MRPL35 Induces Proliferation, Invasion, and Glutamine Metabolism in NSCLC Cells by Upregulating SLC7A5 Expression.

BACKGROUND: Mitochondrial ribosomal protein L35 (MRPL35) has been reported to contribute to the growth of non-small cell lung cancer (NSCLC) cells. However, the functions and mechanisms of MRPL35 on glutamine metabolism in NSCLC remain unclear. METHODS: The detection of mRNA and protein of MRPL35, ubiquitin-specific protease 39 (USP39), and solute carrier family 7 member 5 (SLC7A5) was conducted using qRT-PCR and western blotting. Cell proliferation, apoptosis, and invasion were evaluated using the MTT assay, EdU assay, flow cytometry, and transwell assay, respectively. Glutamine metabolism was analyzed by detecting glutamine consumption, α-ketoglutarate level, and glutamate production. Cellular ubiquitination analyzed the deubiquitination effect of USP39 on MRPL35. An animal experiment was conducted for in vivo analysis. RESULTS: MRPL35 was highly expressed in NSCLC tissues and cell lines, and high MRPL35 expression predicted poor outcome in NSCLC patients. In vitro analyses suggested that MRPL35 knockdown suppressed NSCLC cell proliferation, invasion, and glutamine metabolism. Moreover, MRPL35 silencing hindered tumor growth in vivo. Mechanistically, USP39 stabilized MRPL35 expression by deubiquitination and then promoted NSCLC cell proliferation, invasion, and glutamine metabolism. In addition, MRPL35 positively affected SLC7A5 expression in NSCLC cells in vitro and in vivo. Moreover, the anticancer effects of MRPL35 silencing could be rescued by SLC7A5 overexpression in NSCLC cells. CONCLUSION: MRPL35 expression was stabilized by USP39-induced deubiquitination in NSCLC cells, and knockdown of MRPL35 suppressed NSCLC cell proliferation, invasion, and glutamine metabolism in vitro and impeded tumor growth in vivo by upregulating SLC7A5, providing a promising therapeutic target for NSCLC.

Curcumin synergistically enhances the efficacy of gemcitabine against gemcitabine-resistant cholangiocarcinoma via the targeting LAT2/glutamine pathway.

Cholangiocarcinoma (CCA) is often diagnosed late, leading to incomplete tumor removal, drug resistance and reduced chemotherapy efficacy. Curcumin has the potential for anti-cancer activity through various therapeutic properties and can improve the efficacy of chemotherapy. We aimed to investigate the synergistic effect of a combination of curcumin and gemcitabine against CCA, targeting the LAT2/glutamine pathway. This combination synergistically suppressed proliferation in gemcitabine-resistant CCA cells (KKU-213BGemR). It also resulted in a remarkable degree of CCA cell apoptosis and cell cycle arrest, characterized by a high proportion of cells in the S and G2/M phases. Knockdown of SLC7A8 decreased the expressions of glutaminase and glutamine synthetase, resulting in inhibited cell proliferation and sensitized CCA cells to gemcitabine treatment. Moreover, in vivo experiments showed that a combination curcumin and gemcitabine significantly reduced tumor size, tumor growth rate and LAT2 expression in a gemcitabine-resistant CCA xenograft mouse model. Suppression of tumor progression in an orthotopic CCA hamster model provided strong support for clinical application. In conclusion, curcumin synergistically enhances gemcitabine efficacy against gemcitabine-resistant CCA by induction of apoptosis, partly via inhibiting LAT2/glutamine pathway. This approach may be an alternative strategy for the treatment of gemcitabine-resistant in CCA patients.

HuR controls glutaminase RNA metabolism.

Glutaminase (GLS) is directly related to cell growth and tumor progression, making it a target for cancer treatment. The RNA-binding protein HuR (encoded by the ELAVL1 gene) influences mRNA stability and alternative splicing. Overexpression of ELAVL1 is common in several cancers, including breast cancer. Here we show that HuR regulates GLS mRNA alternative splicing and isoform translation/stability in breast cancer. Elevated ELAVL1 expression correlates with high levels of the glutaminase isoforms C (GAC) and kidney-type (KGA), which are associated with poor patient prognosis. Knocking down ELAVL1 reduces KGA and increases GAC levels, enhances glutamine anaplerosis into the TCA cycle, and drives cells towards glutamine dependence. Furthermore, we show that combining chemical inhibition of GLS with ELAVL1 silencing synergistically decreases breast cancer cell growth and invasion. These findings suggest that dual inhibition of GLS and HuR offers a therapeutic strategy for breast cancer treatment.

Including glutamine in a resource allocation model of energy metabolism in cancer and yeast cells.

Energy metabolism is crucial for all living cells, especially during fast growth or stress scenarios. Many cancer and activated immune cells (Warburg effect) or yeasts (Crabtree effect) mostly rely on aerobic glucose fermentation leading to lactate or ethanol, respectively, to generate ATP. In recent years, several mathematical models have been proposed to explain the Warburg effect on theoretical grounds. Besides glucose, glutamine is a very important substrate for eukaryotic cells-not only for biosynthesis, but also for energy metabolism. Here, we present a minimal constraint-based stoichiometric model for explaining both the classical Warburg effect and the experimentally observed respirofermentation of glutamine (WarburQ effect). We consider glucose and glutamine respiration as well as the respective fermentation pathways. Our resource allocation model calculates the ATP production rate, taking into account enzyme masses and, therefore, pathway costs. While our calculation predicts glucose fermentation to be a superior energy-generating pathway in human cells, different enzyme characteristics in yeasts reduce this advantage, in some cases to such an extent that glucose respiration is preferred. The latter is observed for the fungal pathogen Candida albicans, which is a known Crabtree-negative yeast. Further, optimization results show that glutamine is a valuable energy source and important substrate under glucose limitation, in addition to its role as a carbon and nitrogen source of biomass in eukaryotic cells. In conclusion, our model provides insights that glutamine is an underestimated fuel for eukaryotic cells during fast growth and infection scenarios and explains well the observed parallel respirofermentation of glucose and glutamine in several cell types.

Deciphering glutamine metabolism patterns for malignancy and tumor microenvironment in clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer characterized by metabolic reprogramming. Glutamine metabolism is pivotal in metabolic reprogramming, contributing to the significant heterogeneity observed in ccRCC. Consequently, developing prognostic markers associated with glutamine metabolism could enhance personalized treatment strategies for ccRCC patients. This study obtained RNA sequencing and clinical data from 763 ccRCC cases sourced from multiple databases. Consensus clustering of 74 glutamine metabolism related genes (GMRGs)- profiles stratified the patients into three clusters, each of which exhibited distinct prognosis, tumor microenvironment, and biological characteristics. Then, six genes (SMTNL2, MIOX, TMEM27, SLC16A12, HRH2, and SAA1) were identified by machine-learning algorithms to develop a predictive signature related to glutamine metabolism, termed as GMRScore. The GMRScore showed significant differences in clinical prognosis, expression profile of immune checkpoints, abundance of immune cells, and immunotherapy response of ccRCC patients. Besides, the nomogram incorporating the GMRScore and clinical features showed strong predictive performance in prognosis of ccRCC patients. ALDH18A1, one of the GRMGs, exhibited elevated expression level in ccRCC and was related to markedly poorer prognosis in the integrated cohort, validated by proteomic profiling of 232 ccRCC samples from Fudan University Shanghai Cancer Center (FUSCC). Conducting western blotting, CCK-8, transwell, and flow cytometry assays, we found the knockdown of ALDH18A1 in ccRCC significantly promoted apoptosis and inhibited proliferation, invasion, and epithelial-mesenchymal transition (EMT) in two human ccRCC cell lines (786-O and 769-P). In conclusion, we developed a glutamine metabolism-related prognostic signature in ccRCC, which is tightly linked to the tumor immune microenvironment and immunotherapy response, potentially facilitating precision therapy for ccRCC patients. Additionally, this study revealed the key role of ALDH18A1 in promoting ccRCC progression for the first time.

Origin and Roles of Alanine and Glutamine in Gluconeogenesis in the Liver, Kidneys, and Small Intestine under Physiological and Pathological Conditions.

Alanine and glutamine are the principal glucogenic amino acids. Most originate from muscles, where branched-chain amino acids (valine, leucine, and isoleucine) are nitrogen donors and, under exceptional circumstances, a source of carbons for glutamate synthesis. Glutamate is a nitrogen source for alanine synthesis from pyruvate and a substrate for glutamine synthesis by glutamine synthetase. The following differences between alanine and glutamine, which can play a role in their use in gluconeogenesis, are shown: (i) glutamine appearance in circulation is higher than that of alanine; (ii) the conversion to oxaloacetate, the starting substance for glucose synthesis, is an ATP-consuming reaction for alanine, which is energetically beneficial for glutamine; (iii) most alanine carbons, but not glutamine carbons, originate from glucose; and (iv) glutamine acts a substrate for gluconeogenesis in the liver, kidneys, and intestine, whereas alanine does so only in the liver. Alanine plays a significant role during early starvation, exposure to high-fat and high-protein diets, and diabetes. Glutamine plays a dominant role in gluconeogenesis in prolonged starvation, acidosis, liver cirrhosis, and severe illnesses like sepsis and acts as a substrate for alanine synthesis in the small intestine. Interactions among muscles and the liver, kidneys, and intestine ensuring optimal alanine and glutamine supply for gluconeogenesis are suggested.

Genome-scale metabolic network of human carotid plaque reveals the pivotal role of glutamine/glutamate metabolism in macrophage modulating plaque inflammation and vulnerability.

BACKGROUND: Metabolism is increasingly recognized as a key regulator of the function and phenotype of the primary cellular constituents of the atherosclerotic vascular wall, including endothelial cells, smooth muscle cells, and inflammatory cells. However, a comprehensive analysis of metabolic changes associated with the transition of plaque from a stable to a hemorrhaged phenotype is lacking. METHODS: In this study, we integrated two large mRNA expression and protein abundance datasets (BIKE, n = 126; MaasHPS, n = 43) from human atherosclerotic carotid artery plaque to reconstruct a genome-scale metabolic network (GEM). Next, the GEM findings were linked to metabolomics data from MaasHPS, providing a comprehensive overview of metabolic changes in human plaque. RESULTS: Our study identified significant changes in lipid, cholesterol, and inositol metabolism, along with altered lysosomal lytic activity and increased inflammatory activity, in unstable plaques with intraplaque hemorrhage (IPH+) compared to non-hemorrhaged (IPH-) plaques. Moreover, topological analysis of this network model revealed that the conversion of glutamine to glutamate and their flux between the cytoplasm and mitochondria were notably compromised in hemorrhaged plaques, with a significant reduction in overall glutamate levels in IPH+ plaques. Additionally, reduced glutamate availability was associated with an increased presence of macrophages and a pro-inflammatory phenotype in IPH+ plaques, suggesting an inflammation-prone microenvironment. CONCLUSIONS: This study is the first to establish a robust and comprehensive GEM for atherosclerotic plaque, providing a valuable resource for understanding plaque metabolism. The utility of this GEM was illustrated by its ability to reliably predict dysregulation in the cholesterol hydroxylation, inositol metabolism, and the glutamine/glutamate pathway in rupture-prone hemorrhaged plaques, a finding that may pave the way to new diagnostic or therapeutic measures.

Norovirus NS1/2 protein increases glutaminolysis for efficient viral replication.

Viruses are obligate intracellular parasites that rely on host cell metabolism for successful replication. Thus, viruses rewire host cell pathways involved in central carbon metabolism to increase the availability of building blocks for successful propagation. However, the underlying mechanisms of virus-induced alterations to host metabolism are largely unknown. Noroviruses (NoVs) are highly prevalent pathogens that cause sporadic and epidemic viral gastroenteritis. In the present study, we uncovered several strain-specific and shared host cell metabolic requirements of three murine norovirus (MNV) strains, MNV-1, CR3, and CR6. While all three strains required glycolysis, glutaminolysis, and the pentose phosphate pathway for optimal infection of macrophages, only MNV-1 relied on host oxidative phosphorylation. Furthermore, the first metabolic flux analysis of NoV-infected cells revealed that both glycolysis and glutaminolysis are upregulated during MNV-1 infection of macrophages. Glutamine deprivation affected the viral lifecycle at the stage of genome replication, resulting in decreased non-structural and structural protein synthesis, viral assembly, and egress. Mechanistic studies further showed that MNV infection and overexpression of the non-structural protein NS1/2 increased the enzymatic activity of the rate-limiting enzyme glutaminase. In conclusion, the inaugural investigation of NoV-induced alterations to host glutaminolysis identified NS1/2 as the first viral molecule for RNA viruses that regulates glutaminolysis either directly or indirectly. This increases our fundamental understanding of virus-induced metabolic alterations and may lead to improvements in the cultivation of human NoVs.

Quercetin alleviates inflammation induced by porcine reproductive and respiratory syndrome virus in MARC-145 cells through the regulation of arachidonic acid and glutamine metabolism.

BACKGROUND: Porcine reproductive and respiratory syndrome virus (PRRSV) infection causes severe inflammatory response, respiratory disease and sow reproductive failure. Quercetin is among the widely occurring polypheno found abundantly in nature. Quercetin has anti-inflammatory, anti-oxidative and anti-viral properties. OBJECTIVES: This study aimed to explore the effect and mechanism of quercetin on PRRSV-induced inflammation in MARC-145 cells. METHODS: Observing the cytopathic effect and measurements of inflammatory markers in MARC-145 cells collectively demonstrate that quercetin elicits a curative effect on PRRSV-induced inflammation. Liquid chromatography-mass spectrometry was further used for a non-targeted metabolic analysis of the role of quercetin in the metabolic regulation of PRRSV inflammation in MARC-145 cells. RESULTS: It was shown that quercetin attenuated PRRSV-induced cytopathy in MARC-145 cells. Quercetin treatment inhibited PRRSV replication in MARC-145 cells in a dose-dependent manner. We also found that quercetin inhibited PRRSV-induced mRNA expression and secretion levels of tumour necrosis factor-α, interleukin 1ß and interleukin 6. Metabolomics analysis revealed that quercetin ameliorated PRRSV-induced inflammation. Pathway analysis results revealed that PRRSV-induced pathways including arachidonic acid metabolism, linoleic acid, glycerophospholipid and alanine, aspartate and glutamate metabolism were suppressed by quercetin. Moreover, we confirmed that quercetin inhibited the activation of NF-κB/p65 pathway, probably by attenuating PLA2, ALOX and COX mRNA expression. CONCLUSIONS: These results provide a crucial insight into the molecular mechanism of quercetin in alleviating PRRSV-induced inflammation.

Comparison of physiologically functional compounds in Sika deer Cervus nippon meats obtained from different regions in Japan.

In Japan, the promotion of effective use of many wild deer as food resource has been conducted. However, they are not necessarily utilized effectively. Thus, we focused physiologically functional compounds to find characteristics of Sika deer meats (commercially available) obtained from different regions such as Hokkaido, Wakayama, Tokushima, and Miyazaki prefectures in Japan, making it a valuable resource for future studies and applications. The amount of carnosine, anserine, and balenine in muscle of deer from Wakayama prefecture was significantly lower than that in muscle of deer from other prefectures. The differences of amount of imidazole dipeptides in different prefectures seems to be caused by feed, rearing environment, and breed. The amount of carnitine in deer meat from Hokkaido was significantly lower than that in muscle of deer from other prefectures, while the amount of acetyl-carnitine in deer meat from Miyazaki prefectures was significantly higher than that from other prefectures. The amounts of glutamine, ornithine, and 3-methylhistidine in muscles of deer from Wakayama prefectures were significantly higher than those in muscle of deer from other prefectures. These results might be caused by differences in feeding habits, habitat, the muscle types, and subspecies of deer obtained from four regions in Japan.

Dietary supplement enriched in antioxidants and omega-3 promotes retinal glutamine synthesis.

To prevent ocular pathologies, new generation of dietary supplements have been commercially available. They consist of nutritional supplement mixing components known to provide antioxidative properties, such as unsaturated fatty acid, resveratrol or flavonoids. However, to date, few data evaluating the impact of a mixture mainly composed of those components (Nutrof Total®) on the retina are available. Only one in-vivo preclinical study demonstrated that dietary supplementation (DS) prevents the retina from light-induced retinal degeneration; and only one in-vitro study on Müller cells culture showed that glutamate metabolism cycle was key in oxidative stress response. Therefore, we raised the question about the in-vivo effect of DS on glutamate metabolism in the retina. Herein, we showed that the dietary supplementation promotes in-vivo increase of retinal glutamine amount through a higher glutamine synthesis as observed in-vitro on Muller cells. Therefore, we can suggest that the promotion of glutamine synthesis is part of the protective effect of DS against retinal degeneration, acting as a preconditioning mechanism against retinal degeneration.

SIRT4 Has an Anti-Cancer Role in Cervical Cancer by Inhibiting Glutamine Metabolism via the MEK/ERK/C-Myc Axis.

BACKGROUND/AIM: Glutamine metabolism is crucial in cell proliferation, aging, and apoptosis across various cancer types. Existing research indicates that Sirtuin 4 (SIRT4), primarily located in mitochondria, modulates this process. This study aimed to clarify the regulatory relationship between SIRT4 and glutamine metabolism in cervical cancer. MATERIALS AND METHODS: SIRT4 mRNA levels and their clinical correlation to cervical cancer were analyzed using the UALCAN database. Immunohistochemistry (IHC) was performed to assess SIRT4 protein expression in tissue samples from cervical cancer patients. Transient transfection was employed to create Hela and Siha cell lines with overexpressed SIRT4, mitogen-activated extracellular signal-regulated kinase (MEK), and glutaminase 1 (GLS1). The impact on cellular functions was studied using MTT, soft agar, transwell, and western blotting assays. Glutamate and ATP levels were also measured to evaluate metabolic changes. RESULTS: Low levels of SIRT4 mRNA in cervical cancer tissues correlated with tumor metastasis and poor survival rates. Overexpression of SIRT4 led to suppressed cell proliferation, colony growth, and motility, along with significant down-regulation of GLS expression, a key contributor to glutamine metabolism. Additionally, SIRT4 overexpression resulted in the inactivation of the MEK/ERK/c-myc signaling pathway, while overexpression of MEK reversed these effects. Notably, the inhibitory effects of SIRT4 on cell proliferation, colony formation, migration, and invasion in Hela and Siha cells were significantly attenuated following GLS1 overexpression. CONCLUSION: SIRT4 acts as an anti-cancer agent in cervical cancer by inhibiting glutamine metabolism through the MEK/ERK/c-myc signaling pathway, providing a novel sight for cervical cancer therapy.

Chemical Proteomic Profiling of Protein Dopaminylation in Colorectal Cancer Cells.

Histone dopaminylation is a newly identified epigenetic mark that plays a role in the regulation of gene transcription, where an isopeptide bond is formed between the fifth amino acid of H3 (i.e., glutamine) and dopamine. Recently, we developed a chemical probe to specifically label and enrich histone dopaminylation via bioorthogonal chemistry. Given this powerful tool, we found that histone H3 glutamine 5 dopaminylation (H3Q5dop) was highly enriched in colorectal tumors, which could be attributed to the high expression level of its regulator, transglutaminase 2 (TGM2), in colon cancer cells. Due to the enzyme promiscuity of TGM2, nonhistone proteins have also been identified as dopaminylation targets; however, the dopaminylated proteome in cancer cells still remains elusive. Here, we utilized our chemical probe to enrich dopaminylated proteins from colorectal cancer cells in a bioorthogonal manner and performed the chemical proteomics analysis. Therefore, 425 dopaminylated proteins were identified, many of which are involved in nucleic acid metabolism and transcription pathways. More importantly, a number of dopaminylation sites were identified and attributed to the successful application of our chemical probe. Overall, these findings shed light on the significant association between cellular protein dopaminylation and cancer development, further suggesting that targeting these pathways may become a promising anticancer strategy.

PoRVA G9P[23] and G5P[7] infections differentially promote PEDV replication by reprogramming glutamine metabolism.

PoRVA and PEDV coinfections are extremely common in clinical practice. Although coinfections of PoRVA and PEDV are known to result in increased mortality, the underlying mechanism remains unknown. Here, we found that PoRVA infection promoted PEDV infection in vivo and in vitro and that PoRVA G9P[23] (RVA-HNNY strain) enhanced PEDV replication more significantly than did PoRVA G5P[7] (RVA-SXXA strain). Metabolomic analysis revealed that RVA-HNNY more efficiently induced an increase in the intracellular glutamine content in porcine small intestinal epithelial cells than did RVA-SXXA, which more markedly promoted ATP production to facilitate PEDV replication, whereas glutamine deprivation abrogated the effect of PoRVA infection on promoting PEDV replication. Further studies showed that PoRVA infection promoted glutamine uptake by upregulating the expression of the glutamine transporter protein SLC1A5. In SLC1A5 knockout cells, PoRVA infection neither elevated intracellular glutamine nor promoted PEDV replication. During PoRVA infection, the activity and protein expression levels of glutamine catabolism-related enzymes (GLS1 and GLUD1) were also significantly increased promoting ATP production through glutamine anaplerosis into the TCA cycle. Consistent with that, siRNAs or inhibitors of GLS1 and GLUD1 significantly inhibited the promotion of PEDV replication by PoRVA. Notably, RVA-HNNY infection more markedly promoted SLC1A5, GLS1 and GLUD1 expression to more significantly increase the uptake and catabolism of glutamine than RVA-SXXA infection. Collectively, our findings illuminate a novel mechanism by which PoRVA infection promotes PEDV infection and reveal that the modulation of glutamine uptake is key for the different efficiencies of PoRVA G9P[23] and PoRVA G5P[7] in promoting PEDV replication.

Structural study for substrate recognition of human N-terminal glutamine amidohydrolase 1 in the arginine N-degron pathway.

The N-degron pathway determines the half-life of proteins by selectively destabilizing the proteins bearing N-degrons. N-terminal glutamine amidohydrolase 1 (NTAQ1) plays an essential role in the arginine N-degron (Arg/N-degron) pathway as an initializing enzyme via the deamidation of the N-terminal (Nt) glutamine (Gln). However, the Nt-serine-bound conformation of hNTAQ1 according to the previously identified crystal structure suggests the possibility of other factors influencing the recognition of Nt residues by hNTAQ1. Hence, in the current study, we aimed to further elucidate the substrate recognition of hNTAQ1; specifically, we explored 12 different substrate-binding conformations of hNTAQ1 depending on the subsequent residue of Nt-Gln. Results revealed that hNTAQ1 primarily interacts with the protein Nt backbone, instead of the side chain, for substrate recognition. Here, we report that the Nt backbone of proteins appears to be a key component of hNTAQ1 function and is the main determinant of substrate recognition. Moreover, not all second residues from Nt-Gln, but rather distinctive and charged residues, appeared to aid in detecting substrate recognition. These new findings define the substrate-recognition process of hNTAQ1 and emphasize the importance of the subsequent Gln residue in the Nt-Gln degradation system. Our extensive structural and biochemical analyses provide insights into the substrate specificity of the N-degron pathway and shed light on the mechanism underlying hNTAQ1 substrate recognition. An improved understanding of the protein degradation machinery could aid in developing therapies to promote overall health through enhanced protein regulation, such as targeted protein therapies.

The role of anaplerotic metabolism of glucose and glutamine in insulin secretion: A model approach.

We propose a detailed computational beta cell model that emphasizes the role of anaplerotic metabolism under glucose and glucose-glutamine stimulation. This model goes beyond the traditional focus on mitochondrial oxidative phosphorylation and ATP-sensitive K+ channels, highlighting the predominant generation of ATP from phosphoenolpyruvate in the vicinity of KATP channels. It also underlines the modulatory role of H2O2 as a signaling molecule in the first phase of glucose-stimulated insulin secretion. In the second phase, the model emphasizes the critical role of anaplerotic pathways, activated by glucose stimulation via pyruvate carboxylase and by glutamine via glutamate dehydrogenase. It particularly focuses on the production of NADPH and glutamate as key enhancers of insulin secretion. The predictions of the model are consistent with empirical data, highlighting the complex interplay of metabolic pathways and emphasizing the primary role of glucose and the facilitating role of glutamine in insulin secretion. By delineating these crucial metabolic pathways, the model provides valuable insights into potential therapeutic targets for diabetes.

Particulate matter facilitates amphiregulin-dependent lung cancer proliferation through glutamine metabolism.

Although many cohort studies have reported that long-term exposure to particulate matter (PM) causes lung cancer, the molecular mechanisms underlying the PM-induced increases in lung cancer progression remain unclear. We applied the lung cancer cell line A549 (Parental; A549.Par) to PM for an extended period to establish a mimic PM-exposed lung cancer cell line, A549.PM. Our results indicate that A549.PM exhibits higher cell growth and proliferation abilities compared to A549.Par cells in vitro and in vivo. The RNA sequencing analysis found amphiregulin (AREG) plays a critical role in PM-induced cell proliferation. We observed that PM increases AREG-dependent lung cancer proliferation through glutamine metabolism. In addition, the EGFR/PI3K/AKT/mTOR signaling pathway is involved in PM-induced solute carrier family A1 member 5 (SLC1A5) expression and glutamine metabolism. Our findings offer important insights into how lung cancer proliferation develops upon exposure to PM.

Derivatives of D(-) glutamine-based MMP-2 inhibitors as an effective remedy for the management of chronic myeloid leukemia-Part-I: Synthesis, biological screening and in silico binding interaction analysis.

Chronic myeloid leukemia (CML) is a global issue and the available drugs such as tyrosine kinase inhibitors (TKIs) comprise various toxic effects as well as resistance and cross-resistance. Therefore, novel molecules targeting specific enzymes may unravel a new direction in antileukemic drug discovery. In this context, targeting gelatinases (MMP-2 and MMP-9) can be an alternative option for the development of novel molecules effective against CML. In this article, some D(-)glutamine derivatives were synthesized and evaluated through cell-based antileukemic assays and tested against gelatinases. The lead compounds, i.e., benzyl analogs exerted the most promising antileukemic potential showing nontoxicity in normal cell line including efficacious gelatinase inhibition. Both these lead molecules yielded effective apoptosis and displayed marked reductions in MMP-2 expression in the K562 cell line. Not only that, but both of them also revealed effective antiangiogenic efficacy. Importantly, the most potent MMP-2 inhibitor, i.e., benzyl derivative of p-tosyl D(-)glutamine disclosed stable binding interaction at the MMP-2 active site correlating with the highly effective MMP-2 inhibitory activity. Therefore, such D(-)glutamine derivatives might be explored further as promising MMP-2 inhibitors with efficacious antileukemic profiles for the treatment of CML in the future.

The potential therapeutic targets of glutamine metabolism in head and neck squamous cell carcinoma.

Targeting metabolic reprogramming may be an effective strategy to enhance cancer treatment efficacy. Glutamine serves as a vital nutrient for cancer cells. Inhibiting glutamine metabolism has shown promise in preventing tumor growth both in vivo and in vitro through various mechanisms. Therefore, this review collates recent scientific literature concerning the correlation between glutamine metabolism and cancer treatment. Novel treatment modalities based on amino acid transporters, metabolites, and glutaminase are discussed. Moreover, we demonstrate the relationship between glutamine metabolism and tumor proliferation, drug resistance, and the tumor immune microenvironment, offering new perspectives for the clinical treatment of head and neck squamous cell carcinoma, particularly for combined therapies. Identifying innovative approaches for enhancing the efficacy of glutamine-based metabolic therapy is crucial to improving HNSCC treatment.

Transcranial electrical stimulation modulates emotional experience and metabolites in the prefrontal cortex in a donation task.

Understanding the neural, metabolic, and psychological mechanisms underlying human altruism and decision-making is a complex and important topic both for science and society. Here, we investigated whether transcranial Direct Current Stimulation (tDCS) applied to two prefrontal cortex regions, the ventromedial prefrontal cortex (vmPFC, anode) and the right dorsolateral prefrontal cortex (DLPFC, cathode) can induce changes in self-reported emotions and to modulate local metabolite concentrations. We employed in vivo quantitative MR Spectroscopy in healthy adult participants and quantified changes in GABA and Glx (glutamate + glutamine) before and after five sessions of tDCS delivered at 2 mA for 20 min (active group) and 1 min (sham group) while participants were engaged in a charitable donation task. In the active group, we observed increased levels of GABA in vmPFC. Glx levels decreased in both prefrontal regions and self-reported happiness increased significantly over time in the active group. Self-reported guiltiness in both active and sham groups tended to decrease. The results indicate that self-reported happiness can be modulated, possibly due to changes in Glx concentrations following repeated stimulation. Therefore, local changes may induce remote changes in the reward network through interactions with other metabolites, previously thought to be unreachable with noninvasive stimulation techniques.