the pathogenesis of diabetic corneal endothelial dysfunction

Diabetic mellitus causes various complications, including the corneal endothelial dysfunction (CED) that leads to corneal edema and vision loss, especially in the DM patients with intraocular surgeries. However, the pathogenic mechanism of hyperglycemia-caused CED remains incomplete understood. Here we firstly screened and identified the glutamine contents of anterior humor were significantly reduced in both the type 2 diabetic patients and streptozotocin-induced type 1 diabetic mice. To explore the potential therapeutic effects of glutamine supplement on the protection of diabetic corneal endothelial dysfunction, we performed the anterior chamber perfusion with the addition of L-alanyl-L-glutamine (Ala-Gln), and confirmed that Ala-Gln supplement not only accelerated the resolution of corneal edema and recovery of corneal thickness, but also preserved the regular arrangement and barrier-pomp function of corneal. Mechanistically, we revealed that the supplements of Ala-Gln protect corneal endothelial cells from the deleterious effects of high glucose-induced oxidative stress, mitochondrial dysfunction, and cell apoptosis. Overall, these results indicate the glutamine depletion plays an important role in the diabetic corneal endothelial dysfunction, while the Ala-Gln supplement during intraocular surgery provide an effective prevention strategy through regulating the redox homeostasis and mitochondrial function of corneal endothelial cells.

The mechanism of improving the flavor quality of bighead carp (Aristichthys nobilis) by the short-term micro-flowing water treatment

The short-term micro-flowing water treatment (STMF) has been proven to improve the taste quality of bighead carp. However, few studies have focused on its impact on the aroma quality of bighead carp muscle and the underlying mechanism. This study investigated the effect of STMF on the aroma quality of bighead carp muscle using UPLC–MS/MS-based metabolomics and gas chromatography–mass spectrometry (SAFE–GC–MS) combined with semi-quantitative methods. A total of 56 volatile compounds were found in the bighead carp muscle by SAFE–GC–MS. During the STMF, the contents of hexanal and (E,E)-2,4-heptadienal decreased significantly, which decreased by 24.09 % and 20.80 % after 6 days of the STMF, respectively. However, the contents of (E)-2-octenal and (E)-2-nonenal showed a trend of rising first and then falling, with maximum values at the 6th day of the STMF. The Pearson’s correlation coefficient showed a good correlation between some sensory attributes and aroma compounds. The fatty acid, amino acid, and glutathione metabolism of bighead carp muscle were significantly changed after 2 days of the STMF, with the contents of carnitine and acylcarnitine increased and then the contents of glutamic acid and glutamine increased. The improvement of flavor quality could be related to metabolism of carnitine, glutamic acid, glutamine, and glutathione. This study may help to understand the mechanism of STMF in enhancing the aroma quality of aquatic products.

Urinary chloride excretion in critical illness and acute kidney injury: a paediatric hypothesis-generating cohort study post cardiopulmonary bypass surgery.

Renal chloride metabolism is currently poorly understood but may serve as both a diagnostic and a treatment approach for acute kidney injury. We investigated whether plasma chloride, ammonia and glutamine as well as urinary chloride, ammonium and glutamine concentrations may serve as markers for acute kidney injury in paediatric patients. We conducted a prospective observational trial in a tertiary care paediatric intensive care unit. Ninety-one patients after cardiopulmonary bypass surgery were enrolled. Plasma glutamine, creatinine, (serum) albumin, urinary electrolytes and glutamine were collected pre-cardiopulmonary bypass surgery, at paediatric intensive care unit admission, and at 6, 12, 24, 48 and 72 h after paediatric intensive care unit admission. The urinary strong ion difference was calculated. The median urinary chloride excretion decreased from 51 mmol/L pre-cardiopulmonary bypass to 25 mmol/L at paediatric intensive care unit admission, and increased from 24 h onwards. Patients with acute kidney injury had lower urinary chloride excretion than those without. The median urinary strong ion difference was 59 mmol/L pre-cardiopulmonary bypass, rose to 131 mmol/L at 24 h and fell to 20 mmol/L at 72 h. The plasma chloride rose from 105 mmol/L pre-cardiopulmonary bypass to a maximum of 109 mmol/L at 24 h. At 24 h the plasma chloride concentration was associated with the presence of acute kidney injury. There was no association between plasma or urinary amino acids and chloride excretion or kidney injury. In conclusion, renal chloride excretion decreased in all patients, although this decrease was more pronounced in patients with acute kidney injury. Our findings may reflect a response of the kidneys to critical illness, and acute kidney injury may make these changes more pronounced. Targeting chloride metabolism may offer treatment approaches to acute kidney injury.

Glutamine metabolism promotes human trophoblast cell invasion via COL1A1 mediated by PI3K-AKT pathway

Abnormal trophoblast invasion function is an important cause of recurrent spontaneous abortion (RSA). Recent research has revealed a connection between glutamine metabolism and RSA. However, the interplay between these three factors and their related mechanisms remains unclear. To address this issue, we collected villus tissues from 10 healthy women with induced abortion and from 10 women with RSA to detect glutamine metabolism. Then, the trophoblast cell line HTR-8/SVneo was used in vitro to explore the effect of glutamine metabolism on trophoblast cells invasion, which was tested by transwell assay. We found that the concentration of glutamine in the villi of the normal pregnancy group was significantly higher than that in the RSA group. Correspondingly, the expression levels of key enzymes involved in glutamine synthesis and catabolism, including glutamine synthetase and glutaminase, were significantly higher in the villi of the normal pregnancy group. Regarding trophoblast cells, glutamine markedly enhanced the proliferative and invasive abilities of HTR-8/SVneo cells. Additionally, collagen type I alpha 1 (COL1A1) was confirmed to be a downstream target of glutamine, and glutamine also activated the PI3K-AKT pathway in HTR-8/SVneo cells. These findings indicate that glutamine metabolism facilitates the invasion of trophoblasts by up-regulating COL1A1 expression through the activation of the PI3K-AKT pathway, but the specific mechanism of COL1A1 requires further study.

The Effects of L-citrulline Supplementation on the Athletic Performance, Physiological and Biochemical Parameters, Antioxidant Capacity, and Blood Amino Acid and Polyamine Levels in Speed-Racing Yili Horses.

The objective of this study was to evaluate the effects of pre-exercise L-citrulline supplementation on the athletic performance of Yili speed-racing horses during a high-intensity exercise. On the 20th day of the experiment, blood samples were collected at 3 h and 6 h post-supplementation to measure the amino acid and polyamine concentrations. On the 38th day of the experiment, the horses participated in a 2000 m speed race, and three distinct blood samples were gathered for assessing blood gases, hematological parameters, the plasma biochemistry, antioxidant parameters, and NO concentrations. The results indicate that the L-citrulline group showed a significant increase in the plasma citrulline and arginine concentrations. Conversely, the concentrations of alanine, serine, and threonine were significantly decreased. The glycine concentration decreased significantly, while there was a trend towards an increase in the glutamine concentration. Additionally, the levels of putrescine and spermidine in the plasma of the L-citrulline group were significantly increased. In terms of exercise performance, L-citrulline can improve the exercise performance of sport horses, significantly reduce the immediate post-race lactate levels in Yili horses, and accelerate the recovery of blood gas levels after an exercise. Furthermore, in the L-citrulline group of Yili horses, The levels of the total protein of plasma, superoxide dismutase, catalase, and lactate dehydrogenase were significantly increased both 2 h before and 2 h after the race. The total antioxidant capacity showed a highly significant increase, while the malondialdehyde content significantly decreased. In the immediate post-race period, the creatinine content in the L-citrulline group significantly increased. In conclusion, this study demonstrates that L-citrulline supplementation can influence the circulating concentrations of L-citrulline and arginine in Yili horses, enhance the antioxidant capacity, reduce lactate levels, and improve physiological and biochemical blood parameters, thereby having a beneficial effect on the exercise performance of athletic horses.

Various effects of feeding level on ammonia tolerance in Carassius auratus under different ammonia exposure stress and the underlying mechanisms

Elevated ammonia levels in aquaculture systems could reduce fish growth and survival rates and produce a range of physiological problems. Ammonia toxicity in aquatic environments was regulated by various factors. Feeding was usually reported to help in the detoxification of fish, thereby increasing their capacity to tolerate ammonia nitrogen. However, the impact of different feeding amounts on fish in relation to ammonia exposure stress remains to be determined. To determine how feeding levels affected fish's responses to different ammonia nitrogen concentrations, two acute toxicity experiments were conducted with Carassius auratus gibelio, the major strain of gibel carp in aquaculture systems in China. In Test I, fed Carassius auratus gibelio (3 % body weight) showed a higher survival rate under a specific ammonia exposure stress. 96-h LC50 of NH3-N to 3 %F gibel carp was 1.1 times greater than that for NF (no feeding). In Test II, all fed groups (2 %F and 4 %F) under low and high ammonia stress exhibited improved ammonia detoxification, evidenced by higher liver GSase, GDH, and glutamine concentrations compared with the NF treatment. Muscle glycogen levels in feeding treatments were higher than those in NF, indicating that fed fish have more energy for ammonia detoxification. While compared with low ammonia treatment (2.70 mg L−1 TAN; NH3 0.06 mg L−1), fish exposed to high ammonia levels (26.03 mg L−1 TAN; NH3 0.57 mg L−1) demonstrated a decrease in food consumption, severe histopathological alterations in their liver, gill, and kidney, and decreased GSase, GDH, and glutamine production in the liver and brain. The results partly supported our hypothesis and suggested that increasing feeding enhances gibel carp's tolerance to ammonia nitrogen. The highest detoxification metabolism was observed under low ammonia stress. While excessive ammonia exposure could inhibit feeding and damage the detoxification organs of fish, and thus reduce the detoxification metabolism of gibel carp.

Treatment response of venlafaxine induced alterations of gut microbiota and metabolites in a mouse model of depression.

Antidepressants remain the first-line treatment for depression. However, the factors influencing medication response are still unclear. Accumulating evidence implicates an association between alterations in gut microbiota and antidepressant response. Therefore, the aim of this study is to investigate the role of the gut microbiota-brain axis in the treatment response of venlafaxine. After chronic social defeat stress and venlafaxine treatment, mice were divided into responders and non-responders groups. We compared the composition of gut microbiota using 16S ribosomal RNA sequencing. Meanwhile, we quantified metabolomic alterations in serum and hippocampus, as well as hippocampal neurotransmitter levels using liquid chromatography-mass spectrometry. We found that the abundances of 29 amplicon sequence variants (ASVs) were significantly altered between the responders and non-responders groups. These ASVs belonged to 8 different families, particularly Muribaculaceae. Additionally, we identified 38 and 39 differential metabolites in serum and hippocampus between the responders and non-responders groups, respectively. Lipid, amino acid, and purine metabolisms were enriched in both serum and hippocampus. In hippocampus, the concentrations of tryptophan, phenylalanine, gamma-aminobutyric acid, glutamic acid, and glutamine were increased, while the level of succinic acid was decreased in the responders group, compared with the non-responders group. Our findings suggest that the gut microbiota may play a role in the antidepressant effect of venlafaxine by modulating metabolic processes in the central and peripheral tissues. This provides a novel microbial and metabolic framework for understanding the impact of the gut microbiota-brain axis on antidepressant response.

Gamma-glutamyl transferase secreted by Helicobacter pylori promotes the development of gastric cancer by affecting the energy metabolism and histone methylation status of gastric epithelial cells

BackgroundHelicobacter pylori (H. pylori) infection is critical in the development and occurrence of gastric cancer. H. pylori secretes gamma-glutamyl transferase (GGT), which affects energy metabolism and histone methylation in mesenchymal stem cells. However, its effect on human gastric epithelial cells remains unclear. This study aimed to investigate the effects of GGT on energy metabolism and histone methylation in gastric epithelial cells and determine its role in the development and progression of H. pylori-induced gastric cancer.MethodsA GGT knockout H. pylori strain and mouse gastric cancer model were constructed, and alpha-ketoglutarate (α-KG) was added. The underlying mechanism was investigated using proteomics, immunohistochemistry, Western blotting, and other experimental assays.ResultsH. pylori can colonize the host’s stomach and destroy the gastric epithelium. GGT secreted by H. pylori decreased the concentration of glutamine in the stomach and increased H3K9me3 and H3K27me3 expression, which promoted the proliferation and migration of gastric epithelial cells. Additionally, α-KG reversed this effect. GGT increased the tumorigenic ability of nude mice. GGT, secreted by H. pylori, promoted the expression of ribosomal protein L15 (RPL15), while GGT knockout and supplementation with α-KG and trimethylation inhibitors reduced RPL15 expression and Wnt signaling pathway expression.ConclusionsH. pylori secreted GGT decreased the expression of glutamine and α-KG in gastric epithelial cells, increased the expression of histones H3K9me3 and H3K27me3, and activated the Wnt signaling pathway through RPL15 expression, ultimately changing the biological characteristics of the gastric epithelium and promoting the occurrence of gastric cancer. Altered energy metabolism and histone hypermethylation are important factors involved in this process.Graphical abstract

Hypoactivity and neurochemical alterations in the basal ganglia of female Sprague-Dawley rats after repeated exposure to atrazine.

The herbicide atrazine (ATR) has been one of the most widely used herbicides worldwide. However, due to its indiscriminate use, it has been considered an environmental contaminant. Several studies have classified ATR as an endocrine disruptor, and it has been found to have neurotoxic effects on behavior, along with alterations in the dopaminergic, GABAergic, and glutamatergic systems in the basal ganglia of male rodents. These findings suggest that these neurotransmitter systems are targets of this herbicide. However, there are no studies evaluating the neurotoxicity of ATR in female rodents. Our study aimed to assess the effects of repeated IP injections of 100mg ATR/kg or a vehicle every other day for 2weeks (six injections) on the locomotor activity, content of monoamines, GABA, glutamate, and glutamine in the striatum, nucleus accumbens, ventral midbrain, and prefrontal cortex, and tyrosine hydroxylase (TH) protein levels in striatum and nucleus accumbens of female rats. Repeated 100mg ATR/kg injections immediately decreased all the locomotor activity parameters evaluated, and such hypoactivity persisted for at least 48h after the last ATR administration. The ATR administration increased dopamine and DOPAC content in the nucleus accumbens and the dopamine and DOPAC and serotonin and 5-HIAA content in the ventral midbrain. In contrast, the TH protein levels in the striatum and nucleus accumbens were similar between groups. Meanwhile, GABA, glutamine, and glutamate levels remained unaltered in all brain regions evaluated. The observed behavioral alterations could be associated with the monoamine changes presented by the rats. These data reveal that the nucleus accumbens and ventral midbrain are susceptible to repeated ATR exposure in female rats.

TFAP2A Activates S100A2 to Mediate Glutamine Metabolism and Promote Lung Adenocarcinoma Metastasis.

Lung adenocarcinoma (LUAD) is a fatal disease with metabolic abnormalities. The dysregulation of S100 calcium-binding protein A2 (S100A2), a member of the S100 protein family, is connected to the development of various cancers. The impact of S100A2 on the LUAD occurrence and metastasis, however, has not yet been reported. The functional mechanism of S100A2 on LUAD cell metastasis was examined in this article. The expression of TFAP2A and S100A2 in LUAD tissues and cells was analyzed by bioinformatics and qRT-PCR, respectively. The enrichment pathway analysis was performed on S100A2. Bioinformatics analysis determined the binding relationship between TFAP2A and S100A2, and their interaction was validated through dual-luciferase and chromatin immunoprecipitation experiments. Cell viability was determined using cell counting kit-8 (CCK-8). A transwell assay was performed to analyze the invasion and migration of cells. Immunofluorescence was conducted to obtain vimentin and E-cadherin expression, and a western blot was used to detect the expression of MMP-2, MMP-9, GLS, and GLUD1. The kits measured the NADPH/NADP ratio, glutathione (GSH)/glutathione disulfide (GSSG) levels, and the contents of glutamine, α-KG, and glutamate. S100A2 was upregulated in LUAD tissues and cells, and S100A2 mediated glutamine metabolism to induce LUAD metastasis. Additionally, the transcriptional regulator TFAP2A was discovered upstream of S100A2, and TFAP2A expression was upregulated in LUAD, which indicated that TFAP2A promoted the S100A2 expression. The rescue experiment found that upregulation of S100A2 could reverse the inhibitory effects of silencing TFAP2A on glutamine metabolism and cell metastasis. In conclusion, by regulating glutamine metabolism, the TFAP2A/S100A2 axis facilitated LUAD metastasis. This suggested that targeting S100A2 could be beneficial for LUAD treatment.

A preliminary retrospective evaluation of screening and diagnosis of ornithine transcarbamylase deficiency in high-risk patients at a referral center in Vietnam

IntroductionTo date, newborn screening (NBS) for proximal urea cycle disorders, including Ornithine transcarbamylase deficiency (OTCD), was not recommended due to the lack of appropriate tests and insufficient evidence of the benefits. This study aimed to investigate the potential of tandem mass spectrometry (MS/MS) for OTCD screening and its value in guiding further investigation to obtain a final diagnosis in high-risk patients. MethodsThe study included patients with OTCD referred to the National Children's Hospital between April 2020 and November 2023. A retrospective evaluation of amino acid concentrations measured by MS/MS and their ratios in patients with early-onset and late-onset OTCD was conducted. ResultsWhile all ten early-onset cases had glutamine concentrations above the upper limit, only five of them had citrulline concentrations below the lower limit of the reference interval. Only two late-onset cases had elevated glutamine levels, while all had citrulline within reference intervals. The Cit/Phe ratio was decreased, and the Gln/Cit and Met/Cit ratios were increased in all early-onset OTCD cases, while they were abnormal in only one late-onset case. ConclusionsThe preliminary results suggest that hyperglutaminemia, in combination with low or normal citrulline concentrations and specific ratios (Gln/Cit, Met/Cit, and Cit/Phe), can serve as reliable markers for screening early-onset OTCD in high-risk patients. However, these markers proved less sensitive for detecting the late-onset form, even in symptomatic patients.

Medial prefrontal cortex neurotransmitter abnormalities in posttraumatic stress disorder with and without comorbidity to major depression.

Posttraumatic stress disorder (PTSD) is a chronic psychiatric condition that follows exposure to a traumatic stressor. Though previous in vivo proton (1H) MRS) research conducted at 4 T or lower has identified alterations in glutamate metabolism associated with PTSD predisposition and/or progression, no prior investigations have been conducted at higher field strength. In addition, earlier studies have not extensively addressed the impact of psychiatric comorbidities such as major depressive disorder (MDD) on PTSD-associated 1H-MRS-visible brain metabolite abnormalities. Here we employ 7 T 1H MRS to examine concentrations of glutamate, glutamine, GABA, and glutathione in the medial prefrontal cortex (mPFC) of PTSD patients with MDD (PTSD+MDD+; N= 6) or without MDD (PTSD+MDD-; N= 5), as well as trauma-unmatched controls without PTSD but with MDD (PTSD-MDD+; N= 9) or without MDD (PTSD-MDD-; N= 18). Participants with PTSD demonstrated decreased ratios of GABA to glutamine relative to healthy PTSD-MDD- controls but no single-metabolite abnormalities. When comorbid MDD was considered, however, MDD but not PTSD diagnosis was significantly associated with increased mPFC glutamine concentration and decreased glutamate:glutamine ratio. In addition, all participants with PTSD and/or MDD collectively demonstrated decreased glutathione relative to healthy PTSD-MDD- controls. Despite limited findings in single metabolites, patterns of abnormality in prefrontal metabolite concentrations among individuals with PTSD and/or MDD enabled supervised classification to separate them from healthy controls with 80+% sensitivity and specificity, with glutathione, glutamine, and myoinositol consistently among the most informative metabolites for this classification. Our findings indicate that MDD can be an important factor in mPFC glutamate metabolism abnormalities observed using 1H MRS in cohorts with PTSD.

Predicting performance in attention by measuring key metabolites in the PCC with 7T MRS

The posterior cingulate cortex (PCC) is a key hub of the default mode network and is known to play an important role in attention. Using ultra-high field 7 Tesla magnetic resonance spectroscopy (MRS) to quantify neurometabolite concentrations, this exploratory study investigated the effect of the concentrations of myo-inositol (Myo-Ins), glutamate (Glu), glutamine (Gln), aspartate or aspartic acid (Asp) and gamma-amino-butyric acid (GABA) in the PCC on attention in forty-six healthy participants. Each participant underwent an MRS scan and cognitive testing, consisting of a trail-making test (TMT A/B) and a test of attentional performance. After a multiple regression analysis and bootstrapping for correction, the findings show that Myo-Ins and Asp significantly influence (p < 0.05) attentional tasks. On one hand, Myo-Ins shows it can improve the completion times of both TMT A and TMT B. On the other hand, an increase in aspartate leads to more mistakes in Go/No-go tasks and shows a trend towards enhancing reaction time in Go/No-go tasks and stability of alertness without signal. No significant (p > 0.05) influence of Glu, Gln and GABA was observed.

Exploring the causal relationship between glutamine metabolism and leukemia risk: a Mendelian randomization and LC-MS/MS analysis.

This investigation sought to delineate the causal nexus between plasma glutamine concentrations and leukemia susceptibility utilizing bidirectional Mendelian Randomization (MR) analysis and to elucidate the metabolic ramifications of asparaginase therapy on glutamine dynamics in leukemia patients. A bidirectional two-sample MR framework was implemented, leveraging genetic variants as instrumental variables from extensive genome-wide association studies (GWAS) tailored to populations of European descent. Glutamine quantification was executed through a rigorously validated Liquid Chromatography-Mass Spectrometry/Mass Spectrometry (LC-MS/MS) protocol. Comparative analyses of glutamine levels were conducted across leukemia patients versus healthy controls, pre- and post-asparaginase administration. Statistical evaluations employed inverse variance weighted (IVW) models, MR-Egger regression, and sensitivity tests addressing pleiotropy and heterogeneity. The MR findings underscored a significant inverse association between glutamine levels and leukemia risk (IVW p = 0.03558833), positing lower glutamine levels as a contributory factor to heightened leukemia susceptibility. Conversely, the analysis disclosed no substantive causal impact of leukemia on glutamine modulation (IVW p = 0.9694758). Notably, post-asparaginase treatment, a marked decrement in plasma glutamine concentrations was observed in patients (p = 0.0068), underlining the profound metabolic influence of the therapeutic regimen. This study corroborates the hypothesized inverse relationship between plasma glutamine levels and leukemia risk, enhancing our understanding of glutamine's role in leukemia pathophysiology. The pronounced reduction in glutamine levels following asparaginase intervention highlights the critical need for meticulous metabolic monitoring to refine therapeutic efficacy and optimize patient management in clinical oncology. These insights pave the way for more tailored and efficacious treatment modalities in the realm of personalized medicine.

Potential nutritional and functional matters in yeast culture prepared by soybean meal fermentation.

Yeast culture (YC) is a product fermented on a specific medium, which is a type of postbiotic of anaerobic solid-state fermentation. Although YC has positive effects on the animal growth and health, it contains a variety of beneficial metabolites as dark matter, which have not been quantified. In the present study, liquid chromatography-tandem mass spectrometry is employed to identify the unknown metabolites. Following their identification, the important chemicals are quantified using HPLC-diode array detection methods. Non-targeted metabolomics studies showed that 670 metabolites in total were identified in YC, of which 23 metabolites significantly increased, including organic acids, amino acids, nucleosides and purines, isoflavones, and other substances. The chemical quantitative analysis showed that the contents of succinic acid, aminobutyric acid, glutamine, purine and daidzein increased by 84.42%, 51.07%, 100%, 68.85% and 4.60%, respectively. Therefore, the use of non-targeted metabolomics combined with chemical quantitative analysis to reveal the nutritional and functional substances of YC could help to elucidate the postbiotic mechanism and provide theoretical support for the regulation of the directional accumulation of beneficial metabolites. © 2024 Society of Chemical Industry.

Hypothesis on the potential of repetitive transcranial magnetic stimulation to modulate neurochemical pathways and circadian rhythm in ADHD

Disturbances in the circadian rhythms are generally present in adults subjects with Attention Deficit Hyperactivity Disorder. However, may present in children with the same clinical condition. Poor sleep quality interferes with neural inputs and outputs in areas that are fundamental in neurobiological aspects, such as the dorsolateral prefrontal cortex, which can affect circadian rhythm, cognition, emotional and social control. The dorsolateral prefrontal cortex is an area involved in executive functions and sleep–wake regulation and is underactivated in subjects Attention Deficit Hyperactivity Disorder, which may be one of the main causes of alterations in the circadian cycle. Currently, studies with non-invasive therapeutic methods for adult populations and children with these disorders remain scarce, revealing a significant gap in understanding and treatment. In this context, the aim is investigate the potential effectiveness of repetitive transcranial magnetic stimulation as alternative non-invasive treatment of these disorders. In the present study, it is suggested that use excitatory currents from 10 Hz to 20 Hz in the right dorsolateral prefrontal cortex leads to an improvement in the circadian rhythm mechanism. This is because the excitatory current will promote an increase in dopamine (a neurotransmitter that regulates the circadian cycle) and an increase in glutamate and glutamine concentrations to restore homeostasis in brain regions linked to the sleep–wake cycle.

Deciphering the Role of AMPK in Regulating Integrin Profile of Tumor-Derived Exosomes as a Potential Antimetastatic Strategy

Introduction: Cancer cell adapt their metabolic activity to survive in stressful environments with limited nutrients and oxygen. To sense and respond to nutrient cues, cells rely on a “fuel gauge” protein known as AMP-activated protein kinase (AMPK). While previous work has largely focused on AMPK’s role in cell metabolism, its role in metastasis is poorly defined. Interestingly, AMPK also regulates the membrane trafficking of integrins – key proteins in cell adhesion and migration. Recent studies have also shown that circulating integrins in exosomes are predictive of metastasis. Therefore, understanding the biology of AMPK signaling on the exosomal integrin profile not only allow for better cancer treatments but also help developing a potential predictive biomarker. I hypothesize that AMPK activation alters the integrin profile of exosomes in breast and endometrial cancer. Methods: Breast and endometrial cancer cells, MDA-MB-231 and HEC-1 respectively, will be cultured in full nutrient media conditions. 48 hours before exosome harvest, the media will be changed to minimal specialized media for extracellular vesicles (EV) collection. To induce AMPK activation, cells will be treated with limiting concentrations of glucose and glutamine, or with metabolic poisons 2-deoxyglucose (2-DG) and oligomycin. Total Exosome IsolationTM (TEI) solution will be used to enrich released exosomes that will be subjected to mass spectrometry to analyze the exosomal integrin profiles. Anticipated Results: Exosomes secreted from MDA-MB-231 and HEC-1 cells are expected to contain different exosomal integrin profile in both basal and induced AMPK activation conditions. It is anticipated that integrin subunits that promote metastatic and survival signaling such as αvβ5, α6β4, α6β1, will be upregulated in exosomes following AMPK activation. This could suggest tumor cells adapting to nutrient insufficiency by AMPK activation may present a more aggressive exosomal integrin profile to support cancer progression. Discussion: Understanding how metabolic cues such as nutrient insufficiency impact integrin content of tumour-derived exosomes can help identify novel metabolic drug targets to limit pro-survival and pro-metastatic signaling in primary breast tumors. Conclusion: This study investigates how AMPK activation modulates the exosomal integrin profile in breast and endometrial cancer cells, potentially uncovering predictive biomarkers and therapeutic targets for metastatic cancers.

Causal Associations Between Gut Microbiota, Gut Microbiota-Derived Metabolites, and Alzheimer's Disease: A Multivariable Mendelian Randomization Study.

Multiple studies have demonstrated that the gut microbiome is closely related to the onset of Alzheimer's disease, but the causal relationship between the gut microbiome and AD, as well as potential mediating factors, have not been fully explored. Our aim is to validate the causal relationship between the gut microbiome and the onset of AD and determine the key mechanism by which the gut microbiome mediates AD through blood metabolites using Mendelian randomization (MR) analysis methods. We first conducted bidirectional and mediating MR analyses using gut microbiota, blood amino acid metabolites, and AD-related single nucleotide polymorphisms as research data. In the analysis process, the inverse variance-weighted average method was mainly used as the primary method, with other methods serving as supplementary evidence. Ultimately, we found that six types of gut bacteria and two blood amino acid metabolites have a causal effect on AD. Subsequent mediation analysis proved that decreased glutamine concentration mediates the negative causal effect of Holdemanella bacteria on AD (mediation ratio of 14.5%), and increased serum alanine concentration mediates the positive causal effect of Parabacteroide bacteria on AD (mediation ratio of 9.4%). Our study demonstrates the causality of Holdemanella and Parabacteroides bacteria in the onset of AD and suggests that the reduced glutamine and increased alanine serums concentration may be key nodes in mediating this effect.

Modeling of cell cultivation for monoclonal antibody production processes considering lactate metabolic shifts.

Demand for monoclonal antibodies (mAbs) is rapidly increasing. To achieve higher productivity, there have been improvements to cell lines, operating modes, media, and cultivation conditions. Representative mathematical models are needed to narrow down the growing number of process alternatives. Previous studies have proposed mechanistic models to depict cell metabolic shifts (e.g., lactate production to consumption). However, the impacts of variations of some operating conditions have not yet been fully incorporated in such models. This paper offers a new mechanistic model considering variations in dissolved oxygen and glutamine depletion on cell metabolism applied to a novel Chinese hamster ovary (CHO) cell line. Expressions for the specific rates of lactate production, glutamine consumption, and mAb production were formulated for stirred and shaken-tank reactors. A deeper understanding of lactate metabolic shifts was obtained under different combinations of experimental conditions. Lactate consumption was more pronounced in conditions with higher DO and low glutamine concentrations. The model offers mechanistic insights that are useful for designing advanced operation strategies. It can be used in design space generation and process optimization for better productivity and product quality.