Annurca Apple Polyphenols Ignite Keratin Production in Hair Follicles by Inhibiting the Pentose Phosphate Pathway and Amino Acid Oxidation

Patterned hair loss (PHL) affects around 50% of the adult population worldwide. The negative impact that this condition exerts on people’s life quality has boosted the appearance of over-the-counter products endowed with hair-promoting activity. Nutraceuticals enriched in polyphenols have been recently shown to promote hair growth and counteract PHL. Malus pumila Miller cv. Annurca is an apple native to Southern Italy presenting one of the highest contents of Procyanidin B2. We have recently shown that oral consumption of Annurca polyphenolic extracts (AAE) stimulates hair growth, hair number, hair weight and keratin content in healthy human subjects. Despite its activity, the analysis of the molecular mechanism behind its hair promoting effect is still partially unclear. In this work we performed an unprecedented metabolite analysis of hair follicles (HFs) in mice topically treated with AAE. The metabolomic profile, based on a high-resolution mass spectrometry approach, revealed that AAE re-programs murine HF metabolism. AAE acts by inhibiting several NADPH dependent reactions. Glutaminolysis, pentose phosphate pathway, glutathione, citrulline and nucleotide synthesis are all halted in vivo by the treatment of HFs with AAE. On the contrary, mitochondrial respiration, β-oxidation and keratin production are stimulated by the treatment with AAE. The metabolic shift induced by AAE spares amino acids from being oxidized, ultimately keeping them available for keratin biosynthesis.

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Annurca Apple Polyphenols Protect Murine Hair Follicles from Taxane Induced Dystrophy and Hijacks Polyunsaturated Fatty Acid Metabolism toward β-Oxidation

Nutrients ◽

10.3390/nu10111808 ◽

2018 ◽

Vol 10 (11) ◽

pp. 1808 ◽

Cited By ~ 8

Author(s):

Gennaro Riccio ◽

Eduardo Sommella ◽

Nadia Badolati ◽

Emanuela Salviati ◽

Sara Bottone ◽

...

Keyword(s):

Fatty Acid ◽

Hair Loss ◽

Hair Growth ◽

Treatment Options ◽

Pentose Phosphate ◽

Hair Follicles ◽

Common Side Effect ◽

Safe Alternative ◽

Polyphenolic Extract

Chemotherapy-induced alopecia (CIA) is a common side effect of conventional chemotherapy and represents a major problem in clinical oncology. Even months after the end of chemotherapy, many cancer patients complain of hair loss, a condition that is psychologically difficult to manage. CIA disturbs social and sexual interactions and causes anxiety and depression. Synthetic drugs protecting from CIA and endowed with hair growth stimulatory properties are prescribed with caution by oncologists. Hormones, growth factors, morphogens could unwontedly protect tumour cells or induce cancer cell proliferation and are thus considered incompatible with many chemotherapy regimens. Nutraceuticals, on the contrary, have been shown to be safe and effective treatment options for hair loss. We here show that polyphenols from Malus Pumila Miller cv Annurca are endowed with hair growth promoting activity and can be considered a safe alternative to avoid CIA. In vitro, Annurca Apple Polyphenolic Extract (AAE) protects murine Hair Follicles (HF) from taxanes induced dystrophy. Moreover, in virtue of its mechanism of action, AAE is herein proven to be compatible with chemotherapy regimens. AAE forces HFs to produce ATP using mitochondrial β-oxidation, reducing Pentose Phosphate Pathway (PPP) rate and nucleotides production. As consequence, DNA replication and mitosis are not stimulated, while a pool of free amino acids usually involved in catabolic reactions are spared for keratin production. Moreover, measuring the effect exerted on Poly Unsaturated Fatty Acid (PUFA) metabolism, we prove that AAE promotes hair-growth by increasing the intracellular levels of Prostaglandins F2α (PGF2α) and by hijacking PUFA catabolites toward β-oxidation.

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Interrelationship between the pentose phosphate pathway and nucleotide synthesis in cultured cells of Catharanthus roseus

Plant Science Letters ◽

10.1016/0304-4211(84)90185-8 ◽

1984 ◽

Vol 35 (2) ◽

pp. 123-126 ◽

Cited By ~ 6

Author(s):

Fumiko Hirose ◽

Hiroshi Ashihara

Keyword(s):

Catharanthus Roseus ◽

Pentose Phosphate Pathway ◽

Cultured Cells ◽

Pentose Phosphate ◽

Nucleotide Synthesis

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Quantitative Relationship between the Pentose Phosphate Pathway and the Nucleotide Synthesis in Ascites Tumor Cells

Hoppe-Seyler´s Zeitschrift für physiologische Chemie ◽

10.1515/bchm2.1970.351.1.711 ◽

1970 ◽

Vol 351 (1) ◽

pp. 711-717 ◽

Cited By ~ 15

Author(s):

KARL BRAND ◽

KLAUS DECKNER

Keyword(s):

Tumor Cells ◽

Pentose Phosphate Pathway ◽

Quantitative Relationship ◽

Pentose Phosphate ◽

Ascites Tumor ◽

Nucleotide Synthesis

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p53 coordinates DNA repair with nucleotide synthesis by suppressing PFKFB3 expression and promoting the pentose phosphate pathway

Scientific Reports ◽

10.1038/srep38067 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 30

Author(s):

Derek A. Franklin ◽

Yizhou He ◽

Patrick L. Leslie ◽

Andrey P. Tikunov ◽

Nick Fenger ◽

...

Keyword(s):

Dna Repair ◽

Pentose Phosphate Pathway ◽

Pentose Phosphate ◽

Nucleotide Synthesis

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The Pentose Phosphate Pathway in Cancer: Regulation and Therapeutic Opportunities

Chemotherapy ◽

10.1159/000519784 ◽

2021 ◽

pp. 1-13

Author(s):

Noorhan Ghanem ◽

Chirine El-Baba ◽

Khaled Araji ◽

Riyad El-Khoury ◽

Julnar Usta ◽

...

Keyword(s):

Tumor Cells ◽

Pentose Phosphate Pathway ◽

Aerobic Glycolysis ◽

Nicotinamide Adenine Dinucleotide Phosphate ◽

Pentose Phosphate ◽

Nucleotide Synthesis ◽

Intermediary Metabolites ◽

Dividing Cells ◽

Metabolites Production ◽

Reductive Metabolism

Background: Tumorigenesis is associated with deregulation of nutritional requirements, intermediary metabolites production, and microenvironment interactions. Unlike their normal cell counterparts, tumor cells rely on aerobic glycolysis, through the Warburg effect. Summary: The pentose phosphate pathway (PPP) is a major glucose metabolic shunt that is upregulated in cancer cells. The PPP comprises an oxidative and a nonoxidative phase and is essential for nucleotide synthesis of rapidly dividing cells. The PPP also generates nicotinamide adenine dinucleotide phosphate, which is required for reductive metabolism and to counteract oxidative stress in tumor cells. This article reviews the regulation of the PPP and discusses inhibitors that target its main pathways. Key Message: Exploiting the metabolic vulnerability of the PPP offers potential novel therapeutic opportunities and improves patients’ response to cancer therapy.

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The short isoform of PRLR suppresses the pentose phosphate pathway and nucleotide synthesis through the NEK9-Hippo axis in pancreatic cancer

Theranostics ◽

10.7150/thno.51712 ◽

2021 ◽

Vol 11 (8) ◽

pp. 3898-3915

Author(s):

Huizhen Nie ◽

Pei-Qi Huang ◽

Shu-Heng Jiang ◽

Qin Yang ◽

Li-Peng Hu ◽

...

Keyword(s):

Pancreatic Cancer ◽

Pentose Phosphate Pathway ◽

Pentose Phosphate ◽

Nucleotide Synthesis

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DHEA-Mediated Inhibition of the Pentose Phosphate Pathway Alters Oocyte Lipid Metabolism in Mice

Endocrinology ◽

10.1210/en.2012-2140 ◽

2013 ◽

Vol 154 (12) ◽

pp. 4835-4844 ◽

Cited By ~ 23

Author(s):

Patricia T. Jimenez ◽

Antonina I. Frolova ◽

Maggie M. Chi ◽

Natalia M. Grindler ◽

Alexandra R. Willcockson ◽

...

Keyword(s):

Pentose Phosphate Pathway ◽

Negative Impact ◽

Polycystic Ovary ◽

Nicotinamide Adenine Dinucleotide Phosphate ◽

Pentose Phosphate ◽

Polycystic Ovaries ◽

Estrous Cycles ◽

Hormone Levels ◽

Reduced Nicotinamide Adenine Dinucleotide ◽

Glucose 6 Phosphate Dehydrogenase

Women with polycystic ovary syndrome (PCOS) and hyperandrogenism have altered hormone levels and suffer from ovarian dysfunction leading to subfertility. We have attempted to generate a model of hyperandrogenism by feeding mice chow supplemented with dehydroepiandrosterone (DHEA), an androgen precursor that is often elevated in women with PCOS. Treated mice had polycystic ovaries, low ovulation rates, disrupted estrous cycles, and altered hormone levels. Because DHEA is an inhibitor of glucose-6-phosphate dehydrogenase, the rate-limiting enzyme in the pentose phosphate pathway, we tested the hypothesis that oocytes from DHEA-exposed mice would have metabolic disruptions. Citrate levels, glucose-6-phosphate dehydrogenase activity, and lipid content in denuded oocytes from these mice were significantly lower than controls, suggesting abnormal tricarboxylic acid and pentose phosphate pathway metabolism. The lipid and citrate effects were reversible by supplementation with nicotinic acid, a precursor for reduced nicotinamide adenine dinucleotide phosphate. These findings suggest that elevations in systemic DHEA can have a negative impact on oocyte metabolism and may contribute to poor pregnancy outcomes in women with hyperandrogenism and PCOS.

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Silencing Sirtuin5 induces DNA damage by suppressing the pentose phosphate pathway in a demalonylation-dependent manner: A possible target for anticancer therapy in CRC

10.21203/rs.3.rs-276003/v1 ◽

2021 ◽

Author(s):

Hao-Lian Wang ◽

Yan Chen ◽

Yun-Qian Wang ◽

En-Wei Tao ◽

Juan Tan ◽

...

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Cell Cycle Arrest ◽

Pentose Phosphate Pathway ◽

Pentose Phosphate ◽

Dependent Manner ◽

Class Iii ◽

Nucleotide Synthesis ◽

Cycle Arrest

Abstract A previous study by our research group showed that sirtuin5 (SIRT5), a member of the class III NAD＋-dependent deacetylase family, is highly expressed in colorectal cancer (CRC). The present study showed that deletion of SIRT5 induced cell cycle arrest and apoptosis as a result of continuous and irreparable DNA damage in CRC cells, a consequence of the impaired production of ribose-5-phosphate (R5P) which is essential for nucleotide synthesis. Consistently, the cell cycle arrest and apoptosis induced by SIRT5 silencing could be reversed by supplementation with four nucleotides. Moreover, metabolic profiling revealed that silencing of SIRT5 could inhibit the non-oxidative pentose phosphate pathway (PPP), which produces R5P, required for base ribosylation. Notably, SIRT5 activates transketolase (TKT), the key enzyme in the cellular non-oxidative PPP, by mediating its lysine demalonylation through the interaction between SIRT5 and TKT. Furthermore, the results demonstrated that TKT is essential for the SIRT5-induced malignant phenotypes of CRC, both in vivo and in vitro. These results therefore revealed that the increased lysine malonylation levels of TKT caused by silencing SIRT5 suppresses non-oxidative pentose phosphate metabolism, leading to a low-nucleotide pool. This in turn induces DNA damage in tumor cells and inhibits proliferation, suggesting that SIRT5 may serve as a potential anticancer target.

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