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JCI Insight Aug 2023Proline and its synthesis enzyme pyrroline-5-carboxylate reductase 1 (PYCR1) are implicated in epithelial-mesenchymal transition (EMT), yet how proline and PYCR1...
Proline and its synthesis enzyme pyrroline-5-carboxylate reductase 1 (PYCR1) are implicated in epithelial-mesenchymal transition (EMT), yet how proline and PYCR1 function in allergic asthmatic airway remodeling via EMT has not yet been addressed to our knowledge. In the present study, increased levels of plasma proline and PYCR1 were observed in patients with asthma. Similarly, proline and PYCR1 in lung tissues were high in a murine allergic asthma model induced by house dust mites (HDMs). Pycr1 knockout decreased proline in lung tissues, with reduced airway remodeling and EMT. Mechanistically, loss of Pycr1 restrained HDM-induced EMT by modulating mitochondrial fission, metabolic reprogramming, and the AKT/mTORC1 and WNT3a/β-catenin signaling pathways in airway epithelial cells. Therapeutic inhibition of PYCR1 in wild-type mice disrupted HDM-induced airway inflammation and remodeling. Deprivation of exogenous proline relieved HDM-induced airway remodeling to some extent. Collectively, this study illuminates that proline and PYCR1 involved with airway remodeling in allergic asthma could be viable targets for asthma treatment.
Topics: Animals; Mice; Airway Remodeling; Proline; Asthma; Lung; Hypersensitivity
PubMed: 37432745
DOI: 10.1172/jci.insight.167395 -
The New England Journal of Medicine Sep 2022
Topics: Antiviral Agents; Drug Combinations; Humans; Lactams; Leucine; Nitriles; Proline; Recurrence; Ritonavir; Viral Load; COVID-19 Drug Treatment
PubMed: 36069818
DOI: 10.1056/NEJMc2205944 -
Journal of Wound Care Jan 2021We evaluated the effects of a specialised oral nutritional supplement (ONS) containing arginine and proline, with high vitamin A, C and E, zinc and selenium content, on... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
We evaluated the effects of a specialised oral nutritional supplement (ONS) containing arginine and proline, with high vitamin A, C and E, zinc and selenium content, on the repair of hard-to-heal wounds.
METHOD
Patients with hard-to-heal wounds were evaluated at five timepoints (S0-S4) over four consecutive weeks. At S0 patients were randomised to the specialised ONS (n=15; 25 wounds) or control (n=15; 25 wounds) groups. Posology was 200ml twice daily over the research period. Wound surface area and perimeter were monitored. In addition to the metric data, it was also possible to calculate the rate of wound contraction and the linear growth of the wound edges, looking for wound-healing predictive factors.
RESULTS
A total of 30 patients took part in the study. Mean age was 65 years and 50% of patients had diabetes. Of the total evaluated wounds, 78% were <50cm, 14% were 50-150cm and 8% were >250cm. In 96% of cases, the wounds were in the lower limbs. A statistically significant reduction (p=0.004) in surface area of the wounds due to the specialised ONS, with a performance peak between S1 and S2, was observed. This specialised ONS did not induce changes in blood pressure, blood glucose level or renal function. A mean weekly wound edge growth of 1.85mm in patients with diabetes and 3.0mm in those without diabetes was observed. These results were 2.9 and 4.6 times, respectively, higher than expected, according to the literature.
CONCLUSION
Specialised ONS can be a therapeutic option for hard-to-heal wounds.
Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Dietary Supplements; Female; Humans; Male; Middle Aged; Pressure Ulcer; Proline; Treatment Outcome; Wound Healing; Zinc
PubMed: 33439085
DOI: 10.12968/jowc.2021.30.1.26 -
Molecules and Cells Nov 2022Proline plays a multifaceted role in protein synthesis, redox balance, cell fate regulation, brain development, and other cellular and physiological processes. Here, we... (Review)
Review
Proline plays a multifaceted role in protein synthesis, redox balance, cell fate regulation, brain development, and other cellular and physiological processes. Here, we focus our review on proline metabolism in neurons, highlighting the role of dysregulated proline metabolism in neuronal dysfunction and consequently neurological and psychiatric disorders. We will discuss the association between genetic and protein function of enzymes in the proline pathway and the development of neurological and psychiatric disorders. We will conclude with a potential mechanism of proline metabolism in neuronal function and mental health.
Topics: Humans; Mental Disorders; Proline
PubMed: 36324271
DOI: 10.14348/molcells.2022.0115 -
Current Opinion in Biotechnology Dec 2023Proline is a nonessential amino acid, and its metabolism has been implicated in numerous malignancies. Together with a direct role in regulating cancer cells'... (Review)
Review
Proline is a nonessential amino acid, and its metabolism has been implicated in numerous malignancies. Together with a direct role in regulating cancer cells' proliferation and survival, proline metabolism plays active roles in shaping the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) display high rates of proline biosynthesis to support the production of collagen for the extracellular matrix (ECM). Indeed, impaired proline metabolism in CAFs results in reduced collagen deposition and compromises the growth and metastatic spread of cancer. Moreover, the rate of proline metabolism regulates intracellular reactive oxygen species (ROS) levels, which influence the production and release of cytokines from cancer cells, contributing toward an immune-permissive TME. Hence, targeting proline metabolism is a promising anticancer strategy that could improve patients' outcome and response to immunotherapy.
Topics: Humans; Immune Evasion; Neoplasms; Collagen; Extracellular Matrix; Proline; Tumor Microenvironment
PubMed: 37864905
DOI: 10.1016/j.copbio.2023.103011 -
Journal of Dermatological Science May 2023Difamilast, a topical phosphodiesterase 4 (PDE4) inhibitor, has been shown to be effective for treating atopic dermatitis (AD), but the molecular mechanism involved is...
BACKGROUND
Difamilast, a topical phosphodiesterase 4 (PDE4) inhibitor, has been shown to be effective for treating atopic dermatitis (AD), but the molecular mechanism involved is unclear. Since skin barrier dysfunction including reduced expression of filaggrin (FLG) and loricrin (LOR) contributes to AD development, difamilast treatment may be able to improve this dysfunction. PDE4 inhibition increases transcriptional activity of cAMP-responsive element binding protein (CREB). Therefore, we hypothesized that difamilast may affect FLG and LOR expression via CREB in human keratinocytes.
OBJECTIVE
To elucidate the mechanism by which difamilast regulates FLG and LOR expression via CREB in human keratinocytes.
METHODS
We analyzed normal human epidermal keratinocytes (NHEKs) treated with difamilast.
RESULTS
We observed increases of intracellular cAMP levels and CREB phosphorylation in difamilast (5 μM)-treated NHEKs. Next, we found that difamilast treatment increased mRNA and protein levels of FLG and LOR in NHEKs. Since reduced expression of keratinocyte proline-rich protein (KPRP) is reported to be involved in skin barrier dysfunction in AD, we examined KPRP expression in difamilast-treated NHEKs. We found that difamilast treatment increased mRNA and protein levels of KPRP in NHEKs. Furthermore, KPRP knockdown using siRNA transfection abolished the upregulation of FLG and LOR in difamilast-treated NHEKs. Finally, CREB knockdown canceled the upregulation of FLG, LOR, and KPRP in difamilast-treated NHEKs, indicating that PDE4 inhibition by difamilast treatment positively regulates FLG and LOR expression via the CREB-KPRP axis in NHEKs.
CONCLUSION
These findings may provide further guidance for therapeutic strategies in the treatment of AD using difamilast.
Topics: Humans; Cyclic Nucleotide Phosphodiesterases, Type 4; Filaggrin Proteins; Intermediate Filament Proteins; Keratinocytes; Dermatitis, Atopic; Proline
PubMed: 37156706
DOI: 10.1016/j.jdermsci.2023.04.007 -
Antioxidants & Redox Signaling Feb 2019Proline catabolism refers to the 4-electron oxidation of proline to glutamate catalyzed by the enzymes proline dehydrogenase (PRODH) and l-glutamate γ-semialdehyde... (Review)
Review
SIGNIFICANCE
Proline catabolism refers to the 4-electron oxidation of proline to glutamate catalyzed by the enzymes proline dehydrogenase (PRODH) and l-glutamate γ-semialdehyde dehydrogenase (GSALDH, or ALDH4A1). These enzymes and the intermediate metabolites of the pathway have been implicated in tumor growth and suppression, metastasis, hyperprolinemia metabolic disorders, schizophrenia susceptibility, life span extension, and pathogen virulence and survival. In some bacteria, PRODH and GSALDH are combined into a bifunctional enzyme known as proline utilization A (PutA). PutAs are not only virulence factors in some pathogenic bacteria but also fascinating systems for studying the coordination of metabolic enzymes via substrate channeling. Recent Advances: The past decade has seen an explosion of structural data for proline catabolic enzymes. This review surveys these structures, emphasizing protein folds, substrate recognition, oligomerization, kinetic mechanisms, and substrate channeling in PutA.
CRITICAL ISSUES
Major unsolved structural targets include eukaryotic PRODH, the complex between monofunctional PRODH and monofunctional GSALDH, and the largest of all PutAs, trifunctional PutA. The structural basis of PutA-membrane association is poorly understood. Fundamental aspects of substrate channeling in PutA remain unknown, such as the identity of the channeled intermediate, how the tunnel system is activated, and the roles of ancillary tunnels.
FUTURE DIRECTIONS
New approaches are needed to study the molecular and in vivo mechanisms of substrate channeling. With the discovery of the proline cycle driving tumor growth and metastasis, the development of inhibitors of proline metabolic enzymes has emerged as an exciting new direction. Structural biology will be important in these endeavors.
Topics: Animals; Biocatalysis; Humans; Models, Molecular; Molecular Structure; Proline; Proline Oxidase
PubMed: 28990412
DOI: 10.1089/ars.2017.7374 -
Cells Jul 2022In this paper, we summarize the current knowledge of the role of proline metabolism in the control of the identity of Embryonic Stem Cells (ESCs). An imbalance in... (Review)
Review
In this paper, we summarize the current knowledge of the role of proline metabolism in the control of the identity of Embryonic Stem Cells (ESCs). An imbalance in proline metabolism shifts mouse ESCs toward a stable naïve-to-primed intermediate state of pluripotency. Proline-induced cells (PiCs), also named primitive ectoderm-like cells (EPLs), are phenotypically metastable, a trait linked to a rapid and reversible relocalization of E-cadherin from the plasma membrane to intracellular membrane compartments. The ESC-to-PiC transition relies on the activation of Erk and Tgfβ/Activin signaling pathways and is associated with extensive remodeling of the transcriptome, metabolome and epigenome. PiCs maintain several properties of naïve pluripotency (teratoma formation, blastocyst colonization and 3D gastruloid development) and acquire a few traits of primed cells (flat-shaped colony morphology, aerobic glycolysis metabolism and competence for primordial germ cell fate). Overall, the molecular and phenotypic features of PiCs resemble those of an early-primed state of pluripotency, providing a robust model to study the role of metabolic perturbations in pluripotency and cell fate decisions.
Topics: Animals; Blastocyst; Cell Differentiation; Embryonic Stem Cells; Mice; Proline; Transcriptome
PubMed: 35883568
DOI: 10.3390/cells11142125 -
Amino Acids Dec 2021Proline is a non-essential amino acid with key roles in protein structure/function and maintenance of cellular redox homeostasis. It is available from dietary sources,... (Review)
Review
Proline is a non-essential amino acid with key roles in protein structure/function and maintenance of cellular redox homeostasis. It is available from dietary sources, generated de novo within cells, and released from protein structures; a noteworthy source being collagen. Its catabolism within cells can generate ATP and reactive oxygen species (ROS). Recent findings suggest that proline biosynthesis and catabolism are essential processes in disease; not only due to the role in new protein synthesis as part of pathogenic processes but also due to the impact of proline metabolism on the wider metabolic network through its significant role in redox homeostasis. This is particularly clear in cancer proliferation and metastatic outgrowth. Nevertheless, the precise identity of the drivers of cellular proline catabolism and biosynthesis, and the overall cost of maintaining appropriate balance is not currently known. In this review, we explore the major drivers of proline availability and consumption at a local and systemic level with a focus on cancer. Unraveling the main factors influencing proline metabolism in normal physiology and disease will shed light on new effective treatment strategies.
Topics: Animals; Homeostasis; Humans; Neoplasms; Oxidation-Reduction; Proline; Protein Biosynthesis; Reactive Oxygen Species
PubMed: 34291343
DOI: 10.1007/s00726-021-03051-2 -
The Journal of Clinical Investigation Dec 2023Cell lineage plasticity is one of the major causes for the failure of targeted therapies in various cancers. However, the driver and actionable drug targets in promoting...
Cell lineage plasticity is one of the major causes for the failure of targeted therapies in various cancers. However, the driver and actionable drug targets in promoting cancer cell lineage plasticity are scarcely identified. Here, we found that a G protein-coupled receptor, ADORA2A, is specifically upregulated during neuroendocrine differentiation, a common form of lineage plasticity in prostate cancer and lung cancer following targeted therapies. Activation of the ADORA2A signaling rewires the proline metabolism via an ERK/MYC/PYCR cascade. Increased proline synthesis promotes deacetylases SIRT6/7-mediated deacetylation of histone H3 at lysine 27 (H3K27), and thereby biases a global transcriptional output toward a neuroendocrine lineage profile. Ablation of Adora2a in genetically engineered mouse models inhibits the development and progression of neuroendocrine prostate and lung cancers, and, intriguingly, prevents the adenocarcinoma-to-neuroendocrine phenotypic transition. Importantly, pharmacological blockade of ADORA2A profoundly represses neuroendocrine prostate and lung cancer growth in vivo. Therefore, we believe that ADORA2A can be used as a promising therapeutic target to govern the epigenetic reprogramming in neuroendocrine malignancies.
Topics: Animals; Humans; Male; Mice; Cell Line, Tumor; Epigenesis, Genetic; Lung Neoplasms; Proline; Prostate; Prostatic Neoplasms; Sirtuins
PubMed: 38099497
DOI: 10.1172/JCI168670