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Creatine is a feed additive with physiological pleiotropic properties and also an energy homeostasis protector in vertebrates and is successfully used in terrestrial livestock and aquaculture. Here, two feeding trials were performed to investigate dietary creatine on endogenous creatine metabolism and physiological reprogramming in largemouth bass. The results showed that the endogenous creatine metabolism genes AGAT, GAMT, and SLC6A8 of largemouth bass are highly conserved with the amino acid sequences of other teleosts and are clustered separately from mammals. Among the 16 major tissues in largemouth bass, both creatine synthesis genes (agat, gamt) and transporter gene slc6a8 are most highly expressed in muscle. Muscle has a high threshold but sensitive creatine negative feedback to regulate endogenous creatine metabolism. Dietary creatine intake significantly inhibits endogenous creatine synthesis and transport in muscle in a dose-dependent manner, and this inhibitory effect recovers with a decrease in dietary creatine content. In addition, physiological creatine saturation required prolonged exogenous creatine intake, and it would be shortened by high doses of creatine, which provides guidance for maximizing economic benefits in aquaculture. Metabolome and transcriptome showed that dietary creatine significantly affected the metabolism of the creatine precursor substance—arginine. Exogenous creatine intake spared arginine that would otherwise be used for creatine synthesis, increased arginine levels, and caused reprogramming of arginine metabolism. Overall, these results demonstrate that the addition of creatine to largemouth bass diets is safe and recoverable, and the benefits of creatine intake in largemouth bass are not limited to enhancing the function of creatine itself but also include a reduction in the metabolic burden of essential amino acids to better growth performance. [ABSTRACT FROM AUTHOR]

Simple Summary: This review explores how radiotherapy disrupts critical metabolic pathways in cancer cells. It highlights vulnerabilities in glucose metabolism, lipid synthesis, and amino acid pathways, which radiotherapy exploits to enhance tumour control. Advancements such as nanoparticle-enhanced and FLASH radiotherapy are discussed for their ability to improve precision and reduce damage to healthy tissues. Tools like FDG-PET scans are emphasised for detecting metabolic changes and guiding therapy combinations, such as precision radiotherapy with metabolic inhibitors. This review also outlines future prospects, including personalised metabolic imaging, integration with systemic therapies, targeting tumour-specific metabolic dependencies, and innovations like immune modulation and ferroptosis induction. These approaches aim to transform radiotherapy from a localised treatment to a systemic strategy that targets cancer's metabolic complexities, improving both efficacy and patient outcomes. Radiotherapy has traditionally been viewed as a localised treatment modality, primarily inducing DNA damage to eradicate cancer cells. However, emerging research reveals that radiation also profoundly affects cellular metabolism, particularly in reprogramming tumour cells' energy production and survival pathways. This article explores the role of metabolic reprogramming in the response of cancer cells to radiotherapy, highlighting how these biological processes can be leveraged to enhance treatment efficacy and overcome resistance. Radiotherapy is also discussed, focusing on how metabolic and molecular profiling of tumours can help personalise radiation treatments to improve outcomes. [ABSTRACT FROM AUTHOR]

Metabolic flexibility is key for the function of myeloid cells. Arginine metabolism is integral to the regulation of myeloid cell responses. Nitric oxide (NO) production from arginine is vital for the antimicrobial and pro-inflammatory responses. Conversely, the arginase 1 (ARG1)-dependent switch between the branch of NO production and polyamine synthesis downregulates inflammation and promotes recovery of tissue homeostasis. Creatine metabolism is key for energy supply and proline metabolism is required for collagen synthesis. Myeloid ARG1 also regulates extracellular arginine availability and T cell responses in parasitic diseases and cancer. Cancer, surgery, sepsis and persistent inflammation in chronic inflammatory diseases, such as neuroinflammatory diseases or arthritis, are associated with dysregulation of arginine metabolism in myeloid cells. Here, we review current knowledge on arginine metabolism in different myeloid cell types, such as macrophages, neutrophils, microglia, osteoclasts, tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs) and myeloid-derived suppressor cells (MDSCs). A deeper understanding of the function of arginine metabolism in myeloid cells will improve our knowledge on the pathology of several diseases and may set the platform for novel therapeutic applications. [ABSTRACT FROM AUTHOR]

Background: As a typical medicinal food homology species, Chinese herbal medicine Astragali radix (AR) has been widely used to regulate the human immune system worldwide. However, the human immunomodulation of AR and its corresponding mechanisms remain unclear. Methods: First, following a fortnight successive AR administration, the changes in immune cytokines and immune cells from 20 healthy human subjects were used as immune indicators to characterize the immunomodulatory effects of AR. Subsequently, ultra-high-performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UHPLC-Q-TOF/MS) based lipidomics and metabolomics analysis was performed on human serum, urine, and feces samples to investigate the changes in metabolic profiles. Then, 16S rRNA gene sequencing of feces samples was adopted for the changes of human gut microbiota. Finally, correlation analysis was conducted on the gut microbiome, metabolome/lipidome data, and immune indicators. Results: AR displayed good safety in clinical use and posed a minor impact on gut microbiota major genera, global metabolic profiles, and immune cells. Meanwhile, AR could significantly up-regulate anti-inflammatory cytokines, down-regulate serum creatinine and pro-inflammatory cytokines, promote the anabolism of arginine, glycerolipid, sphingolipid, and purine, and the catabolism of phenylalanine and glycerophospholipid. Moreover, these AR-induced changes were closely correlated with significantly decreased Granulicatella, slightly higher Bifidobacterium, Ruminococcus, and Subdoligranulum, and slightly lower Blautia. Conclusion: The study clearly demonstrated that AR could modulate the human immune, by modifying the metabolism of amino acids, lipids, and purines in a microbiota-related way. Trial registration ChiCTR, ChiCTR2100054765. Registered 26 December 2021-Prospectively registered, https://www.chictr.org.cn/historyversionpub.html?regno=ChiCTR2100054765 [ABSTRACT FROM AUTHOR]

This study aimed to investigate the metabolic mechanisms underlying the combination of patent foramen ovale (PFO) and migraine by assessing metabolite expression before and after interventional occlusion surgery. The study included 11 PFO patients from the Heart Center of Xinjiang Medical University Affiliated Hospital of Traditional Chinese Medicine, who underwent transcatheter PFO intervention and occlusion surgery between January 2018 and February 2023, and 11 healthy controls. Blood samples were collected pre-surgery, 3 days post-surgery, and 30 days post-surgery for metabolomics analysis. The goal was to identify differentially expressed metabolites between groups. Statistical analyses were performed to evaluate these metabolites alongside migraine disability, assessed using the Migraine Disability Assessment (MIDAS) score. Preliminary analysis of metabolic pathways was also conducted. Results showed significant differences in serum metabolites, including dopamine, L-proline, L-tyrosine, D-proline, acetylcarnitine, and dulcitol, between PFO migraine patients and healthy controls based on Liquid Chromatography-Mass Spectrometry (LC-MS) non-targeted metabolomics analysis. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of these metabolites revealed enrichment in protein digestion, absorption, and metabolic signaling pathways, highlighting the role of metabolism in the disease process. Elevated levels of dopamine and other metabolites were found in migraine patients, with differential metabolites primarily associated with the arginine metabolic pathway, suggesting its importance in the condition's progression. Additionally, patients with PFO and migraine showed significant improvements in headache frequency, duration, and severity post-treatment (p < 0.05), though accompanying symptoms did not show statistically significant changes (p > 0.05). Overall, interventional closure surgery for PFO significantly alleviates headache symptoms in patients. [ABSTRACT FROM AUTHOR]

It is known that 1,7-dihydroxy-3,4-dimethoxyxanthone (XAN), derived from Securidaca inappendiculata Hassk., exhibits anti-inflammatory and analgesic activities and inhibits M1 polarization of macrophages. However, its ability to alleviate inflammation induced by pro-inflammatory cytokines in THP-1 cells and its anti-inflammatory mechanisms remain unclear. THP-1 cells were treated with phorbol 12-myristate-13-acetate to differentiate and divided into three groups. They were stimulated with lipopolysaccharide (LPS) and interferon-γ (IFN-γ). The toxicity of XAN was assessed using Cell Counting Kit-8, and the expression of various genes and proteins was analyzed using real-time quantitative polymerase chain reaction, flow cytometry, and western blotting. Transmission electron microscopy was used to observe changes in mitochondrial structure. XAN at concentrations ≤ 10 µg/mL did not affect THP-1 cell viability and reduced the mRNA expression of pro-inflammatory factors, including interleukin (IL)-1β, inducible nitric oxide synthase (iNOS), NOD-like receptor thermal protein domain protein 3 (NLRP3), and tumor necrosis factor-α (TNF-α). XAN also increased the levels of anti-inflammatory factors, including chemokine ligand 22, mannose receptor (CD206), IL-10, peroxisome proliferator-activated receptor-γ, and transglutaminase 2. Additionally, XAN downregulated the expression of inflammation-related proteins iNOS, NLRP3, and IL-1β; significantly increased the expression of arginase 1, ornithine decarboxylase, and arginine metabolism-related proteins and genes; inhibited mitochondrial damage; and reduced reactive oxygen species (ROS) generation. XAN enhanced the arginine metabolism pathway, prevented mitochondrial damage, reduced ROS levels, and provided an effective defensive response against LPS/IFN-γ-induced inflammation. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the mediating role of the activation degree of arginine-proline metabolism in the association of coal dust and decreased lung function. Methods: Cumulative dust exposure (CDE) represented coal dust exposure, whereas the hydroxyproline-to-arginine concentration ratio (Hyp/Arg) in bronchoalveolar lavage fluid gauged arginine-proline metabolism activation. Pulmonary function indicators, including predicted value of forced vital capacity (FVC%pred), forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC%), and the ratio of actual to predicted value of FEV1 (FEV1%pred), diffusing capacity of the lungs for carbon monoxide (DLCO%pred), difference value between alveolar air and arterial partial oxygen pressure (P(A-a) O2), and 6-minutewalking distance test (6MWT), were assessed. Results: Findings revealed a significant association between elevated CDE and increased Hyp/Arg, increased P(A-a) O2, decreased 6MWT, DLCO%pred, and decreased FVC%pred. However, no statistically significant association was found between CDE and FEV1%pred or FEV1/FVC%. The mediating effect of Hyp/Arg was significant for CDE's impact on P(A-a) O2 and DLCO%pred but not on 6MWT and FVC%pred. Conclusions: These results highlight the role of Hyp/Arg in mediating the association between CDE and lung function parameters, shedding light on potential therapeutic avenues for mitigating coal dust-induced lung function impairment. [ABSTRACT FROM AUTHOR]

Arginine–glycine–glycine motif proteins play a crucial role in determining mRNA fate. Suppressor of clathrin deficiency 6 (Scd6) is a conserved arginine–glycine–glycine motif containing ribonucleoprotein (RNP) condensate–resident, translation repressor, and decapping activator protein in Saccharomyces cerevisiae. Identifying protein factors that can modulate Scd6 function is critical to understanding the regulation of mRNA fate by Scd6. In this study, using an approach that combined mRNA tethering assay with flow cytometry, we screened 50 genes for their role in modulating the translation repression activity of Scd6. We identified 8 conserved modulators with human homologs. Of these, we further characterized in detail guanine nucleotide exchange factor Rho1 multicopy suppressor 2 (Rom2) and glycolytic enzyme triose phosphate dehydrogenase 3 (Tdh3), which, respectively, impede and promote translation repression activity of Scd6. Our study reveals that Rom2 negatively regulates the arginine methylation of Scd6 and antagonizes its localization to P-bodies. Tdh3 , on the other hand, promotes Scd6 interaction with Hmt1 , thereby promoting the arginine methylation of Scd6 and enhanced eIF4G1 interaction, which is known to promote its repression activity. Identifying these novel modulators provides exciting new insights into the role of a metabolic enzyme of the glycolytic pathway and guanine nucleotide exchange factor implicated in the cell wall integrity pathway in regulating Scd6 function and, thereby, cytoplasmic mRNA fate. [ABSTRACT FROM AUTHOR]

Objectives: To explore the effect of protein arginine methyltransferase 5 (PRMT5) on tooth extraction sockets healing, we established an extraction sockets model in osteoblast‐conditional Prmt5 knockout mice. The results provided clues for promoting extraction sockets healing in clinical settings. Materials and Methods: Maxillary first molars were extracted from 6 to 8‐week‐old mice to establish an extraction fossa model. Microcomputed tomography (Micro‐CT), histology, and immunostaining assays were performed on samples harvested at 3‐, 7‐, and 14‐day post‐extraction. Prmt5‐silenced cell lines were employed to explore the regulatory mechanisms underlying the osteigenic differentiation. Results: PRMT5 expression was higher in the early stage of socket healing. Micro‐CT analysis showed that the percentage of new bone in the extraction sockets was lower in OC‐Cre; Prmt5fl/fl mice than in the control group, consistent with Masson staining. We found that, Prmt5 deficiency delayed the osteogenesis during extraction socket healing, which might be achieved through the decrease of H4R3me2s in the Sp7 promoter region. Conclusion: PRMT5 in osteoblasts may promote the differentiation of osteoblasts by regulating the Sp7 promoter H4R3me2s and participate in the healing of tooth extraction sockets. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effects of serine/arginine-rich splicing factor 7 (SRSF7) on proliferation, migration and invasion of hepatocellular carcinoma (HCC) HepG2 cells and the possible mechanisms. Methods: Differential expression of SRSF7 between HCC and adjacent non-tumor tissues and its relationship with patient prognosis were analyzed online using The Cancer Genome Atlas (TCGA) and Kaplan Meier Plotter. HepG2 cells were cultured routinely and transfected with SRSF7 RNA knockdown sequences (siSRSF7#1 and siSRSF7#2), control sequences (NC), SRSF7 overexpression vector (hSRSF7-oe), and control vector (hSRSF7-nc) using transfection reagents. Accordingly, the cells were divided into NC group, siSRSF7#1 group, siSRSF7#2 group, NC + hSRSF7-nc group, siSRSF7 + hSRSF7-nc group, and siSRSF7 + hSRSF7-oe group. The mRNA and protein expression levels of SRSF7 in each group of cells were detected by qPCR and WB assay. The proliferation, migration, and invasion abilities of each group of cells were assessed by MTS assay, plate clone formation assay, scratch assay, and Transwell invasion assay. WB assay was used to detect the expression of JAK1/STAT3 signaling pathway related proteins in HepG2 cells of each group. Results: Database analysis showed that SRSF7 mRNA is highly expressed in HCC tissues (P < 0.001), and its high expression is associated with poor prognosis in HCC patients (P < 0.05). Knockdown of SRSF7 significantly reduced the proliferation, migration, and invasion abilities of HepG2 cells (all P < 0.01). The phosphorylation levels of JAK1 and STAT3 in the SRSF7 knockdown cells were significantly reduced (both P < 0.05), while overexpression of SRSF7 resulted in a significant increase in JAK1 and STAT3 phosphorylation levels (both P < 0.05). Conclusion: SRSF7 is highly expressed in HCC tissues and may promote the proliferation, migration, and invasion of HepG2 cells by regulating the JAK1/STAT3 signaling pathway. [ABSTRACT FROM AUTHOR]

ObjectiveNecrotizing enterocolitis (NEC) is a gastrointestinal emergency with relatively high morbidity and mortality in neonates. The role of microRNAs (miRNAs) in NEC is not yet entirely clear. This study aimed to explore the mechanism of miR-122-5p in NEC.MethodsDifferentially expressed (DE) miRNAs were sequenced in control and NEC mice. The DEmiRNA-mRNA regulatory network was constructed and the bioinformatics analysis was performed to identify the target mRNAs and potential roles of the DEmiRNAs. The miR-122-5p activation was explored in vitro in the human intestinal epithelial cell (FHs74Int) and rat intestinal epithelial cell (IEC-6). In vivo, mice were transinfected with miR-122-5p inhibitor before the NEC occurred. Mass spectrometry was used to qualify the concentrations of amino acids, and the viability of intestinal stem cell (ISC) was accessed to verify the biological function.ResultsPreliminarily, 15 miRNAs were found to be differentially expressed between NEC group and control group. Subsequent bioinformatics analysis revealed that miR-122-5p significantly contributes to the arginine metabolism in NEC through the DEmiRNA-mRNA regulatory network, with PRODH2 and ALDH18A1 being identified as its target genes. In vitro, miR-122-5p mimic inhibited the expression of PRODH2 and ALDH18A1 in the FHs74Int cells and IEC-6 cells. In vivo, inhibition of miR-122-5p led to increased expression of PRODH2 and ALDH18A1, along with elevated arginine levels. Following transfection with a miR-122-5p inhibiting adenovirus, the survival rate of NEC mice improved, and intestinal injury was alleviated.ConclusionMiR-122-5p inhibition could impact arginine metabolism by targeting PRODH2 and ALDH18A1, thereby mitigating intestinal injury in NEC.

Abstract Background Salidroside (SAL), derived from Rhodiola, shows protective effects in pulmonary arterial hypertension (PAH) models, but its mechanisms are not fully elucidated. Objectives Investigate the therapeutic effects and the mechanism of SAL on PAH. Methods Monocrotaline was used to establish a PAH rat model. SAL’s impact on oxidative stress and inflammatory responses in lung tissues was analyzed using immunohistochemistry, ELISA, and Western blot. Untargeted metabolomics explored SAL’s metabolic regulatory mechanisms. Results SAL significantly reduced mean pulmonary artery pressure, right ventricular hypertrophy, collagen deposition, and fibrosis in the PAH rats. It enhanced antioxidant enzyme levels, reduced inflammatory cytokines, and improved NO bioavailability by upregulating endothelial nitric oxide synthase (eNOS), soluble guanylate cyclase (sGC), cyclic guanosine monophosphate (cGMP), and protein kinase G (PKG) and decreases the expression of endothelin-1 (ET-1). Metabolomics indicated SAL restored metabolic balance in PAH rats, particularly in arginine metabolism. Conclusions SAL alleviates PAH by modulating arginine metabolism, enhancing NO synthesis, and improving pulmonary vascular remodeling.

Background: Optimal balance between macro- and microcirculation in critically ill patients is crucial for ensuring optimal organ perfusion. Nitric oxide (NO) is a regulator of vascular hemostasis and tone. The availability of NO is controlled by asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and the availability of the NO substrates arginine and homoarginine. We investigated the changes in plasma concentrations of ADMA, SDMA, arginine, and homoarginine days 1–5 of intensive care unit (ICU) admission and the association between the change in concentration days 1–3 and 30-day all-cause mortality. Methods: Single-center cohort study of adult critically ill patients from the ICU at Copenhagen University Hospital – North Zealand. ADMA, SDMA, arginine, and homoarginine (NO-biomarkers) were measured on days 1–5. Initially, we determined the changes in NO-biomarkers days 1–5 with linear mixed models, and subsequently how the changes in NO-biomarkers days 1–3 were associated with 30-day all-cause mortality. Post-hoc we analyzed the association between plasma concentration at admission and 30-day all-cause mortality. Results: In total 567 out of 577 patients had plasma samples from days 1–5. Plasma concentrations of ADMA and arginine increased from days 1–5. SDMA concentrations increased from days 1–2, followed by a decrease from days 2–5. Concentrations of homoarginine did not change from days 1–3 but slightly increased from days 3–5. In total 512 patients were alive 3 days after ICU admission. Among these patients, a daily twofold increase in ADMA concentration from days 1–3 was associated with decreased mortality in multivariate analysis (HR 0.45; 95% CI 0.21–0.98; p = 0.046). An increase in SDMA, arginine, or homoarginine was not associated with mortality. Post-hoc we found that a twofold increase in ADMA or SDMA concentrations at admission was associated with mortality (HR 1.78; 95% CI 1.24–2.57; p = 0.0025, and HR 1.41; 95% CI 1.05–1.90; p = 0.024, respectively). Conclusions: Increasing ADMA concentrations on days 1–3 are inversely associated with mortality, however not with the same strength as high ADMA or SDMA concentrations at admission. We suggest that admission concentrations are the focus of future research on ADMA and SDMA as predictors of mortality or potential therapeutical targets in ICU patients. [ABSTRACT FROM AUTHOR]

Background: Salidroside (SAL), derived from Rhodiola, shows protective effects in pulmonary arterial hypertension (PAH) models, but its mechanisms are not fully elucidated. Objectives: Investigate the therapeutic effects and the mechanism of SAL on PAH. Methods: Monocrotaline was used to establish a PAH rat model. SAL's impact on oxidative stress and inflammatory responses in lung tissues was analyzed using immunohistochemistry, ELISA, and Western blot. Untargeted metabolomics explored SAL's metabolic regulatory mechanisms. Results: SAL significantly reduced mean pulmonary artery pressure, right ventricular hypertrophy, collagen deposition, and fibrosis in the PAH rats. It enhanced antioxidant enzyme levels, reduced inflammatory cytokines, and improved NO bioavailability by upregulating endothelial nitric oxide synthase (eNOS), soluble guanylate cyclase (sGC), cyclic guanosine monophosphate (cGMP), and protein kinase G (PKG) and decreases the expression of endothelin-1 (ET-1). Metabolomics indicated SAL restored metabolic balance in PAH rats, particularly in arginine metabolism. Conclusions: SAL alleviates PAH by modulating arginine metabolism, enhancing NO synthesis, and improving pulmonary vascular remodeling. [ABSTRACT FROM AUTHOR]

Background: The prevalence of sarcopenia is increasing in worldwide with accelerated aging process. The high dietary protein intakes are associated with improved muscle mass and strength especially in Asian countries. However, there are few researches on amino acid levels or mechanism exploration. We conducted a case-control study to explore the amino acid metabolic characteristics and potential mechanism of elderly women with sarcopenia using targeted amino acid metabolomics approach combined with an analysis of dietary intake. Methods: For our case-control study, we recruited women (65–75 y) from a Shanghai community with 50 patients with sarcopenia and 50 healthy controls. The consensus updated by the Asian Working Group on Sarcopenia in 2019 was used to screening for sarcopenia and control groups. We collected fasting blood samples and evaluated dietary intake. We used the amino acid-targeted metabolomics by ultra performance liquid chromatography tandem mass spectrometry to identify metabolic differentials between the case and control groups and significantly enriched metabolic pathways. Results: The case (sarcopenia) group had a lower intake of energy, protein, and high-quality protein (P < 0.05) compared to the control (healthy) group. We identified four differential amino acids: arginine (P < 0.001) and cystine (P = 0.003) were lower, and taurine (P = 0.001) were higher in the case group. Conclusion: Low levels of arginine in elderly women are associated with a higher risk of sarcopenia. [ABSTRACT FROM AUTHOR]

Objective: To clarify the potential mechanism of Banxia Xiexin Decoction (BXD) on colorectal cancer (CRC) from the perspective of metabolomics. Methods: Forty male C57BL/6 mice were randomly divided into normal control (NC), azoxymethane/dextran sulfate sodium (AOM/DSS) model, low-dose BXD (L-BXD), high-dose BXD (H-BXD) and mesalamine (MS) groups according to a random number table, 8 mice in each group. Colorectal cancer model was induced by AOM/DSS. BXD was administered daily at doses of 3.915 (L-BXD) and 15.66 g/kg (H-BXD) by gavage for consecutive 21 days, and 100 mg/kg MS was used as positive control. Following the entire modeling cycle, colon length of mice was measured and quantity of colorectal tumors were counted. The spleen and thymus index were determined by calculating the spleen/thymus weight to body weight. Inflammatory cytokine and changes of serum metabolites were analyzed by enzyme-linked immunosorbent assay kits and ultra performance liquid chromatography-quadrupole/time-of-flight mass spectrometry (UPLC-Q/TOF-MS), respectively. Results: Notably, BXD supplementation protected against weight loss, mitigated tumor formation, and diminished histologic damage in mice treated with AOM/DSS (P<0.05 or P<0.01). Moreover, BXD suppressed expression of serum inflammatory enzymes, and improved the spleen and thymus index (P<0.05). Compared with the normal group, 102 kinds of differential metabolites were screened in the AOM/DSS group, including 48 potential biomarkers, involving 18 main metabolic pathways. Totally 18 potential biomarkers related to CRC were identified, and the anti-CRC mechanism of BXD was closely related to D-glutamine and D-glutamate metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, arginine biosynthesis, nitrogen metabolism and so on. Conclusion: BXD exerts partial protective effects on AOM/DSS-induced CRC by reducing inflammation, protecting organism immunity ability, and regulating amino acid metabolism. [ABSTRACT FROM AUTHOR]

ABSTRACT Medical modulation of sex hormone levels is a cornerstone of treatment for many conditions that impact well-being, including cancer, fertility/infertility, gender dysphoria, and chronic metabolic diseases such as diabetes and obesity. The microbial residents of the intestine, known as the microbiota, interact with sex hormones in the intestine, and there is correlative evidence that this interaction is bidirectional. Based on these published findings, we hypothesized that transgender individuals receiving exogenous testosterone as part of their gender-affirming medical treatment might undergo changes in their intestinal microbiome. To test this, we collected 26 stool samples from nine individuals before and up to 8 months after initiation of treatment with exogenous testosterone and subjected these samples to metagenomic analysis. While no species were significantly associated with the duration of testosterone therapy, pathways that generate glutamate increased in abundance, while those that consume glutamate decreased. Glutamate is a precursor of arginine, and testosterone is known to increase levels of arginine and its metabolites in the plasma. We hypothesize that testosterone increases the uptake of glutamate by enterocytes, thus decreasing access of the microbiota to this amino acid. While this pilot study establishes the impact of testosterone therapy on the intestinal microbiome, a more comprehensive study is necessary to establish the impact of testosterone-driven metagenomic shifts on the stool metatranscriptome, the stool metabolome, and the plasma metabolome.IMPORTANCEThe human intestine is inhabited by a large community of microbes known as the microbiome. Members of the microbiome consume the diet along with their human host. Thus, the metabolomes of the host and microbe are intricately linked. Testosterone alters the plasma metabolome. In particular, plasma levels of arginine and its metabolites and testosterone are positively correlated. To investigate the impact of exogenous testosterone on the microbiome, we analyzed the stool metagenomes of transgender individuals before and after the initiation of testosterone treatment. In this pilot project, we found a modest impact on the microbiome community structure but an increase in the abundance of metabolic pathways that generate glutamate and spare glutamate consumption. We propose that the host uses glutamate to generate arginine, decreasing the amount available for the microbiome.

The importance of amino acid metabolism has been gradually recognized, and the relationship between arginine metabolism and tumors has become a hot topic. Arginine is a conditionally essential amino acid, which is closely related to the occurrence, growth and metastasis of tumors. The formation of an immunosuppressive microenvironment, and the phenotypic changes, maturation and functional status of myeloid immune cells are also inseparable from arginine metabolism. This article mainly elucidates how arginine metabolism affects tumors and the role of arginine in anti-tumor immunity, summarizes the main myeloid immune cells in the tumor microenvironment, and briefly summarizes the tumor treatment strategies that target the arginine metabolism pathway. [ABSTRACT FROM AUTHOR]

Arginine and tryptophan are pivotal in orchestrating cytokine-driven macrophage polarization and immune activation. Specifically, interferon-gamma (IFN-g) stimulates inducible nitric oxide synthase (iNOS) expression), leading to the conversion of arginine into citrulline and nitric oxide (NO), while Interleukin-4 (IL4) promotes arginase activation, shifting arginine metabolism toward ornithine. Concomitantly, IFN-g triggers indoleamine 2,3-dioxygenase 1 (IDO1) and Interleukin-4 induced 1 (IL4i1), resulting in the conversion of tryptophan into kynurenine and indole-3-pyruvic acid. These metabolic pathways are tightly regulated by NAD+-dependent sirtuin proteins, with Sirt2 and Sirt5 playing integral roles. In this review, we present novel insights that augment our understanding of the metabolic pathways of arginine and tryptophan following Mycobacterium tuberculosis infection, particularly their relevance in macrophage responses. Additionally, we discuss arginine methylation and demethylation and the role of Sirt2 and Sirt5 in regulating tryptophan metabolism and arginine metabolism, potentially driving macrophage polarization. [ABSTRACT FROM AUTHOR]

Carbon (C) and nitrogen (N) metabolisms participate in N source-regulated secondary metabolism in medicinal plants, but the specific mechanisms involved remain to be investigated. By using nitrate (NN), ammonium (AN), urea (UN), and glycine (GN), respectively, as sole N sources, we found that N sources remarkably affected the contents of diterpenoid lactone components along with C and N metabolisms reprograming in Andrographis paniculata, as compared to NN, the other three N sources raised the levels of 14-deoxyandrographolide, andrographolide, dehydroandrographolide (except UN), and neoandrographolide (except AN) with a prominent accumulation of farnesyl pyrophosphate (FPP). These N sources also raised the photosynthetic rate and the levels of fructose and/or sucrose but reduced the activities of phosphofructokinase (PFK), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), phosphoenolpyruvate carboxylase (PEPC) and pyruvate dehydrogenase (PDH). Conversely, phosphoenolpyruvate carboxykinase (PEPCK) and malate enzyme (ME) activities were upregulated. Simultaneously, citrate, cis-aconitate and isocitrate levels declined, and N assimilation was inhibited. These results indicated that AN, UN and GN reduced the metabolic flow of carbohydrates from glycolysis into the TCA cycle and downstream N assimilation. Furthermore, they enhanced arginine and GABA metabolism, which increased C replenishment of the TCA cycle, and increased ethylene and salicylic acid (SA) levels. Thus, we proposed that the N sources reprogrammed C and N metabolism, attenuating the competition of N assimilation for C, and promoting the synthesis and accumulation of andrographolide through plant hormone signaling. To obtain a higher production of andrographolide in A. paniculata, AN fertilizer is recommended in its N management. [ABSTRACT FROM AUTHOR]

The SAM1 and SAM2 genes encode for S-Adenosylmethionine (AdoMet) synthetase enzymes, with AdoMet serving as the main cellular methyl donor. We have previously shown that independent deletion of these genes alters chromosome stability and AdoMet concentrations in opposite ways in Saccharomyces cerevisiae. To characterize other changes occurring in these mutants, we grew wildtype, sam1Δ /sam1 Δ , and sam2Δ /sam2 Δ strains in 15 different Phenotypic Microarray plates with different components and measured growth variations. RNA-Sequencing was also carried out on these strains and differential gene expression determined for each mutant. We explored how the phenotypic growth differences are linked to the altered gene expression, and hypothesize mechanisms by which loss of the SAM genes and subsequent AdoMet level changes, impact pathways and processes. We present 6 stories, discussing changes in sensitivity or resistance to azoles, cisplatin, oxidative stress, arginine biosynthesis perturbations, DNA synthesis inhibitors, and tamoxifen, to demonstrate the power of this novel methodology to broadly profile changes due to gene mutations. The large number of conditions that result in altered growth, as well as the large number of differentially expressed genes with wide-ranging functionality, speaks to the broad array of impacts that altering methyl donor abundance can impart. Our findings demonstrate that some cellular changes are directly related to AdoMet-dependent methyltransferases and AdoMet availability, some are directly linked to the methyl cycle and its role in production of several important cellular components, and others reveal impacts of SAM gene mutations on previously unconnected pathways. [ABSTRACT FROM AUTHOR]

Simple Summary: Targeting amino acid metabolism in leukemia therapy presents both opportunities and challenges. While disrupting amino acid utilization can hinder cancer cell growth and enhance treatment efficacy, achieving selective targeting to minimize damage to healthy cells is crucial. This review explores novel strategies for amino acid depletion-based treatments in leukemia, highlighting the potential of combining these approaches with traditional chemotherapeutics and immunotherapies to overcome resistance and improve patient outcomes. Cancer cells demand amino acids beyond their usage as "building blocks" for protein synthesis. As a result, targeting amino acid acquisition and utilization has emerged as a pivotal strategy in cancer treatment. In the setting of leukemia therapy, compelling examples of targeting amino acid metabolism exist at both pre-clinical and clinical stages. This review focuses on summarizing novel insights into the metabolism of glutamine, asparagine, arginine, and tryptophan in leukemias, and providing a comprehensive discussion of perturbing their metabolism to improve the therapeutic outcomes. Certain amino acids, such as glutamine, play a vital role in the energy metabolism of cancer cells and the maintenance of redox balance, while others, such as arginine and tryptophan, contribute significantly to the immune microenvironment. Therefore, assessing the efficacy of targeting amino acid metabolism requires comprehensive strategies. Combining traditional chemotherapeutics with novel strategies to perturb amino acid metabolism is another way to improve the outcome in leukemia patients via overcoming chemo-resistance or promoting immunotherapy. In this review, we also discuss several ongoing or complete clinical trials, in which targeting amino acid metabolism is combined with other chemotherapeutics in treating leukemia. [ABSTRACT FROM AUTHOR]

Gene mutations located in VraSR and GraSR, two-component regulatory systems have been reported to cause vancomycin resistance in vancomycin-intermediate Staphylococcus aureus (VISA). Subsequent comparative proteomic profiling between vancomycin-susceptible S. aureus (VSSA) and VISAs of the Mu50 genetic lineage revealed up-regulated level of catabolic ornithine carbamoyltransferase (ArcB) in the latter, suggesting a role of arginine catabolism in VISA development. This study aimed to further investigate metabolic pathways associated with VISA development using liquid chromatography mass spectrometry (LCMS)-based untargeted metabolomic profiling. Metabolite profiles were compared among 3 isogenic strains of the Mu50 lineage: Mu50Ω (VSSA), Mu50Ω-vraSm (VISA) and Mu50Ω-vraSm-graRm (VISA). Intracellular levels of α-hydroxyglutaric acid, choline, lysine, malic acid, N-acetylornithine, nicotinamide, and cystathionine were found to be significantly different between VISAs compared to VSSA. VISA cells were found to have lower levels of intracellular citrulline and extracellular arginine, with higher extracellular level of ornithine compared to VSSA. These differences in metabolite levels between VISA and VSSA suggested the importance of arginine metabolism. Activation of the arginine deiminase pathway (ADI) in VISAs of the Mu50 lineage could be further explored as a target for antibiotic development. [ABSTRACT FROM AUTHOR]

As a potential treatment strategy for low immunogenic triple negative breast cancer (TNBC), photodynamic therapy (PDT) induced antitumor immunotherapy is greatly limited by the immunosuppressive tumor microenvironment (ITM), especially the M2 phenotype tumor-associated macrophages (TAMs). The balance of arginine metabolism plays an important role in TAMs polarization. Herein, a multifunctional nanoplatform (defined as HN-HFPA) was employed to burst the anti-tumor immunity of TNBC post PDT by reeducating TAMs through interfering the TAMs-associated arginine metabolism. The L -arginine (L -Arg) was loaded in the hollow cavity of HN-HFPA, which could not only generate nitric oxide (NO) for tumor therapy, but also serve as a substrate of arginine metabolism pathway. As an inhibitor of arginases-1 (Arg-1) of M2 TAMs, L -norvaline (L -Nor) was modified to the hyaluronic acid (HA), and coated in the surface of HFPA. After degradation of HA by hyaluronidase in tumor tissue and GSH-mediated disintegration, HN-HFPA depleted intracellular GSH, produced remarkable reactive oxygen species (ROS) under light irradiation and released L -Arg to generate NO, which induced tumor immunogenic cell death (ICD). Real-time ultrasound imaging of tumor was realized taking advantage of the gas feature of NO. The L -Nor suppressed the Arg-1 overexpressed in M2, which skewed the balance of arginine metabolism and reversed the ITM with increased ratios of M1 and CD8+ T cells, finally resulted in amplified antitumor immune response and apparent tumor metastasis inhibition. This study remodeled ITM to strengthen immune response post PDT, which provided a promising treatment strategy for TNBC. The multifunctional nanodrugs (HN-HFPA) mediated high-efficient photodynamic immunotherapy by promoting photodynamic therapy elicited ICD and regulating arginine metabolism in tumor associated macrophages (TAMs) to remodel immunosuppressive tumor microenvironment (ITM), resulting in significant inhibition of primary and metastatic murine TNBCs in vivo. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract Background Inflammatory bowel disease (IBD) is a global disease with a growing public health concern and is associated with a complex interplay of factors, including the microbiota and immune system. Resveratrol, a natural anti-inflammatory and antioxidant agent, is known to relieve IBD but the mechanism involved is largely unexplored. Methods This study examines the modulatory effect of resveratrol on intestinal immunity, microbiota, metabolites, and related functions and pathways in the BALB/c mice model of IBD. Mouse RAW264.7 macrophage cell line was used to further explore the involvement of the macrophage-arginine metabolism axis. The treatment outcome was assessed through qRT-PCR, western blot, immunofluorescence, immunohistochemistry, and fecal 16S rDNA sequencing and UHPLC/Q-TOF–MS. Results Results showed that resveratrol treatment significantly reduced disease activity index (DAI), retained mice weight, repaired colon and spleen tissues, upregulated IL-10 and the tight junction proteins Occludin and Claudin 1, and decreased pro-inflammatory cytokines IL-1β, IL-6, and TNF-α. Resveratrol reduced the number of dysregulated metabolites and improved the gut microbial community structure and diversity, including reversing changes in the phyla Bacteroidetes, Proteobacteria, and Firmicutes, increasing ‘beneficial’ genera, and decreasing potential pathogens such as Lachnoclostridium, Acinobacter, and Serratia. Arginine–proline metabolism was significantly different between the colitis-treated and untreated groups. In the colon mucosa and RAW264.7 macrophage, resveratrol regulated arginine metabolism towards colon protection by increasing Arg1 and Slc6a8 and decreasing iNOS. Conclusion This uncovers a previously unknown mechanism of resveratrol treatment in IBD and provides the microbiota-macrophage-arginine metabolism axis as a potential therapeutic target for intestinal inflammation.

Simple Summary: Sensitive and specific circulating biomarkers for the early detection of pancreatic ductal adenocarcinoma (PDAC) are urgently needed to improve the survival outcomes of this malignancy. Small extracellular vesicles (sEVs) from cancer cells carry biomolecules of cellular origin that can be released into the circulation. Studies have shown that plasma sEV molecules, such as proteins and microRNAs, are potential indicators of PDAC. However, post-translational modifications of plasma sEV proteins, such as arginine methylation patterns, have never been examined as potential circulating biomarkers for PDAC. Protein arginine methylation is considered a relatively stable post-translational modification, and is a newly established molecular feature of PDAC. We thus speculated that arginine methylation patterns in plasma sEVs are non-invasive biomarkers for pancreatic ductal adenocarcinoma. In this report, we demonstrate that protein arginine methylation patterns are altered in plasma sEVs derived from patients with early-stage PDAC, with these findings supporting the development of these patterns as biomarkers for PDAC. Small extracellular vesicles (sEVs) contain lipids, proteins and nucleic acids, which often resemble their cells of origin. Therefore, plasma sEVs are considered valuable resources for cancer biomarker development. However, previous efforts have been largely focused on the level of proteins and miRNAs in plasma sEVs, and the post-translational modifications of sEV proteins, such as arginine methylation, have not been explored. Protein arginine methylation, a relatively stable post-translational modification, is a newly described molecular feature of PDAC. The present study examined arginine methylation patterns in plasma sEVs derived from patients with early-stage PDAC (n = 23) and matched controls. By utilizing the arginine methylation-specific antibodies for western blotting, we found that protein arginine methylation patterns in plasma sEVs are altered in patients with early-stage PDAC. Specifically, we observed a reduction in the level of symmetric dimethyl arginine (SDMA) in plasma sEV proteins derived from patients with early- and late-stage PDAC. Importantly, immunoprecipitation followed by proteomics analysis identified a number of arginine-methylated proteins exclusively present in plasma sEVs derived from patients with early-stage PDAC. These results indicate that arginine methylation patterns in plasma sEVs are potential indicators of PDAC, a new concept meriting further investigation. [ABSTRACT FROM AUTHOR]

Enterococcus faecalis is a commensal bacterium in the gastrointestinal (GI) tract of humans and other organisms. E. faecalis also causes infections in root canals, wounds, the urinary tract, and on heart valves. E. faecalis metabolizes arginine through the arginine deiminase pathway, which converts arginine to ornithine and releases ATP, ammonia, and CO2. E. faecalis arginine metabolism also affects virulence of other pathogens during co-culture. E. faecalis may encounter elevated levels of arginine in the GI tract or the oral cavity, where arginine is used as a dental therapeutic. Little is known about how E. faecalis responds to growth in arginine in the absence of other bacteria. To address this, we used RNAseq and additional assays to measure growth, gene expression, and biofilm formation in E. faecalis OG1RF grown in arginine. We demonstrate that arginine decreases E. faecalis biofilm production and causes widespread differential expression of genes related to metabolism, quorum sensing, and polysaccharide synthesis. Growth in arginine also increases aggregation of E. faecalis and promotes decreased susceptibility to the antibiotics ampicillin and ceftriaxone. This work provides a platform for understanding how the presence of arginine in biological niches affects E. faecalis physiology and virulence of surrounding microbes. [ABSTRACT FROM AUTHOR]

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Abstract Introduction Immune factors contribute to the onset of myelodysplastic syndrome (MDS). Arginine metabolism affects tumor‐associated macrophage (TAM) polarization. This study investigated the infiltration of TAMs and effect of arginine metabolism key enzymes on MDS prognosis. Methods We used the GEO (Gene Express Omnibus database) dataset “GSE19429” to analyze and compare metabolism‐associated pathways between MDS patients with excess blasts and those without. The markers of TAMs and arginine metabolism key enzymes, including CD68, iNOS, ARG1 and ASS1 were included in this study. A cohort of 79 patients with acute myeloid leukemia or MDS extracted from GenomicScape's online data mining platform was used to analyze the prognostic significance of the mRNA levels. Fifty‐eight patients with primary MDS admitted to Sichuan University's West China Hospital from 2013 to 2017 were evaluated for protein levels. The coexpression of CD68, iNOS, and ARG1 was investigated using an Opal polychromatic immunofluorescence kit. Results The “Arginine and proline metabolism” pathways (padjusted = 0.01) were associated with excess blasts in patients with MDS. In the mRNA expression cohort, patients with low NOS2 (or iNOS) and high ARG1, ASS1, and CD68 expression levels had worse prognosis. Patients with high CD68 (p = 0.01), high iNOS (p

Colorectal cancer (CRC) is the third most common cancer in the world, with increasing morbidity and mortality. The current diagnosis and treatment plan rely on early detection and comprehensive treatment based on surgery. Still, most patients are in the middle and advanced stage at the time of diagnosis, and the therapeutic effect is very limited. Immunotherapy is a new cancer treatment method. The most commonly used are immune checkpoint inhibitors, specifically anti PD-1/PD-L1 interaction. However, immunotherapy has limitations, with its therapeutic effect closely related to the immune response in the tumor microenvironment. In recent years, the effect of arginine metabolism disorder on the occurrence and development of cancer and tumor immune regulation has attracted wide attention. Studies have confirmed that cancer cells cannot survive without arginine and arginine metabolites. In addition, arginine is essential for the proliferation, differentiation, and survival of tumor-infiltrating lymphocytes. High arginine levels can promote the anti-tumor immune response, thus increasing the effect of tumor immunotherapy. In this paper, the molecular mechanisms of arginine metabolism in the development and immune regulation of CRC are reviewed, with the authors hoping to provide potential evidence for the development of immunotherapy for CRC. Abbreviation CRC = Colorectal cancer, dMMR = Mismatch repair deficient, MSI-H = Microsatellite highly Instability, MSS = Microsatellite stability, TME = Tumor microenvironment, MHC = Major histocompatibility complex, pMMR = Mismatch repair proficient, NOS = Nitric Oxide synthase, NO = Nitric oxide, ASS-1 = Arginine succinate synthetase 1, ASL = Argininosuccinate lyase, ARG = arginase, CAT = Cationic amino acid transporter, AGAT = Arginine-glycine amidinotransferase, ADC = Arginine decarboxylase, ADI = Arginine deiminase, ODC = Ornithine decarboxylase, GCN2 = General control non-depressible 2, mTOR = Mammalian target of rapamycin, HIF-1 = Hypoxia-inducible factor 1, VEGF = Vascular endothelial growth factor, ICI = Immune checkpoint inhibitor, ORR = Objective response rate, DCR = Disease control rate, OS = Overall survival, PFS = Progress free survival, TIL = Tumor-infiltrating lymphocyte, TCM = Central memory T cell

Background: Sepsis is a life-threatening disease with a poor prognosis, and metabolic disorders play a crucial role in its development. This study aims to identify key metabolites that may be associated with the accurate diagnosis and prognosis of sepsis. Methods: Septic patients and healthy individuals were enrolled to investigate metabolic changes using non-targeted liquid chromatography-high-resolution mass spectrometry metabolomics. Machine learning algorithms were subsequently employed to identify key differentially expressed metabolites (DEMs). Prognostic-related DEMs were then identified using univariate and multivariate Cox regression analyses. The septic rat model was established to verify the effect of phenylalanine metabolism-related gene MAOA on survival and mean arterial pressure after sepsis. Results: A total of 532 DEMs were identified between healthy control and septic patients using metabolomics. The main pathways affected by these DEMs were amino acid biosynthesis, phenylalanine metabolism, tyrosine metabolism, glycine, serine and threonine metabolism, and arginine and proline metabolism. To identify sepsis diagnosis-related biomarkers, support vector machine (SVM) and random forest (RF) algorithms were employed, leading to the identification of four biomarkers. Additionally, analysis of transcriptome data from sepsis patients in the GEO database revealed a significant up-regulation of the phenylalanine metabolism-related gene MAOA in sepsis. Further investigation showed that inhibition of MAOA using the inhibitor RS-8359 reduced phenylalanine levels and improved mean arterial pressure and survival rate in septic rats. Finally, using univariate and multivariate cox regression analysis, six DEMs were identified as prognostic markers for sepsis. Conclusions: This study employed metabolomics and machine learning algorithms to identify differential metabolites that are associated with the diagnosis and prognosis of sepsis patients. Unraveling the relationship between metabolic characteristics and sepsis provides new insights into the underlying biological mechanisms, which could potentially assist in the diagnosis and treatment of sepsis. Trial registration: This human study was approved by the Ethics Committee of the Research Institute of Surgery (2021–179) and was registered by the Chinese Clinical Trial Registry (Date: 09/12/2021, ChiCTR2200055772). [ABSTRACT FROM AUTHOR]

Disulfide bond A oxidoreductase‐like protein (DsbA‐L) drives acute kidney injury (AKI) by directly upregulating the expression of voltage‐dependent anion‐selective channels in proximal tubular cells. However, the role of DsbA‐L in immune cells remains unclear. In this study, we used an LPS‐induced AKI mouse model to assess the hypothesis that DsbA‐L deletion attenuates LPS‐induced AKI and explore the potential mechanism of DsbA‐L action. After 24 hours of LPS exposure, the DsbA‐L knockout group exhibited lower serum creatinine levels compared to the WT group. Furthermore, peripheral levels of the inflammatory cytokine IL‐6 were decreased. Transcriptomic data analysis revealed a significant down‐regulation in the IL‐17 and tumor necrosis factor pathways in DsbA‐L knockout mice following LPS induction. Metabolomic analysis suggested that arginine metabolism was significantly different between the WT and DsbA‐L knockout groups after LPS treatment. Notably, the M1 polarization of macrophages in the kidneys of DsbA‐L knockout AKI mice was significantly reduced. Expression of the transcription factors NF‐κB and AP‐1 was downregulated after DsbA‐L knockout. Our results suggest that DsbA‐L regulates LPS‐mediated oxidative stress, promotes M1 polarization of macrophages, and induces expression of inflammatory factors via the NF‐κB/AP‐1 pathway. [ABSTRACT FROM AUTHOR]

Background: Inflammatory bowel disease (IBD) is a global disease with a growing public health concern and is associated with a complex interplay of factors, including the microbiota and immune system. Resveratrol, a natural anti-inflammatory and antioxidant agent, is known to relieve IBD but the mechanism involved is largely unexplored. Methods: This study examines the modulatory effect of resveratrol on intestinal immunity, microbiota, metabolites, and related functions and pathways in the BALB/c mice model of IBD. Mouse RAW264.7 macrophage cell line was used to further explore the involvement of the macrophage-arginine metabolism axis. The treatment outcome was assessed through qRT-PCR, western blot, immunofluorescence, immunohistochemistry, and fecal 16S rDNA sequencing and UHPLC/Q-TOF–MS. Results: Results showed that resveratrol treatment significantly reduced disease activity index (DAI), retained mice weight, repaired colon and spleen tissues, upregulated IL-10 and the tight junction proteins Occludin and Claudin 1, and decreased pro-inflammatory cytokines IL-1β, IL-6, and TNF-α. Resveratrol reduced the number of dysregulated metabolites and improved the gut microbial community structure and diversity, including reversing changes in the phyla Bacteroidetes, Proteobacteria, and Firmicutes, increasing 'beneficial' genera, and decreasing potential pathogens such as Lachnoclostridium, Acinobacter, and Serratia. Arginine–proline metabolism was significantly different between the colitis-treated and untreated groups. In the colon mucosa and RAW264.7 macrophage, resveratrol regulated arginine metabolism towards colon protection by increasing Arg1 and Slc6a8 and decreasing iNOS. Conclusion: This uncovers a previously unknown mechanism of resveratrol treatment in IBD and provides the microbiota-macrophage-arginine metabolism axis as a potential therapeutic target for intestinal inflammation. [ABSTRACT FROM AUTHOR]

Abstract Objective In this study, differentially expressed metabolites of vascular endothelial cells were examined to further understand the metabolic regulation of ischemic injury by untargeted metabolomics. Method Human umbilical vein endothelial cells (HUVECs) were selected to construct an ischemia model using oxygen–glucose deprivation (OGD) and 0, 3, 6, and 9 h of treatment. After that, cell survival levels were determined by CCK8 detection. Flow cytometry, ROS detection, JC-1 detection, and western blotting were used to measure apoptosis and oxidative stress in cells. Then, combined with UPLC Orbitrap/MS, we verified the impacted metabolism pathways by western blotting and RT‒PCR. Results CCK8 assays showed that the survival of HUVECs was decreased with OGD treatment. Flow cytometry and the expression of cleaved caspase 3 showed that the apoptosis levels of HUVECs increased following OGD treatment. The ROS and JC-1 results further suggested that oxidative stress injury was aggravated. Then, combined with the heatmap, KEGG and IPA, we found that arginine metabolism was differentially altered during different periods of OGD treatment. Furthermore, the expression of four arginine metabolism-related proteins, ASS1, ARG2, ODC1 and SAT1, was found to change during treatment. Conclusion Arginine metabolism pathway-related proteins were significantly altered by OGD treatment, which suggests that they may have a potential role in ischemic injury.

As the only oxygenic phototrophs among prokaryotes, cyanobacteria employ intricate mechanisms to regulate common metabolic pathways. These mechanisms include small protein inhibitors exerting their function by protein–protein interaction with key metabolic enzymes and regulatory small RNAs (sRNAs). Here we show that the sRNA NsiR4, which is highly expressed under nitrogen limiting conditions, interacts with the mRNA of the recently described small protein PirA in the model strain Synechocystis sp. PCC 6803. In particular, NsiR4 targets the pirA 5ʹUTR close to the ribosome binding site. Heterologous reporter assays confirmed that this interaction interferes with pirA translation. PirA negatively impacts arginine synthesis under ammonium excess by competing with the central carbon/nitrogen regulator PII that binds to and thereby activates the key enzyme of arginine synthesis, N-acetyl-L-glutamate-kinase (NAGK). Consistently, ectopic nsiR4 expression in Synechocystis resulted in lowered PirA accumulation in response to ammonium upshifts, which also affected intracellular arginine pools. As NsiR4 and PirA are inversely regulated by the global nitrogen transcriptional regulator NtcA, this regulatory axis enables fine tuning of arginine synthesis and conveys additional metabolic flexibility under highly fluctuating nitrogen regimes. Pairs of small protein inhibitors and of sRNAs that control the abundance of these enzyme effectors at the post-transcriptional level appear as fundamental building blocks in the regulation of primary metabolism in cyanobacteria.

Objectives: Diabetic Nephropathy (DN) is a serious complication of diabetes, the diagnosis and treatment of DN is still limited. Sinomenine (SIN) is an active extract of herbal medicine and has been applied into the therapy of DN. Methods: In the part of bioinformatic analyses, network pharmacology and molecular docking analyses were conducted to predict the important pathway of SIN treatment for DN. In-vivo study, DN rats were randomized to be treated with vehicle or SIN (20 mg/kg or 40 mg/kg) daily by gavage for 8 weeks. Then, the pharmacological effect of SIN on DN and the potential mechanisms were also evaluated by 24 h albuminuria, histopathological examination, transcriptomics, and metabolomics. Results: Firstly, network pharmacology and molecular docking were performed to show that SIN might improve DN via AGEs/RAGE, IL-17, JAK, TNF pathways. Urine biochemical parameters showed that SIN treatment could significantly reduce 24 h albuminuria of DN rats. Transcriptomics analysis found SIN could affect DN progression via inflammation and EMT pathways. Metabolic pathway analysis found SIN would mainly involve in arginine biosynthesis, linoleic acid metabolism, arachidonic acid metabolism, and glycerophospholipid metabolism to affect DN development. Conclusions: We confirmed that SIN could inhibit the progression of DN via affecting multiple genes and metabolites related pathways. [ABSTRACT FROM AUTHOR]

Aim: Uterine cervical cancer (UCC) is the fourth most common cancer in women, responsible for more than 300 000 deaths worldwide. Its early detection, by cervical cytology, and prevention, by vaccinating against human papilloma virus, greatly contribute to reducing cervical cancer mortality in women. However, penetration of the effective prevention of UCC in Japan remains low. Plasma metabolome analysis is widely used for biomarker discovery and the identification of cancer‐specific metabolic pathways. Here, we aimed to identify predictive biomarkers for the diagnosis and radiation sensitivity of UCC using wide‐targeted plasma metabolomics. Methods: We analyzed 628 metabolites in plasma samples obtained from 45 patients with UCC using ultra‐high‐performance liquid chromatography with tandem mass spectrometry. Results: The levels of 47 metabolites were significantly increased and those of 75 metabolites were significantly decreased in patients with UCC relative to healthy controls. Increased levels of arginine and ceramides, and decreased levels of tryptophan, ornithine, glycosylceramides, lysophosphatidylcholine, and phosphatidylcholine were characteristic of patients with UCC. Comparison of metabolite profiles in groups susceptible and non‐susceptible to radiation therapy, a treatment for UCC, revealed marked variations in polyunsaturated fatty acid, nucleic acid, and arginine metabolism in the group not susceptible to treatment. Conclusions: Our findings suggest that the metabolite profile of patients with UCC may be an important indicator for distinguishing these patients from healthy cohorts, and may also be useful for predicting sensitivity to radiotherapy. [ABSTRACT FROM AUTHOR]

Introduction: Immune factors contribute to the onset of myelodysplastic syndrome (MDS). Arginine metabolism affects tumor‐associated macrophage (TAM) polarization. This study investigated the infiltration of TAMs and effect of arginine metabolism key enzymes on MDS prognosis. Methods: We used the GEO (Gene Express Omnibus database) dataset "GSE19429" to analyze and compare metabolism‐associated pathways between MDS patients with excess blasts and those without. The markers of TAMs and arginine metabolism key enzymes, including CD68, iNOS, ARG1 and ASS1 were included in this study. A cohort of 79 patients with acute myeloid leukemia or MDS extracted from GenomicScape's online data mining platform was used to analyze the prognostic significance of the mRNA levels. Fifty‐eight patients with primary MDS admitted to Sichuan University's West China Hospital from 2013 to 2017 were evaluated for protein levels. The coexpression of CD68, iNOS, and ARG1 was investigated using an Opal polychromatic immunofluorescence kit. Results: The "Arginine and proline metabolism" pathways (padjusted = 0.01) were associated with excess blasts in patients with MDS. In the mRNA expression cohort, patients with low NOS2 (or iNOS) and high ARG1, ASS1, and CD68 expression levels had worse prognosis. Patients with high CD68 (p = 0.01), high iNOS (p < 0.01), low ARG1 (p = 0.01), and negative ASS1 (p = 0.02) protein expression levels had better prognoses. iNOS and ARG1 were coexpressed with CD68 in MDS patients with or without excess blasts, respectively. Conclusions: Arginine metabolism may contribute to the prognosis of patients with MDS by affecting TAM polarization. [ABSTRACT FROM AUTHOR]

[Objectives] The present study aimed to explore the effects of fine particulate matters (PM2.5) from pig house on polarization-related metabolism including arginine metabolism and glycolysis and the TLR4-NF-κB signaling pathway in porcine alveolar macrophages. [Methods] The experiment used porcine alveolar macrophage cell line(3D4/21)as the cell model, and set different concentrations of PM2.5 (0, 25, 50 and 100 μg·mL-1) and different treatment time(4, 8, 12, 16, 20 and 24 h)for the cell treatment, and the cells were collected to measure arginine metabolism, glycolysis and related indicators of the TLR4-NF-κB signaling pathway. [Results]The results showed that after 12 hours of PM2.5 treatment, the concentration of nitric oxide (NO) in the cell supernatant gradually increased with the raising concentration of PM2.5. When the PM2.5 concentration was higher than 50 μg·mL-1, the NO concentration reached a significant level as compared with the control group (P<0.01). The cells were cultured for different time with 50 μg·mL-1 PM2.5, the results showed that the concentration of NO in cell supernatant gradually increased within 16 hours treatment, with the prolongation of the cell treatment time, the effect of PM2.5 on the cells gradually decreased. Further, the treatment of PM2.5 reduced the activity of arginase in the cells, and the 50 μg·mL-1 treatment of PM2.5 showed a significant difference(P<0.01). At the same time, with the raising concentration of PM2.5, the value of lactate production/glucose consumption (L/G) was increased (P<0.05), indicating that the ratio of intracellular glucose to lactate conversion increased, and the mRNA expression levels of glycolysis-related genes GLUT-1 and GAPDH significantly increased (P<0.05); 100 μg·mL-1 PM2.5 significantly increased the mRNA expression level of IL-1β (P<0.01); and after 50 μg·mL-1 PM2.5 treatment, the mRNA expression level of the M2 macrophage marker CD206 significantly decreased (P<0.05). The TLR4-NF-κB signaling pathway was significantly activated after PM2.5 treatment(P<0.05). [Conclusions]These results indicated that PM2.5 from pig house promoted the occurrence of inflammatory response in porcine alveolar macrophages, and at the same time promoted the metabolic conversion of intracellular arginine and glucose metabolism to M1 phenotypic characteristics. [ABSTRACT FROM AUTHOR]

Simple Summary: There is a need to identify new translational prognostic biomarkers in head and neck cancer. Metabolomics, the study of small molecules resulting from cellular metabolism, is an emerging and promising field regarding head and neck cancer. We performed metabolomics on patients' blood prior to treatment and found that it can divide patients into high-risk and low-risk groups based on their cancer progression and survival. We believe our study provides compelling results to consider metabolomics as a translational prognostic biomarker and that it may offer novel information for patient risk stratification. With continued research, we hope to gain a fuller understanding of how metabolomics may aid in the early detection, prognosis, treatment monitoring, and targeted therapies of head and neck cancer. There is growing evidence that the metabolism is deeply intertwined with head and neck squamous cell carcinoma (HNSCC) progression and survival but little is known about circulating metabolite patterns and their clinical potential. We performed unsupervised hierarchical clustering of 209 HNSCC patients via pre-treatment plasma metabolomics to identify metabolic subtypes. We annotated the subtypes via pathway enrichment analysis and investigated their association with overall and progression-free survival. We stratified the survival analyses by smoking history. High-resolution metabolomics extracted 186 laboratory-confirmed metabolites. The optimal model created two patient clusters, of subtypes A and B, corresponding to 41% and 59% of the study population, respectively. Fatty acid biosynthesis, acetyl-CoA transport, arginine and proline, as well as the galactose metabolism pathways differentiated the subtypes. Relative to subtype B, subtype A patients experienced significantly worse overall and progression-free survival but only among ever-smokers. The estimated three-year overall survival was 61% for subtype A and 86% for subtype B; log-rank p = 0.001. The association with survival was independent of HPV status and other HNSCC risk factors (adjusted hazard ratio = 3.58, 95% CI: 1.46, 8.78). Our findings suggest that a non-invasive metabolomic biomarker would add crucial information to clinical risk stratification and raise translational research questions about testing such a biomarker in clinical trials. [ABSTRACT FROM AUTHOR]

A polyherbal formulation with hepatoprotective and choleretic properties combining pharmacological potential of eight medicinal plants was developed in Nargiz Medical center (Republic of Azerbaijan) for the use as herbal tea. To explore the effect of polyherbal composition on the metabolism of LPS-stimulated macrophages in vitro. The qualitative and quantitative phytochemical analysis was conducted using specific color reactions and gas chromatography-mass spectrometry (GC–MS). Nitric oxide (NO) assay was determined using the Griess reaction. Reactive oxygen species (ROS) generation was measured using ROS-sensitive fluorescence indicator, H2DCFDA, by flow cytometry. Arginase activity was examined by colorimetric method. The studied polyherbal formulation exerted anti-inflammatory activity in LPS-stimulated macrophages which was evidenced by dose-dependent decrease of ROS generation and by shift of arginine metabolism to the increase of arginase activity and decrease of NO release. Our findings suggest that the herbal tea reduces macrophage inflammatory activity, that provide an important rationale to utilize it for the attenuation of chronic inflammation typical of hepatobiliary disorders. [ABSTRACT FROM AUTHOR]

Objectives: Periodontal disease occurs frequently in patients with limited cutaneous systemic sclerosis (lcSSc) while data about underlying pathways contributing to periodontal changes are scarce. The aim of this study was to evaluate periodontal disease and to investigate its association with endothelial dysfunction and clinical changes in patients with lcSSc. Methods: In 38 lcSSc patients and 38 controls, periodontal status was evaluated by disease‐specific questionnaire, dental examination including bleeding on probing (BOP), pocket depth, and plaque index, and dental panoramic radiograph. Periodontopathogen bacteria were collected subgingivally using paper points and interleukin‐1 (IL‐1) gene polymorphisms were evaluated using buccal swabs. Endothelial dysfunction was measured by flow‐mediated dilatation, pulse‐wave velocity and biochemical analysis, including arginine metabolites and endothelial microparticles. Additionally, lcSSc‐specific clinical changes and parameters were recorded. Results: Periodontitis was present in 31 patients with lcSSc (81.6%) and in 27 controls (71.1%) (p =.280). LcSSc patients had a lower teeth number (p =.039) and Eikenella corrodens was to a higher degree detectable in patients with lcSSc (p =.041) while the remaining periodontal parameters revealed no differences between both cohorts. Significant correlations between parameters of arterial stiffness, EUSTAR index, number of teeth and BOP were observed (all p <.05). Detection of Prevotella intermedia was associated with selected IL‐1 gene polymorphisms (p =.032) and Porphyromonas gingivalis was associated with severe periodontitis (p =.041). Conclusion: Periodontal disease may occur frequently in patients with lcSSc and may be associated with arterial stiffness and with SSc activity. [ABSTRACT FROM AUTHOR]

Abstract Background Asymmetric dimethylarginine (ADMA), which is significantly elevated in the plasma of cancer patients, is formed via intracellular recycling of methylated proteins and serves as a precursor for resynthesis of arginine. However, the cause of ADMA elevation in cancers and its impact on the regulation of tumor immunity is not known. Methods Three mouse breast cell lines (normal breast epithelial HC11, breast cancer EMT6 and triple negative breast cancer 4T1) and their equivalent 3D stem cell culture were used to analyze the secretion of ADMA using ELISA and their responses to ADMA. Bone marrow-derived macrophages and/or RAW264.7 cells were used to determine the impact of increased extracellular ADMA on macrophage-tumor interactions. Gene/protein expression was analyzed through RNAseq, qPCR and flow cytometry. Protein functional analyses were conducted via fluorescent imaging (arginine uptake, tumor phagocytosis) and enzymatic assay (arginase activity). Cell viability was measured via MTS assay and/or direct cell counting using Countess III FL system. Results For macrophages, ADMA impaired proliferation and phagocytosis of tumor cells, and even caused death in cultures incubated without arginine. ADMA also led to an unusual macrophage phenotype, with increased expression of arginase, cd163 and cd206 but decreased expression of il10 and dectin-1. In contrast to the severely negative impacts on macrophages, ADMA had relatively minor effects on proliferation and survival of mouse normal epithelial HC11 cells, mouse breast cancer EMT6 and 4T1 cells, but there was increased expression of the mesenchymal markers, vimentin and snail2, and decreased expression of the epithelial marker, mucin-1 in EMT6 cells. When tumor cells were co-cultured ex vivo with tumor antigen in vivo-primed splenocytes, the tumor cells secreted more ADMA and there were alterations in the tumor cell arginine metabolic landscape, including increased expression of genes involved in arginine uptake, metabolism and methylation, and decreased expression of a gene that is responsible for arginine demethylation. Additionally, interferon-gamma, a cytokine involved in immune challenge, increased secretion of ADMA in tumor cells, a process attenuated by an autophagy inhibitor. Conclusion Our results suggest initial immune attack promotes autophagy in tumor cells, which then secrete ADMA to manipulate macrophage polarization favoring tumor tolerance.

Aim: The extent of the spread of inflammation determines the severity of acute pancreatitis (AP). Methylated arginine residues (MAR), a type of inflammatory mediator, reduce nitric oxide levels and cause vasoconstriction-induced endothelial damage. This study aimed to investigate MAR and related amino acids during acute pancreatic inflammation. Material and Method: This prospective, quasi-experimental study was conducted with patients diagnosed with AP and an age-matched control group. The patient samples were taken during the diagnosis and recovery time, whereas during the study for the control group. Mainly, Asymmetric dimethylarginine (ADMA), Arginine (ARG), Citrulline (CIT), and related chemicals were studied via a mass spectrometer. Results: A total of 30 patients with AP (mean age=53.3±17.8) and 30 controls (mean age=53.4±18.0) were included in the study. All patients were identified as non-severe (n=8) and severe (n=22). A decrease was detected in the patients' ADMA levels compared to the control group (p=0.01). MAR did not differ concerning disease severity (p > 0.05). However, MAR levels decreased higher in patients with diabetes or chronic kidney disease (CKD). Between the two samplings, the ARG level and ARG to ADMA ratio increased, while the MAR and CIT to ARG ratio decreased. Conclusion: Our results showed that MAR levels decreased with AP recovery. The start of a decrease in the high-level blood MAR may indicate the healing of pancreatic inflammation. AP inflammation may be more destructive in patients with diabetes or CKD.

Simple Summary: PRMT5 is overexpressed and activated in various human cancers, including breast cancer. This study aims to dissect the mechanism underlying how PRMT5 is dysregulated in cancers. Our results demonstrate that TRAF6-mediated ubiquitination plays an important role in the regulation of PRMT5 activity and cell proliferation. Thus, inhibition of TRAF6 is a possible strategy for improving PRMT5 targeted therapy. Protein arginine methyltransferase 5 (PRMT5) is the primary enzyme generating symmetric dimethylarginine (sDMA) on numerous substrates, through which it regulates many cellular processes, such as transcription and DNA repair. Aberrant expression and activation of PRMT5 is frequently observed in various human cancers and associated with poor prognosis and survival. However, the regulatory mechanisms of PRMT5 remain poorly understood. Here, we report that TRAF6 serves as an upstream E3 ubiquitin ligase to promote PRMT5 ubiquitination and activation. We find that TRAF6 catalyzes K63-linked ubiquitination of PRMT5 and interacts with PRMT5 in a TRAF6-binding-motif-dependent manner. Moreover, we identify six lysine residues located at the N-terminus as the primarily ubiquitinated sites. Disruption of TRAF6-mediated ubiquitination decreases PRMT5 methyltransferase activity towards H4R3 in part by impairing PRMT5 interaction with its co-factor MEP50. As a result, mutating the TRAF6-binding motifs or the six lysine residues significantly suppresses cell proliferation and tumor growth. Lastly, we show that TRAF6 inhibitor enhances cellular sensitivity to PRMT5 inhibitor. Therefore, our study reveals a critical regulatory mechanism of PRMT5 in cancers. [ABSTRACT FROM AUTHOR]

The pathogenesis of inflammatory bowel disease (IBD) is related to genetic susceptibility, enteric dysbiosis, and uncontrolled, chronic inflammatory responses that lead to colonic tissue damage and impaired intestinal absorption. As a consequence, patients with IBD are prone to nutrition deficits after each episode of disease resurgence. Nutritional supplementation, especially for protein components, is often implemented during the remission phase of IBD. Notably, ingested nutrients could affect the progression of IBD and the prognostic outcome of patients; therefore, they should be cautiously evaluated prior to being used for IBD intervention. Arginine (Arg) is a semi-essential amino acid required for protein synthesis and intimately associated with gut pathophysiology. To help optimize arginine-based nutritional intervention strategies, the present work summarizes that during the process of IBD, patients manifest colonic Arg deficiency and the turbulence of Arg metabolic pathways. The roles of Arg–nitric oxide (catalyzed by inducible nitric oxide synthase) and Arg–urea (catalyzed by arginases) pathways in IBD are debatable; the Arg–polyamine and Arg–creatine pathways are mainly protective. Overall, supplementation with Arg is a promising therapeutic strategy for IBD; however, the dosage of Arg may need to be carefully tailored for different individuals at different disease stages. Additionally, the combination of Arg supplementation with inhibitors of Arg metabolic pathways as well as other treatment options is worthy of further exploration. [ABSTRACT FROM AUTHOR]