bims-polyam Biomed News
on Polyamines
Issue of 2022‒09‒25
twelve papers selected by
Sebastian J. Hofer
University of Graz
  1. Elucidating the Role of Chmp1 Overexpression in the Transport of Polyamines in Drosophila melanogaster.
  2. Understanding the Polyamine and mTOR Pathway Interaction in Breast Cancer Cell Growth.
  3. Identification and Characterization of Novel Small-Molecule SMOX Inhibitors.
  4. The role of polyamine metabolism in remodeling immune responses and blocking therapy within the tumor immune microenvironment.
  5. Target of Rapamycin Mediated Ornithine Decarboxylase Antizyme Modulate Intracellular Putrescine and Ganoderic Acid Content in Ganoderma lucidum.
  6. Expression of Polyamine Oxidase in Fibroblasts Induces MMP-1 and Decreases the Integrity of Extracellular Matrix.
  7. A combination of a graphene quantum dots-cationic red dye donor-acceptor pair and cucurbit[7]uril as a supramolecular sensor for ultrasensitive detection of cancer biomarkers spermine and spermidine.
  8. A dopamine-gated learning circuit underpins reproductive state-dependent odor preference in Drosophila females.
  9. Evaluation of Intrafollicular Syndecan 1, Glypican 3, and Spermidine Levels in Women with Diminished Ovarian Reserve.
  10. Role of Polyamines as Biomarkers in Lymphoma Patients: A Pilot Study.
  11. Association between Serum Spermidine and TyG Index: Results from a Cross-Sectional Study.
  12. Natural Activators of Autophagy Increase Maximal Walking Distance and Reduce Oxidative Stress in Patients with Peripheral Artery Disease: A Pilot Study.
  1. Med Sci (Basel). 2022 Aug 25. pii: 45. [Epub ahead of print]10(3):
    Elucidating the Role of Chmp1 Overexpression in the Transport of Polyamines in Drosophila melanogaster.
    Coryn L Stump, Robert A Casero, Otto Phanstiel, Justin R DiAngelo, Shannon L Nowotarski.
      Polyamines are small organic cations that are essential for many biological processes such as cell proliferation and cell cycle progression. While the metabolism of polyamines has been well studied, the mechanisms by which polyamines are transported into and out of cells are poorly understood. Here, we describe a novel role of Chmp1, a vesicular trafficking protein, in the transport of polyamines using a well-defined leg imaginal disc assay in Drosophila melanogaster larvae. We show that Chmp1 overexpression had no effect on leg development in Drosophila, but does attenuate the negative impact on leg development of Ant44, a cytotoxic drug known to enter cells through the polyamine transport system (PTS), suggesting that the overexpression of Chmp1 downregulated the PTS. Moreover, we showed that the addition of spermine did not rescue the leg development in Chmp1-overexpressing leg discs treated with difluoromethylornithine (DFMO), an inhibitor of polyamine metabolism, while putrescine and spermidine did, suggesting that there may be unique mechanisms of import for individual polyamines. Thus, our data provide novel insight into the underlying mechanisms that are involved in polyamine transport and highlight the utility of the Drosophila imaginal disc assay as a fast and easy way to study potential players involved in the PTS.
    Keywords:  Chmp1; Drosophila melanogaster; imaginal disc assay; polyamine transport system
    DOI:  https://doi.org/10.3390/medsci10030045
  2. Med Sci (Basel). 2022 Sep 10. pii: 51. [Epub ahead of print]10(3):
    Understanding the Polyamine and mTOR Pathway Interaction in Breast Cancer Cell Growth.
    Oluwaseun Akinyele, Heather M Wallace.
      The polyamines putrescine, spermidine and spermine are nutrient-like polycationic molecules involved in metabolic processes and signaling pathways linked to cell growth and cancer. One important pathway is the PI3K/Akt pathway where studies have shown that polyamines mediate downstream growth effects. Downstream of PI3K/Akt is the mTOR signaling pathway, a nutrient-sensing pathway that regulate translation initiation through 4EBP1 and p70S6K phosphorylation and, along with the PI3K/Akt, is frequently dysregulated in breast cancer. In this study, we investigated the effect of intracellular polyamine modulation on mTORC1 downstream protein and general translation state in two breast cancer cell lines, MCF-7 and MDA-MB-231. The effect of mTORC1 pathway inhibition on the growth and intracellular polyamines was also measured. Results showed that polyamine modulation alters 4EBP1 and p70S6K phosphorylation and translation initiation in the breast cancer cells. mTOR siRNA gene knockdown also inhibited cell growth and decreased putrescine and spermidine content. Co-treatment of inhibitors of polyamine biosynthesis and mTORC1 pathway induced greater cytotoxicity and translation inhibition in the breast cancer cells. Taken together, these data suggest that polyamines promote cell growth in part through interaction with mTOR pathway. Similarly intracellular polyamine content appears to be linked to mTOR pathway regulation. Finally, dual inhibition of polyamine and mTOR pathways may provide therapeutic benefits in some breast cancers.
    Keywords:  4E-BP1; growth; mTOR pathway; p70SK1 and translation initiation; phosphorylation; polyamines
    DOI:  https://doi.org/10.3390/medsci10030051
  3. Med Sci (Basel). 2022 Aug 30. pii: 47. [Epub ahead of print]10(3):
    Identification and Characterization of Novel Small-Molecule SMOX Inhibitors.
    Amelia B Furbish, Ahmed S Alford, Pieter Burger, Yuri K Peterson, Tracy Murray-Stewart, Robert A Casero, Patrick M Woster.
      The major intracellular polyamines spermine and spermidine are abundant and ubiquitous compounds that are essential for cellular growth and development. Spermine catabolism is mediated by spermine oxidase (SMOX), a highly inducible flavin-dependent amine oxidase that is upregulated during excitotoxic, ischemic, and inflammatory states. In addition to the loss of radical scavenging capabilities associated with spermine depletion, the catabolism of spermine by SMOX results in the production of toxic byproducts, including H2O2 and acrolein, a highly toxic aldehyde with the ability to form adducts with DNA and inactivate vital cellular proteins. Despite extensive evidence implicating SMOX as a key enzyme contributing to secondary injury associated with multiple pathologic states, the lack of potent and selective inhibitors has significantly impeded the investigation of SMOX as a therapeutic target. In this study, we used a virtual and physical screening approach to identify and characterize a series of hit compounds with inhibitory activity against SMOX. We now report the discovery of potent and highly selective SMOX inhibitors 6 (IC50 0.54 μM, Ki 1.60 μM) and 7 (IC50 0.23 μM, Ki 0.46 μM), which are the most potent SMOX inhibitors reported to date. We hypothesize that these selective SMOX inhibitors will be useful as chemical probes to further elucidate the impact of polyamine catabolism on mechanisms of cellular injury.
    Keywords:  acrolein; excitotoxicity; neuronal injury; oxidative stress; polyamine oxidase; polyamines; spermine oxidase
    DOI:  https://doi.org/10.3390/medsci10030047
  4. Front Immunol. 2022 ;13 912279
    The role of polyamine metabolism in remodeling immune responses and blocking therapy within the tumor immune microenvironment.
    Jiachun Lian, Yanfang Liang, Hailiang Zhang, Minsheng Lan, Ziyu Ye, Bihua Lin, Xianxiu Qiu, Jincheng Zeng.
      The study of metabolism provides important information for understanding the biological basis of cancer cells and the defects of cancer treatment. Disorders of polyamine metabolism is a common metabolic change in cancer. With the deepening of understanding of polyamine metabolism, including molecular functions and changes in cancer, polyamine metabolism as a new anti-cancer strategy has become the focus of attention. There are many kinds of polyamine biosynthesis inhibitors and transport inhibitors, but not many drugs have been put into clinical application. Recent evidence shows that polyamine metabolism plays essential roles in remodeling the tumor immune microenvironment (TIME), particularly treatment of DFMO, an inhibitor of ODC, alters the immune cell population in the tumor microenvironment. Tumor immunosuppression is a major problem in cancer treatment. More and more studies have shown that the immunosuppressive effect of polyamines can help cancer cells to evade immune surveillance and promote tumor development and progression. Therefore, targeting polyamine metabolic pathways is expected to become a new avenue for immunotherapy for cancer.
    Keywords:  T cell; adaptive immune; immunotherapy; innate immune; metabolism; polyamine; tumor immune microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2022.912279
  5. Microbiol Spectr. 2022 Sep 20. e0163322
    Target of Rapamycin Mediated Ornithine Decarboxylase Antizyme Modulate Intracellular Putrescine and Ganoderic Acid Content in Ganoderma lucidum.
    Tao Wu, Jiale Xia, Feng Ge, Hao Qiu, Li Tian, Xiaotian Liu, Rui Liu, Ailiang Jiang, Jing Zhu, Liang Shi, Hanshou Yu, Mingwen Zhao, Ang Ren.
      Putrescine (Put) has been shown to play an important regulatory role in cell growth in organisms. As the primary center regulating the homeostasis of polyamine (PA) content, ornithine decarboxylase antizyme (AZ) can regulate PA content through feedback. Nevertheless, the regulatory mechanism of Put is poorly understood in fungi. Here, our analysis showed that GlAZ had a modulate effect on intracellular Put content by interacting with ornithine decarboxylase (ODC) proteins and reducing its intracellular protein levels. In addition, GlAZ upregulated the metabolic pathway of ganoderic acid (GA) biosynthesis in Ganoderma lucidum by modulating the intracellular Put content. However, a target of rapamycin (TOR) was found to promote the accumulation of intracellular Put after the GlTOR inhibitor Rap was added exogenously, and unbiased analyses demonstrated that GlTOR may promote Put production through its inhibitory effect on the level of GlAZ protein in GlTOR-GlAZ-cosilenced strains. The effect of TOR on fungal secondary metabolism was further explored, and the content of GA in the GlTOR-silenced strain after the exogenous addition of the inhibitor Rap was significantly increased compared with that in the untreated wild-type (WT) strain. Silencing of TOR in the GlTOR-silenced strains caused an increase in GA content, which returned to the WT state after replenishing Put. Moreover, the content of GA in GlTOR-GlAZ-cosilenced strains was also not different from that in the WT strain. Consequently, these results strongly indicate that GlTOR affects G. lucidum GA biosynthesis via GlAZ. IMPORTANCE Research on antizyme (AZ) in fungi has focused on the mechanism by which AZ inhibits ornithine decarboxylase (ODC). Moreover, there are existing reports on the regulation of AZ protein translation by TOR. However, little is known about the mechanisms that influence AZ in fungal secondary metabolism. Here, both intracellular Put content and GA biosynthesis in G. lucidum were shown to be regulated through protein interactions between GlAZ and GlODC. Furthermore, exploration of upstream regulators of GlAZ suggested that GlAZ was regulated by the upstream protein GlTOR, which affected intracellular Put levels and ganoderic acid (GA) biosynthesis. The results of our work contribute to the understanding of the upstream regulation of Put and provide new insights into PA regulatory systems and secondary metabolism in fungi.
    Keywords:  Ganoderma lucidum; ODC; TOR; ornithine decarboxylase antizyme; putrescine; secondary metabolic
    DOI:  https://doi.org/10.1128/spectrum.01633-22
  6. Int J Mol Sci. 2022 Sep 10. pii: 10487. [Epub ahead of print]23(18):
    Expression of Polyamine Oxidase in Fibroblasts Induces MMP-1 and Decreases the Integrity of Extracellular Matrix.
    Hae Dong Jeong, Jin Hyung Kim, Go Eun Kwon, Seung-Taek Lee.
      Polyamine oxidase (PAOX) (N1-acetylpolyamine oxidase) is a major enzyme in the polyamine catabolism pathway that generates hydrogen peroxide. Hydrogen peroxide plays a crucial role in skin aging via extracellular matrix (ECM) degradation by increasing the matrix metalloproteinase-1 (MMP-1) levels. We analyzed the integrity of the ECM in foreskin fibroblasts using PAOX expression. PAOX increased the MMP-1 secretion and type Ι collagen degradation in 2D and 3D cultures of fibroblasts, respectively. Similarly, PAOX overexpression increased the messenger ribonucleic acid (mRNA) level of MMP-1. PAOX expression induced polyamine catabolism, decreased the spermine levels, and increased the putrescine levels. However, the exogenous polyamine treatment did not change the MMP-1 and type I collagen levels as much as PAOX expression. PAOX expression increased the reactive oxygen species (ROS) production in fibroblasts, and exogenous hydrogen peroxide increased both the ROS production and MMP-1 secretion. Furthermore, N-acetylcysteine, an antioxidant, reversed the PAOX-induced ROS production and MMP-1 secretion. PAOX induced the signaling pathways that activate activator protein-1 (AP-1) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), which are important transcription factors for MMP-1 transactivation. We concluded that PAOX increased the ROS levels in fibroblasts, leading to an increase in MMP-1 expression. Therefore, we propose that PAOX is a potential target molecule in protecting the ECM integrity.
    Keywords:  extracellular matrix; fibroblast; matrix metalloproteinase-1; polyamine; polyamine oxidase; reactive oxygen species
    DOI:  https://doi.org/10.3390/ijms231810487
  7. J Mater Chem B. 2022 Sep 22.
    A combination of a graphene quantum dots-cationic red dye donor-acceptor pair and cucurbit[7]uril as a supramolecular sensor for ultrasensitive detection of cancer biomarkers spermine and spermidine.
    Akhil A Bhosle, Mainak Banerjee, Sharanabasava D Hiremath, Dilawar S Sisodiya, Viraj G Naik, Nilotpal Barooah, Achikanath C Bhasikuttan, Anjan Chattopadhyay, Amrita Chatterjee.
      In a unique approach, the combination of a donor-acceptor pair of hydroxy graphene quantum dots (GQDs-OH) and a red-emissive donor-two-acceptor (D-2-A) type dye with pyridinium units (BPBP) and the well-known host cucurbit[7]uril (CB[7]) has been exploited as a supramolecular sensing assembly for the detection of cancer biomarkers spermine and spermidine in aqueous media at the sub-ppb level based on the affinity-driven exchange of guests from the CB[7] portal. In the binary conjugate, green fluorescent GQDs-OH transfers energy to trigger the emission of the dye BPBP and itself remains in the turn-off state. CB[7] withdraws the dye from the surface of GQDs-OH by strong host-guest interactions with its portal, making GQDs-OH fluoresce again to produce a ratiometric response. In the presence of spermine (SP) or spermidine (SPD), their strong affinity with CB[7] forces the ejection of the fluorophore to settle on the GQDs-OH surface, and the strong green emission of GQDs-OH turns off to device a supramolecular sensor for the detection of SP/SPD. The DFT studies revealed interesting excited-state charge-transfer conjugate formation between BPBP and GQDs leading to turn-on emission of the dye, and further supported the stronger binding modes of BPBP-CB[7], indicating the retrieval of the emission of GQDs. The assembly-disassembly based sensing mechanism was also established by Job's plot analysis, particle size analysis, zeta potential, time-resolved spectroscopy, ITC studies, microscopic studies, etc. The supramolecular sensing assembly is highly selective to SP and SPD, and showed nominal interference from other biogenic amines, amino acids, various metal ions, and anions. The limits of detection (LODs) were 0.1 ppb and 0.9 ppb for spermine and spermidine, respectively. The potential for the real-world application of this sensing assembly was demonstrated by spiking SP and SPD in human urine and blood serum with a high %recovery.
    DOI:  https://doi.org/10.1039/d2tb01269c
  8. Elife. 2022 Sep 21. pii: e77643. [Epub ahead of print]11
    A dopamine-gated learning circuit underpins reproductive state-dependent odor preference in Drosophila females.
    Ariane C Boehm, Anja B Friedrich, Sydney Hunt, Paul Bandow, K P Siju, Jean-Francois De Backer, Julia Claussen, Marie-Helen Link, Thomas F Hofmann, Corinna Dawid, Ilona C Grunwald Kadow.
      Motherhood induces a drastic, sometimes long-lasting, change in internal state and behavior in many female animals. How a change in reproductive state or the discrete event of mating modulates specific female behaviors is still incompletely understood. Using calcium imaging of the whole brain of Drosophila females, we find that mating does not induce a global change in brain activity. Instead, mating modulates the pheromone response of dopaminergic neurons innervating the fly's learning and memory center, the mushroom body (MB). Using the mating-induced increased attraction to the odor of important nutrients, polyamines, we show that disruption of the female fly's ability to smell, for instance the pheromone cVA, during mating leads to a reduction in polyamine preference for days later indicating that the odor environment at mating lastingly influences female perception and choice behavior. Moreover, dopaminergic neurons including innervation of the β'1 compartment are sufficient to induce the lasting behavioral increase in polyamine preference. We further show that MB output neurons (MBON) of the β'1 compartment are activated by pheromone odor and their activity during mating bidirectionally modulates preference behavior in mated and virgin females. Their activity is not required, however, for the expression of polyamine attraction. Instead, inhibition of another type of MBON innervating the β'2 compartment enables expression of high odor attraction. In addition, the response of a lateral horn (LH) neuron, AD1b2, which output is required for the expression of polyamine attraction, shows a modulated polyamine response after mating. Taken together, our data in the fly suggests that mating-related sensory experience regulates female odor perception and expression of choice behavior through a dopamine-gated learning circuit.
    Keywords:  D. melanogaster; neuroscience
    DOI:  https://doi.org/10.7554/eLife.77643
  9. Reprod Sci. 2022 Sep 21.
    Evaluation of Intrafollicular Syndecan 1, Glypican 3, and Spermidine Levels in Women with Diminished Ovarian Reserve.
    Sefik Gokce, Dilsad Herkiloglu, Ozge Cevik, Volkan Turan.
      We aimed to evaluate the levels of Spermidine, Syndecan 1, and Glypican 3 (GPC3) in the follicle fluid of women with diminished ovarian reserve (DOR) and to examine the relationship of these markers with the number of embryos and clinical pregnancy. A total of 27 women with DOR and 34 women with normal ovarian reserve who underwent in vitro fertilization procedure were included in this prospectively designed study. Spermidine, Syndecan 1, and GPC3 levels were studied in the follicle fluid samples taken from the women at the time of oocyte retrieval by ELISA method, and their relations with the cycle outcomes were examined. The mean age was found as 38.1 ± 7.4 years in the DOR group and 35.1 ± 5.2 years in the control group (p = 0.027). When adjusted for age and body mass index, while the median Spermidine level was significantly higher (p < 0.001), both Syndecan 1 (p < 0.001) and GPC3 (p = 0.006) were significantly lower in the DOR group compared with control group. The cut-off value of Spermidine for clinical pregnancy prediction was found as 74.08 ng/mL with 78.9% sensitivity and 57.1% specificity [OR: 5 (95% CI: 1.4-17.6); AUC: 0.621; p = 0.138], while it was 0.96 ng/mL with 84.2% sensitivity and 59.5% specificity [OR: 7.8 (95% CI: 2-31.1); AUC: 0.701; p = 0.004] for GP3 and 1.15 ng/mL with 78.9 sensitivity and 57.1% specificity [OR: 5 (95% CI: 1.4-17.6); AUC: 0.680; p = 0.009] for Syndecan 1. Intrafollicular spermidine, Syndecan 1, and GPC3 levels may have a role in ovarian aging. Further randomized controlled studies in a larger population are needed for the relationship of these markers with cycle and pregnancy outcomes.
    Keywords:  Diminished ovarian reserve; Glypican 3; In vitro fertilization; Pregnancy; Spermidine; Syndecan 1
    DOI:  https://doi.org/10.1007/s43032-022-01085-9
  10. Diagnostics (Basel). 2022 Sep 04. pii: 2151. [Epub ahead of print]12(9):
    Role of Polyamines as Biomarkers in Lymphoma Patients: A Pilot Study.
    Donatella Coradduzza, Adriana Ghironi, Emanuela Azara, Nicola Culeddu, Sara Cruciani, Angelo Zinellu, Margherita Maioli, Maria Rosaria De Miglio, Serenella Medici, Claudio Fozza, Ciriaco Carru.
      Lymphomas represent a heterogeneous and widely diversified group of neoplastic diseases rising from a variety of lymphoid subsets at heterogeneous differentiation stages. These lymphoproliferative disorders lead to the clinicopathological complexity of the classification of lymphoid neoplasms, describing to date more than 40 categories of non-Hodgkin's lymphoma (NHL) and 5 categories of Hodgkin's lymphoma (HL). Inflammation has been shown to play a key role in the evolution of cancer diseases, and it might be interesting to understand their role also in the context of lymphoid neoplasms. Among circulating biomarkers, the role of polyamines belonging to the arginine and lysine metabolism is relevant. Through modern analytical methods, such as mass spectrometry (MS), we are enabled to increase knowledge and improve our understanding of cancer metabolism. In this study, high-resolution mass spectrometry was used in combination with high-performance liquid chromatography (LC-HRMS) to measure serum levels of polyamines and identify possible diagnostic circulating biomarkers, potentially allowing a more accurate assessment of the diagnostic stratification of lymphoma patients and robust comparisons between different patient groups.
    Keywords:  biomarkers; lymphoma; polyamines
    DOI:  https://doi.org/10.3390/diagnostics12092151
  11. Nutrients. 2022 Sep 17. pii: 3847. [Epub ahead of print]14(18):
    Association between Serum Spermidine and TyG Index: Results from a Cross-Sectional Study.
    Rui Zhang, Jiahui Xu, Ruixue Li, Zhecong Yu, Wei Yuan, Hanshu Gao, Wenjing Feng, Cuiying Gu, Zhaoqing Sun, Liqiang Zheng.
      BACKGROUND: Although animal experiments have shown that spermidine (SPD) affects insulin resistance (IR), the evidence for this in humans is still scarce. We aimed to investigate the associations between serum SPD levels and the TyG index in the adult population.METHODS: A cross-sectional study was carried out with 4336 participants, all of whom were adults aged 35+ years. The SPD levels in serum were detected using high performance liquid chromatography with a fluorescence detector (HPLC-FLD). The triglyceride-glucose (TyG) index was calculated as Ln [fasting triglycerides (TG) (mg/dL) × fasting glucose (mg/dL)/2].
    RESULTS: After multivariable adjustment, including demographic characteristics, behavioral factors associated with heath, and a history of taking medicine, SPD was inversely associated with the TyG index (β = -0.036; SE: 0.009; p &lt; 0.001). Furthermore, each increase of 1 lnSPD significantly decreased the risk of IR with an odds ratio (ORs) (95% confidence intervals (CIs)) of 0.89 (0.83-0.96). Relative to the first quintile, the multivariate-adjusted ORs (95% CIs) for the third and fourth quartile group were 0.80 (0.65, 0.99) and 0.71 (0.57, 0.88), respectively.
    CONCLUSIONS: In conclusion, SPD was inversely associated with the TyG index. Our findings inform future exploratory research on the further mechanism of the association between spermidine and IR.
    Keywords:  TyG index; cross-sectional study; epidemiology; insulin resistance; spermidine
    DOI:  https://doi.org/10.3390/nu14183847
  12. Antioxidants (Basel). 2022 Sep 18. pii: 1836. [Epub ahead of print]11(9):
    Natural Activators of Autophagy Increase Maximal Walking Distance and Reduce Oxidative Stress in Patients with Peripheral Artery Disease: A Pilot Study.
    Ombretta Martinelli, Mariangela Peruzzi, Simona Bartimoccia, Alessandra D'Amico, Simona Marchitti, Speranza Rubattu, Giovanni Alfonso Chiariello, Luca D'Ambrosio, Sonia Schiavon, Fabio Miraldi, Wael Saade, Mizar D'Abramo, Annachiara Pingitore, Lorenzo Loffredo, Cristina Nocella, Maurizio Forte, Pasquale Pignatelli.
      Trehalose, spermidine, nicotinamide, and polyphenols have been shown to display pro-autophagic and antioxidant properties, eventually reducing cardiovascular and ischemic complications. This study aimed to investigate whether a mixture of these components improves maximal walking distance (MWD) in peripheral artery disease (PAD) patients. Nitrite/nitrate (NOx), endothelin-1, sNOX2-dp, H2O2 production, H2O2 break-down activity (HBA), ATG5 and P62 levels, flow-mediated dilation (FMD), and MWD were evaluated in 20 PAD patients randomly allocated to 10 g of mixture or no-treatment in a single-blind study. The above variables were assessed at baseline and 60 days after mixture ingestion. Compared with baseline, mixture intake significantly increased MWD (+91%; p &lt; 0.01) and serum NOx (+96%; p &lt; 0.001), whereas it significantly reduced endothelin-1 levels (-30%, p &lt; 0.01). Moreover, mixture intake led to a remarkable reduction in sNOX2dp (-31%, p &lt; 0.05) and H2O2 (-40%, p &lt; 0.001) and potentiated antioxidant power (+110%, p &lt; 0.001). Finally, mixture ingestion restored autophagy by increasing ATG5 (+43%, p &lt; 0.01) and decreasing P62 (-29%, p &lt; 0.05). No changes in the above-mentioned variables were observed in the no-treatment group. The treatment with a mixture of trehalose, spermidine, nicotinamide, and polyphenols improves MWD in PAD patients, with a mechanism possibly related to NOX2-mediated oxidative stress downregulation and autophagic flux upregulation. Clinical Trial Registration unique identifier: NCT04061070.
    Keywords:  autophagy; oxidative stress; peripheral artery disease; polyphenols; trehalose
    DOI:  https://doi.org/10.3390/antiox11091836
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