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Nature Aug 2022In response to hormones and growth factors, the class I phosphoinositide-3-kinase (PI3K) signalling network functions as a major regulator of metabolism and growth,...
In response to hormones and growth factors, the class I phosphoinositide-3-kinase (PI3K) signalling network functions as a major regulator of metabolism and growth, governing cellular nutrient uptake, energy generation, reducing cofactor production and macromolecule biosynthesis. Many of the driver mutations in cancer with the highest recurrence, including in receptor tyrosine kinases, Ras, PTEN and PI3K, pathologically activate PI3K signalling. However, our understanding of the core metabolic program controlled by PI3K is almost certainly incomplete. Here, using mass-spectrometry-based metabolomics and isotope tracing, we show that PI3K signalling stimulates the de novo synthesis of one of the most pivotal metabolic cofactors: coenzyme A (CoA). CoA is the major carrier of activated acyl groups in cells and is synthesized from cysteine, ATP and the essential nutrient vitamin B5 (also known as pantothenate). We identify pantothenate kinase 2 (PANK2) and PANK4 as substrates of the PI3K effector kinase AKT. Although PANK2 is known to catalyse the rate-determining first step of CoA synthesis, we find that the minimally characterized but highly conserved PANK4 is a rate-limiting suppressor of CoA synthesis through its metabolite phosphatase activity. Phosphorylation of PANK4 by AKT relieves this suppression. Ultimately, the PI3K-PANK4 axis regulates the abundance of acetyl-CoA and other acyl-CoAs, CoA-dependent processes such as lipid metabolism and proliferation. We propose that these regulatory mechanisms coordinate cellular CoA supplies with the demands of hormone/growth-factor-driven or oncogene-driven metabolism and growth.
Topics: Acetyl Coenzyme A; Adenosine Triphosphate; Cell Proliferation; Coenzyme A; Cysteine; Lipid Metabolism; Mass Spectrometry; Metabolomics; Pantothenic Acid; Phosphatidylinositol 3-Kinase; Phosphorylation; Phosphotransferases (Alcohol Group Acceptor); Proto-Oncogene Proteins c-akt; Signal Transduction
PubMed: 35896750
DOI: 10.1038/s41586-022-04984-8 -
Nature Metabolism Nov 2023Tumors are intrinsically heterogeneous and it is well established that this directs their evolution, hinders their classification and frustrates therapy. Consequently,...
Tumors are intrinsically heterogeneous and it is well established that this directs their evolution, hinders their classification and frustrates therapy. Consequently, spatially resolved omics-level analyses are gaining traction. Despite considerable therapeutic interest, tumor metabolism has been lagging behind this development and there is a paucity of data regarding its spatial organization. To address this shortcoming, we set out to study the local metabolic effects of the oncogene c-MYC, a pleiotropic transcription factor that accumulates with tumor progression and influences metabolism. Through correlative mass spectrometry imaging, we show that pantothenic acid (vitamin B) associates with MYC-high areas within both human and murine mammary tumors, where its conversion to coenzyme A fuels Krebs cycle activity. Mechanistically, we show that this is accomplished by MYC-mediated upregulation of its multivitamin transporter SLC5A6. Notably, we show that SLC5A6 over-expression alone can induce increased cell growth and a shift toward biosynthesis, whereas conversely, dietary restriction of pantothenic acid leads to a reversal of many MYC-mediated metabolic changes and results in hampered tumor growth. Our work thus establishes the availability of vitamins and cofactors as a potential bottleneck in tumor progression, which can be exploited therapeutically. Overall, we show that a spatial understanding of local metabolism facilitates the identification of clinically relevant, tractable metabolic targets.
Topics: Humans; Mice; Animals; Female; Breast Neoplasms; Pantothenic Acid; Proto-Oncogene Proteins c-myc; Transcription Factors; Vitamins
PubMed: 37946084
DOI: 10.1038/s42255-023-00915-7 -
Current Issues in Molecular Biology Sep 2021Dexpanthenol (D-panthenol) is a precursor of vitamin B5 (pantothenic acid) and is widely used for dietary supplements and topical applications. D-panthenol has long been...
Dexpanthenol (D-panthenol) is a precursor of vitamin B5 (pantothenic acid) and is widely used for dietary supplements and topical applications. D-panthenol has long been used in hair care products for the purpose of anti-hair loss, its effects and the underlying mechanisms, however, were barely reported. In this study, the effects of D-panthenol on human hair follicle cells, including dermal papilla cells (hDPCs) and outer root sheath cells (hORSCs), were investigated. D-panthenol enhanced the cell viability, increasing the cellular proliferation marker Ki67 in cultured hDPCs. The markers for apoptosis (Caspase3/9) and cell senescence (p21/p16), reported to be expressed in aged or resting phase follicles, were significantly reduced by D-panthenol. Anagen-inducing factors (ALP; β-catenin; versican), which trigger or elongate the anagen phase, were stimulated by D-panthenol. On the other hand, D-panthenol reduced TGF-β1 expressions in both mRNA and protein levels. The expression of VEGF, which is important for peripheral blood vessel activation; was up-regulated by D-panthenol treatment. In cultured hORSCs, cell proliferation and viability were enhanced, while the mRNA expression of cell senescence markers (p21/p16) was significantly down-regulated. The expressions of both VEGF and its receptor (VEGFR) were up-regulated by D-panthenol. In conclusion, our data suggest that the hair growth stimulating activity of D-panthenol was exerted by increasing the cell viability, suppressing the apoptotic markers, and elongating the anagen phase in hair follicles.
Topics: Antigens, Surface; Apoptosis; Biomarkers; Cell Proliferation; Cells, Cultured; Cellular Senescence; Gene Expression; Gene Expression Regulation; Hair Follicle; Humans; Pantothenic Acid; RNA, Messenger; Vitamin B Complex
PubMed: 34698060
DOI: 10.3390/cimb43030097 -
Food & Nutrition Research 2023Pantothenic acid, also referred to as vitamin B, is a water-soluble vitamin that has essential functions in the body as a component of coenzyme A (CoA) and acyl carrier... (Review)
Review
Pantothenic acid, also referred to as vitamin B, is a water-soluble vitamin that has essential functions in the body as a component of coenzyme A (CoA) and acyl carrier protein (ACP). It is widely distributed in animal and plant-source foods. Nutritional deficiency of pantothenic acid is rare and toxicity negligible. Information on pantothenic acid intakes in the Nordic countries is limited and biomarker data from Nordic and Baltic populations is missing. Due to a lack of data, no dietary reference values (DRVs) were given for pantothenic acid in the Nordic Nutrition Recommendations (NNR) since 2012. The aim of this scoping review was to examine recent evidence relevant for updating the DRVs for NNR2023. Scientific literature since 2012 on associations of pantothenic acid with health-related issues in Nordic and Baltic countries was searched. No health concerns related to pantothenic acid were identified.
PubMed: 38187802
DOI: 10.29219/fnr.v67.10255 -
International Journal of Environmental... Apr 2023Proper nutrition is critical for optimal performance in endurance athletes. However, it is unclear if endurance athletes are meeting all their energy and nutrient needs....
Proper nutrition is critical for optimal performance in endurance athletes. However, it is unclear if endurance athletes are meeting all their energy and nutrient needs. We examined if endurance athletes are meeting their nutritional requirements and if this differed by sex. Ninety-five endurance athletes (n = 95; 50.5% men; 34.9 ± 12.9 y) participated in the study. Dietary intake was evaluated using the 24 h dietary recall method. Energy and nutrient intakes were calculated using the ESHA Food Processor Diet Analysis Software and compared against reference nutrient intakes. Endurance athletes did not consume the recommended amount of energy (76.8% of athletes), carbohydrates (95.8%), linoleic acid (75.8%), α-linolenic acid (ALA) (77.9%), eicosatetraenoic and docosahexaenoic acid (96.8%), dietary fiber (49.5%), vitamins D (93.7%), E (71.6%), and K (54.7%), folate (54.7%), pantothenic acid (70.5%), biotin (83.2%), manganese (58.9%), magnesium (56.8%), chromium (91.6%), molybdenum (93.7%), choline (85.3%), and potassium (56.8%), and consumed too much saturated fat (50.5%) and sodium (94.7%) than recommended. Fisher's Exact test showed that the requirements for dietary fiber (70.8% vs. 27.7%), ALA (87.5% vs. 68.1%), and total water (70.8% vs. 44.7%) were not met by more men versus women ( < 0.05). The needs for protein (70.2% vs. 25%) and vitamin B12 (46.8% vs. 22.9%) were not met by more women compared to men ( < 0.05). These findings need to be confirmed by a larger study.
Topics: Male; Humans; Female; Energy Intake; Micronutrients; Nutritional Status; Diet; Athletes; Dietary Fiber; Nutritional Requirements
PubMed: 37107749
DOI: 10.3390/ijerph20085469 -
Brain Sciences Jul 2023Dietary constituents may affect the progression of Parkinson's disease (PD). This study aimed to assess the contribution of dietary intake of vitamins and minerals to...
BACKGROUND AND OBJECTIVE
Dietary constituents may affect the progression of Parkinson's disease (PD). This study aimed to assess the contribution of dietary intake of vitamins and minerals to the severity, motor and non-motor symptoms, and risk of PD.
METHODS
In this case-control study, 120 patients with PD and 50 healthy participants participated. Dietary intake of vitamins and minerals was determined using a 147-item food frequency questionnaire. The severity of PD was determined by the Unified Parkinson's Disease Rating Scale (UPDRS).
RESULTS
Patients with PD had lower intake of several vitamins and minerals including lycopene, thiamine, vitamin B6, vitamin B12, pantothenic acid, magnesium, zinc, manganese, selenium, chromium, and phosphorus, but had higher intake of α-tocopherol. High dietary intake of vitamin A, α-carotene, β-cryptoxanthin, vitamin C, and α-tocopherol were correlated with increased odds of PD. High intake of lycopene, thiamin, vitamin B6, pantothenic acid, magnesium, zinc, manganese, chromium, and phosphorous correlated with reduced odds of PD. The predictive power of α-tocopherol concerning the risk of PD was stronger relative to other vitamins. Dietary intake of pantothenic acid was negatively correlated with PD severity and symptoms of motor examination and complication. The severity and motor symptoms of PD were also negatively correlated with β-carotene, vitamin C, riboflavin, vitamin B6, and biotin intake. The UPDRS total score and motor symptoms in PD patients were negatively correlated with phosphorus, magnesium, zinc, manganese, and chromium, and strongly with potassium intake.
CONCLUSION
The findings indicate that adequate dietary intake of vitamins and minerals may have a preventive effect on developing PD and progression of motor decline.
PubMed: 37509049
DOI: 10.3390/brainsci13071119 -
Shokuhin Eiseigaku Zasshi. Journal of... 2023A simple and reliable analytical method has been developed for the determination of pantothenic acid in food. For the high-protein food, 20 mL of water was added to 2 g...
A simple and reliable analytical method has been developed for the determination of pantothenic acid in food. For the high-protein food, 20 mL of water was added to 2 g of sample, and after homogenization extraction, 1 mL of 15% zinc sulfate solution was added, mixed well, centrifuged, and the supernatant was filtered to make the test solution. For the low-protein food, 20 mL of 1% formic acid solution was added to 2 g of sample, homogenized, extracted, centrifuged, and the supernatant was filtered to make the test solution. The HPLC separation was carried out on a L-column2 ODS column with 0.02 mol/L phosphate solution (pH 3.0)- acetonitrile (95 : 5) as the mobile phase, and detected at 200 nm. The LC-MS/MS conditions were L-column2 ODS as the separation column, 5 mmol/L ammonium formate (containing 0.01% formic acid)-methanol (85 : 15) as the mobile phase, and multiple reaction monitoring (MRM) was used for detection. The recoveries of pantothenic acid in milk powder and nutritional food products were more than 88% with high precision. As a result of analyzing commetrcially available foods labeled as containing pantothenic acid, analytical values almost identical to the labeled values were obtained, and a high correlation was observed between the values obtained by HPLC and LC-MS/MS.
Topics: Chromatography, High Pressure Liquid; Chromatography, Liquid; Pantothenic Acid; Tandem Mass Spectrometry
PubMed: 36858591
DOI: 10.3358/shokueishi.64.47 -
Veterinary Pathology Jan 2023This report describes 2 events of degenerative myelopathy in 4- to 27-day-old piglets, with mortality rates reaching 40%. Sows were fed rations containing low levels of...
This report describes 2 events of degenerative myelopathy in 4- to 27-day-old piglets, with mortality rates reaching 40%. Sows were fed rations containing low levels of pantothenic acid. Piglets presented with severe depression, weakness, ataxia, and paresis, which were more pronounced in the pelvic limbs. No significant gross lesions were observed. Histologically, there were degeneration and necrosis of neurons in the spinal cord, primarily in the thoracic nucleus in the thoracic and lumbar segments, and motor neurons in nucleus IX of the ventral horn in the cervical and lumbar intumescence. Minimal-to-moderate axonal and myelin degeneration was observed in the dorsal funiculus of the spinal cord and in the dorsal and ventral nerve roots. Immunohistochemistry demonstrated depletion of acetylcholine neurotransmitters in motor neurons and accumulation of neurofilaments in the perikaryon of neurons in the thoracic nucleus and motor neurons. Ultrastructurally, the thoracic nucleus neurons and motor neurons showed dissolution of Nissl granulation. The topographical distribution of the lesions indicates damage to the second-order neurons of the spinocerebellar tract, first-order axon cuneocerebellar tract, and dorsal column-medial lemniscus pathway as the cause of the conscious and unconscious proprioceptive deficit, and damage to the alpha motor neuron as the cause of the motor deficit. Clinical signs reversed and no new cases occurred after pantothenic acid levels were corrected in the ration, and piglets received parenteral administration of pantothenic acid. This study highlights the important and practical use of detailed neuropathological analysis to refine differential diagnosis.
Topics: Animals; Swine; Female; Pantothenic Acid; Spinal Cord; Neurons; Medulla Oblongata; Spinal Cord Diseases; Swine Diseases
PubMed: 36250539
DOI: 10.1177/03009858221128920