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Responses of POX to various stress stimuli and their metabolic consequences. ATP, adenosine triphosphate; COX2, cyclooxygenase-2; ETC, electron transport chain; GADD, growth arrest DNA damage; GLU, glutamic acid; HIF-1α, hypoxia-inducible factor-1α; NAD, nicotinamide adenine dinucleotide; NADP, nicotinamide adenine dinucleotide phosphate; PPARγ, peroxisomal proliferator-activated receptor gamma; POX, proline oxidase; PRO, proline; Pyr, pyruvate; ROS, reactive oxygen species.
Source publication
Proline, the only proteinogenic secondary amino acid, is metabolized by its own family of enzymes responding to metabolic stress and participating in metabolic signaling. Collagen in extracellular matrix, connective tissue, and bone is an abundant reservoir for proline. Matrix metalloproteinases degrading collagen are activated during stress to mak...
Contexts in source publication
Context 1
... discovery that POX/PRODH played a role in apoptosis was the beginning of a new era in research in the proline metabolic pathway (Figure 3). In contrast to earlier studies emphasizing homeostasis and whole-organism regulation, the new paradigm suggested that the proline metabolic pathway was mobilized primarily under conditions of stress, was local- ized to a microenvironment, and could use as substrate not only free cellular proline but also Responses of POX to various stress stimuli and their metabolic consequences. ...
Context 2
... POX/PRODH is upregulated in response to three types of stress, i.e., genotoxic stress, inflammatory stress, and metabolic stress, and the enzymatic activity catalyzed by POX/PRODH yields a number of products, how and under what conditions is this activity relevant to cancer (Figure 3)? First, electrons from proline are transferred to a flavine adenine dinucleotide at the enzyme active site. ...
Citations
... Free proline concentration increased considerably. Recent studies show that proline regulates biochemical processes [45][46][47]. The antioxidant capabilities of proline may explain the considerable rise in its concentration in response to oxidative stress in this study [47]. ...
... The findings suggest that proline synthesis regulates DNA proliferation and repair [46,47]. Summing up, we observed an induction of oxidative stress in the hearts of rats demonstrating depressive-like behavior. ...
Chronic variable mild stress (CVS) in rats is a well-established paradigm for inducing depressive-like behaviors and has been utilized extensively to explore potential therapeutic interventions for depression. While the behavioral and neurobiological effects of CVS have been extensively studied, its impact on myocardial function remains largely unexplored. To induce the CVS model, rats were exposed to various stressors over 40 days. Behavioral assessments confirmed de-pressive-like behavior. Biochemical analyses revealed alterations in myocardial metabolism, including changes in NAD+ and NADP+, and NADPH concentrations. Free amino acid analysis indicated disturbances in myocardial amino acid metabolism. Evaluation of oxidative DNA damage demonstrated an increased number of abasic sites in the DNA of rats exposed to CVS. Molecular analysis showed significant changes in gene expression associated with glucose metabolism, oxidative stress, and cardiac remodeling pathways. Histological staining revealed minor morphological changes in the myocardium of CVS-exposed rats, including increased acidophilicity of cells, collagen deposition surrounding blood vessels, and glycogen accumulation. This study provides novel insights into the impact of chronic stress on myocardial function and metabolism, highlighting potential mechanisms linking depression and cardiovascular diseases. Understanding these mechanisms may aid in the development of targeted therapeutic strategies to mitigate the adverse cardiovascular effects of depression.
... Therefore, alterations in tryptophan levels could potentially impact neurobehavioral functions in male mice post-irradiation [47,48]. The role of proline in various physiological processes, including collagen formation, antioxidant defense, and cell signaling, is well-established in the scientific literature [49,50]. PABA may possess antioxidant properties and could potentially protect against oxidative stress-induced damage [51]. ...
Exposure to ionizing radiation, accidental or intentional, may lead to delayed effects of acute radiation exposure (DEARE) that manifest as injury to organ systems, including the kidney, heart, and brain. This study examines the role of activated protein C (APC), a known mitigator of radiation-induced early toxicity, in long-term plasma metabolite and lipid panels that may be associated with DEARE in APCHi mice. The APCHi mouse model used in the study was developed in a C57BL/6N background, expressing the D168F/N173K mouse analog of the hyper-activatable human D167F/D172K protein C variant. This modification enables increased circulating APC levels throughout the mouse’s lifetime. Male and female cohorts of C57BL/6N wild-type and APCHi transgenic mice were exposed to 9.5 Gy γ-rays with their hind legs shielded to allow long-term survival that is necessary to monitor DEARE, and plasma was collected at 6 months for LC-MS-based metabolomics and lipidomics. We observed significant dyslipidemia, indicative of inflammatory phenotype, upon radiation exposure. Additionally, observance of several other metabolic dysregulations was suggestive of gut damage, perturbations in TriCarboxylic Acid (TCA) and urea cycles, and arginine metabolism. We also observed gender- and genotype-modulated metabolic perturbations post radiation exposure. The APCHi mice showed near-normal abundance for several lipids. Moreover, restoration of plasma levels of some metabolites, including amino acids, citric acid, and hypoxanthine, in APCHi mice is indicative of APC-mediated protection from radiation injuries. With the help of these findings, the role of APC in plasma molecular events after acute γ-radiation exposure in a gender-specific manner can be established for the first time.
... and encodes a 33.4-kDa enzyme that consists of 319 amino acids (7). Phang et al (8) previously found that the PYCR1 protein is mainly localized to the mitochondria and forms a decameric structure of two main structural domains, namely the N-and C-terminal domains. The N-terminal domain folds to bind NAD(P)H, whilst the C-terminal domain contains an α-helix to bind other substrates, such as Pyrroline 5-carboxylate (P5C) or L-Thiazolidine-4-carboxylate (T4C,thiaproline) (9,10). ...
Although recombinant human TNF-related apoptosis-inducing ligand (TRAIL) protein exhibits antitumor activity in a number of lung and liver cancer cells and tumor-bearing animals, TRAIL resistance has substantially restricted its clinical application. Pyrroline-5-carboxylate reductase 1 (PYCR1) is a key enzyme in the regulation of proline synthesis. PYCR1 is highly expressed in various types of malignant tumor, in which it has been implicated in 5-fluorouracil resistance. However, the possible relationship between PYCR1 and TRAIL resistance remains unclear. In the present study, both reverse transcription-quantitative PCR and western blotting were performed. The results indicated that H1299 cells had higher PYCR1 expression levels and were less sensitive to TRAIL compared with the TRAIL-sensitive cell line, H460. PYCR1 knockdown in H1299 cells increased TRAIL sensitivity, increased the localization of death receptors (DRs) on the cell surface and activated Caspase-3/8. By contrast, overexpression of PYCR1 in H1299 cells decreased TRAIL sensitivity, reduced the distribution of DRs on the cell surface and suppressed the activation of Caspase-3/8. Taken together, these results suggested that PYCR1 promoted TRAIL resistance in the non-small cell lung cancer cell line, H1299, by preventing redistribution of DRs to the plasma membrane. This in turn inhibited TRAIL-mediated cell apoptosis by reducing the activation of Caspase-3/8.
... Arginine and its metabolites are essential for tissue remodeling, growth and development and immune regulation in mammals (Flynn et al., 2002). Proline and its metabolites are needed as scavengers of oxygen free radicals and regulators of the redox balance (Phang et al., 2010). D-amino acids help to maintain an ecological balance of beneficial bacteria and resist external environmental pressure (Alvarez et al., 2018). ...
Aims
The aim of this study was to investigate the effects of chlorogenic acid (CGA) on the intestinal microorganisms and metabolites in broilers during lipopolysaccharide (LPS)-induced immune stress.
Methods
A total of 312 one-day-old Arbor Acres (AA) broilers were randomly allocated to four groups with six replicates per group and 13 broilers per replicate: (1) MS group (injected with saline and fed the basal diet); (2) ML group (injected with 0.5 mg LPS/kg and fed the basal diet); (3) MA group (injected with 0.5 mg LPS/kg and fed the basal diet supplemented with 1,000 mg/kg CGA); and (4) MB group (injected with saline and fed the basal diet supplemented with 1,000 mg/kg CGA).
Results
The results showed that the abundance of beneficial bacteria such as Bacteroidetes in the MB group was significantly higher than that in MS group, while the abundance of pathogenic bacteria such as Streptococcaceae was significantly decreased in the MB group. The addition of CGA significantly inhibited the increase of the abundance of harmful bacteria such as Streptococcaceae, Proteobacteria and Pseudomonas caused by LPS stress. The population of butyric acid-producing bacteria such as Lachnospiraceae and Coprococcus and beneficial bacteria such as Coriobacteriaceae in the MA group increased significantly. Non-targeted metabonomic analysis showed that LPS stress significantly upregulated the 12-keto-tetrahydroleukotriene B4, riboflavin and mannitol. Indole-3-acetate, xanthurenic acid, L-formylkynurenine, pyrrole-2-carboxylic acid and L-glutamic acid were significantly down-regulated, indicating that LPS activated inflammation and oxidation in broilers, resulting in intestinal barrier damage. The addition of CGA to the diet of LPS-stimulated broilers significantly decreased 12-keto-tetrahydro-leukotriene B4 and leukotriene F4 in arachidonic acid metabolism and riboflavin and mannitol in ABC transporters, and significantly increased N-acetyl-L-glutamate 5-semialdehyde in the biosynthesis of amino acids and arginine, The presence of pyrrole-2-carboxylic acid in D-amino acid metabolism and the cecal metabolites, indolelactic acid, xanthurenic acid and L-kynurenine, indicated that CGA could reduce the inflammatory response induced by immune stress, enhance intestinal barrier function, and boost antioxidant capacity.
Conclusion
We conclude that CGA can have a beneficial effect on broilers by positively altering the balance of intestinal microorganisms and their metabolites to inhibit intestinal inflammation and barrier damage caused by immune stress.
... [5] Besides, proline acts as a signalling molecule, a sensor of cellular energy status, and a source of pyrroline-5-carboxylate (P5C) and superoxide anion, which participate in redox reactions in the animal body. [6,7] Whereas in the case of plants, proline metabolism can influence programmed cell death of plant tissues, having protective or scavenging features, as well as it stabilizes the cellular homeostasis during stress conditions. [8]. ...
L-Proline, the exclusive secondary amino acid with proteinogenic properties, is a vital contributor to body metabolism and the maintenance of muscle repairs, playing a pivotal role in numerous physiological processes in the human body. However, the current understanding of proline sensing is limited. In this study, we have used Tetraaminophenylporphyrin (TAPP) covalently functionalized graphene quantum dot (GQD) as a probe for the selective and sensitive detection of L-Proline. Analytical studies carried out under the optimized conditions reveal a good linear range of 9.8×10−5 M to 3.5×10−3 M with 1.6×10−7 M limit of detection. Photophysical studies reveal a ground state complex formation between the probe and proline which is responsible for the turn-off behaviour. This is not present in the case of the individual components GQD and TAPP separately which highlights the importance of covalent functionalization. The stabilization energy of the complex between the probe and different aminoacids and the corresponding hydrogen bond distances between these two moieties were calculated theoretically using density functional theory. This corroborates the enhanced stability of complex formation and the selectivity of probe towards proline compared to other aminoacids. The practical utility of the developed probe for the detection of proline in real samples like commercial milk and artificial urine is also demonstrated by spike recovery analysis which results in a recovery percent and RSD values within the acceptable limit.
... Hyp is a type of proline (Pro) metabolite, which is a unique amino acid specific in scavenging oxidants and regulating apoptosis (Phang, et al., 2010). Generally, the content of Hyp can better reflect the collagen content. ...
The nutritional quality of three edible parts (gonads, hepatopancreas and muscles) of Chinese mitten crabs (CMCs) from rice field culture and pond culture was firstly compared in our current study. It was found that the contents of mineral elements and volatile compounds in rice CMCs were superior to those in pond CMCs, and the antioxidant enzyme activities of rice CMCs were markedly higher than those of pond CMCs. Besides, the total free amino acid levels in the edible parts of pond CMCs were higher than those of rice CMCs. Compared with other tissues, the nucleotide and equivalent umami concentrations of the gonads in female rice CMCs were the maximum. Overall, both types of crabs demonstrated good nutritional quality, which met human nutrition and dietary needs. In comparison, the quality of rice CMCs was better than that of pond CMCs.
... L-Glutamic-gamma-semialdehyde is the metabolic intermediate stage of arginine and proline, proline is an effective osmotic regulation substance, can maintain the cell membrane structure and the stability of the protein subcellular structure, and has the role of scavenging reactive oxygen [82] when the animal body is experiencing stress, injury, pregnancy, postpartum, etc. The demand for proline increases dramatically [83]. Proline plays an important role in the growth and health of fish. ...
The incorporation of probiotics into the diet of large yellow croaker has been demonstrated by several studies to confer partial disease resistance. Bacillus halophilic isolated from the intestinal flora was used to study its effects on performance growth indicators, intestinal tissue structure, intestinal flora and the metabolism of Larimichthys crocea. A total of 180 fishes with an initial body weight of (164.00 ± 54.00) g were fed diets with three different concentrations of Bacillus halophilic: 0 cfu/mL (FC0, control group), 10⁸ cfu/mL (FC8, treatment group), and 10¹² cfu/mL (FC12, treatment group). The results showed that there were no significant differences in specific growth rate among all groups (P > 0.05). Compared to the FC0 group, the final body weight and Weight gain rate were significantly higher in FC8 and FC12 groups (P < 0.05). The Survival of the FC12 group significantly improved (P < 0.05). Compared to the FC0 group, crude protein content in muscle of the FC8 group significantly increased (P < 0.05), crude fat content significantly increased in the FC12 group (P < 0.05), crude protein content in whole fish experimental groups significantly increased (P < 0.05), and ash content significantly increased in the FC8 group (P < 0.05). In terms of antioxidant ability, the content of LZM in blood increased significantly in the FC8 group (P < 0.05), GSH content in liver of the FC12 group increased significantly (P < 0.05), while the content of MDA and AKP in blood and liver had no significant difference (P > 0.05). At the level of intestinal structure, there were no significant differences in villus height, crypt depth and goblet cell number between control group and treatment groups (P > 0.05). At the phylum level, Firmicutes was the dominant phylum, and the genus level, Lactobacillus and Bacteroides were the dominant bacteria in FC8 and FC12. A total of 1070 metabolites were identified, among which lipid metabolites accounted for 46.7%. Metabolites were involved in six main ways, mainly related to the metabolism of amino acids and lipids. The correlation analysis between microbes and metabolites showed that the intestinal flora of Larimichthys crocea could promote the synthesis of metabolites, among which Bacteroides and Megamonas could promote the synthesis of beneficial metabolites such as amino acids and vitamins. Through this study, we found that Bacillus halophilic can significantly improve growth, the antioxidant immunity ability and promote the expression of growth related metabolites, with the FC12 group being the better successful.
... Proline, along with its derivatives such as hydroxyproline and glycine, constitutes the primary components of the extracellular matrix. Both mitochondrial function and extracellular matrix turnover play crucial roles in RPE function and the pathogenesis of AMD (9,24). Second, mutations of multiple genes involved in proline metabolism, including OAT, P5C dehydrogenase, and P5C reductase, cause inherited retinal degenerations and RPE atrophy in patients and animal models (9,(25)(26)(27). ...
It is known that metabolic defects in the retinal pigment epithelium (RPE) can cause degeneration of its neighboring photoreceptors in the retina, leading to retinal degenerative diseases such as age-related macular degeneration. However, how RPE metabolism supports the health of the neural retina remains unclear. The retina requires exogenous nitrogen sources for protein synthesis, neurotransmission, and energy metabolism. Using ¹⁵N tracing coupled with mass spectrometry, we found human RPE can utilize the nitrogen in proline to produce and export 13 amino acids, including glutamate, aspartate, glutamine, alanine, and serine. Similarly, we found this proline nitrogen utilization in the mouse RPE/choroid but not in the neural retina of explant cultures. Coculture of human RPE with the retina showed that the retina can take up the amino acids, especially glutamate, aspartate, and glutamine, generated from proline nitrogen in the RPE. Intravenous delivery of ¹⁵N proline in vivo demonstrated ¹⁵N-derived amino acids appear earlier in the RPE before the retina. We also found proline dehydrogenase, the key enzyme in proline catabolism is highly enriched in the RPE but not the retina. The deletion of proline dehydrogenase blocks proline nitrogen utilization in RPE and the import of proline nitrogen–derived amino acids in the retina. Our findings highlight the importance of RPE metabolism in supporting nitrogen sources for the retina, providing insight into understanding the mechanisms of the retinal metabolic ecosystem and RPE-initiated retinal degenerative diseases.
... The potential for altered Overview of proline metabolic pathways. A schematic representation of the key steps in proline metabolism, as adapted and modified from a previous study (Phang et al., 2010). Proline and pyrroline-5-carboxylate interconvert and form the proline cycle, wherein proline dehydrogenase 1 converts proline to pyrroline-5-carboxylate and pyrroline-5-carboxylate reductase 1 and/or 2 reduce pyroline-5-carboxylate to proline. ...
Recently, we demonstrated that supplementing (with 3 mg Se per day) the diets of growing beef steers grazing on Se-deficient toxic endophyte-infected tall fescue-based forage with either organic Se (OSe, SEL-PLEX) or a 1:1 blend (MIX) of OSe and inorganic Se (ISe, sodium selenite) in vitamin–mineral mixes, rather than inorganic forms of Se, ameliorated several classic serum symptoms of fescue toxicosis. Importantly, higher levels of hepatic glutamine synthetase activity were observed in MIX and OSe steers. Accordingly, transcriptome level and targeted mRNA expression analyses were conducted on the same liver tissue to determine if Se treatments affected other hepatic metabolic pathways, especially those that are responsible for supplying substrates of glutamine synthetase. The effect of ISe, OSe, and MIX treatments ( n = 8/treatment) on the relative abundances of mRNA [determined using microarray and real-time reverse-transcription PCR (RT-PCR)] and protein (determined using Western blotting) in liver tissue was assessed by ANOVA. Fisher’s protected LSD procedure was used to separate treatment means, with significance being declared at p ≤ 0.05. Microarray analysis identified ( p < 0.01, false discovery rate of< 33%) 573 annotated differentially expressed gene (DEG) transcripts. Canonical pathway analysis identified the DEGs that are central to glutamine and glutamate biosynthesis/degradation and proline biosynthesis. Targeted RT-PCR analyses found that MIX and OSe steers had lower periportal ammonia-assimilation and urea-synthesizing capacities (lower glutaminase 2, key ornithine cycle enzymes, and mitochondrial ornithine/citrulline exchanger mRNA) than ISe steers. In addition, MIX and OSe steers had a higher capacity for pericentral ammonia assimilation (higher glutamine synthetase activity) and a higher capacity for the production of glutamate in pericentral hepatocytes from α-ketoglutarate (higher levels of glutamine dehydrogenase, and decreased levels of arginase 2 and ornithine aminotransferase and mRNA). The form of supplemental Se also affected steers’ capacity for hepatic proline metabolism, with OSe steers having a higher capacity for proline synthesis and MIX steers having a higher capacity for pyroline-5-carboxylate synthesis. In conclusion, supplementing the diets of growing beef steers grazing on toxic endophyte-infected tall fescue with MIX and OSe in vitamin–mineral mixes, rather than with inorganic forms of Se, shifts hepatic ammonia assimilation from periportal urea production to pericentral glutamine production, thus potentially increasing whole-animal N efficiency by increasing the supply of hepatic-synthesized glutamine.
... Rahman and colleagues reported a study where seawater from the southern coastal area of Bangladesh induced salinity stress in 1-month-old gliricidia seedlings for 90 days and showed that seawater-induced salinity negatively affected several growth-related attributes. They also showed enhanced accumulation of proline, the proteinogenic secondary amino acid that participates in metabolic signaling and is known to be metabolized by its own family of enzymes responding to stress (Phang et al., 2010), postulating that it might help adjust the plant to water deficit conditions (Rahman et al., 2019). ...
