Tetrahexyldecyl Ascorbate (THDC) Degrades Rapidly under Oxidative Stress but Can Be Stabilized by Acetyl Zingerone to Enhance Collagen Production and Antioxidant Effects
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PROVIDER: PRJNA755263 | ENA |
REPOSITORIES: ENA
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Project description:Tetrahexyldecyl Ascorbate (THDC) is an L-ascorbic acid precursor with improved stability and ability to penetrate the epidermis. The stability and transdermal penetration of THDC, however, may be compromised by the oxidant-rich environment of human skin. In this study, we show that THDC is a poor antioxidant that degrades rapidly when exposed to singlet oxygen. This degrada-tion, however, was prevented by combination with acetyl zingerone (AZ) as a stabilizing antiox-idant. As a standalone ingredient, THDC led to unexpected activation of type I interferon signaling, but this pro-inflammatory effect was blunted in the presence of AZ. Moreover, the combination of THDC and AZ increased expression of genes associated with phospholipid homeostasis and keratinocyte differentiation, along with repression of MMP1 and MMP7 expression, inhibition of MMP enzyme activity, and increased production of collagen proteins by dermal fibroblasts. Lastly, whereas THDC alone reduced viability of keratinocytes exposed to oxidative stress, this effect was completely abrogated by the addition of AZ to THDC. These results show that AZ is an effective antioxidant stabilizer of THDC and that combination of these products may improve ascorbic acid delivery. This provides a step towards reaching the full potential of ascorbate as an active ingredient in topical preparations.
2021-08-17 | GSE182177 | GEO
Project description:Tetrahexyldecyl Ascorbate (THDC) is an L-ascorbic acid precursor with improved stability and ability to penetrate the epidermis. The stability and transdermal penetration of THDC, however, may be compromised by the oxidant-rich environment of human skin. In this study, we show that THDC is a poor antioxidant that degrades rapidly when exposed to singlet oxygen. This degradation, however, was prevented by combination with acetyl zingerone (AZ) as a stabilizing antioxidant. As a standalone ingredient, THDC led to unexpected activation of type I interferon signaling, but this pro-inflammatory effect was blunted in the presence of AZ. Moreover, the combination of THDC and AZ increased expression of genes associated with phospholipid homeostasis and keratinocyte differentiation, along with repression of MMP1 and MMP7 expression, inhibition of MMP enzyme activity, and increased production of collagen proteins by dermal fibroblasts. Lastly, whereas THDC alone reduced viability of keratinocytes exposed to oxidative stress, this effect was completely abrogated by the addition of AZ to THDC. These results show that AZ is an effective antioxidant stabilizer of THDC and that combination of these products may improve ascorbic acid delivery. This provides a step towards reaching the full potential of ascorbate as an active ingredient in topical preparations.
| S-EPMC8395926 | biostudies-literature
Project description:The aim was to investigate mechanisms contributing to quercetinâs previously described effects on cell-proliferation and -differentiation, which contradicted its proposed anti-carcinogenic potency. In a 10-day experiment, 40 µM quercetin stabilized by 1mM ascorbate reduced Caco-2 differentiation up to 50% (P<0.001). Caco-2 RNA from days 5 and 10, hybridized on HG-U133A2.0 Affymetrix® GeneChips®, showed 1,743 affected genes on both days (P<0.01). All 14 Caco-2 differentiation-associated genes showed decreased expression (P<0.01), including intestinal alkaline phosphatase that was confirmed technically (qRT-PCR) and functionally (enzyme-activity). The 1,743 genes contributed to 27 affected pathways (P<0.05) categorized under 6 gene ontology (GO) processes, including apoptosis and cell-cycle. Genes within these GO-processes showed fold changes that suggest increased cell-survival and -proliferation. Furthermore, quercetin downregulated expression of genes involved in tumor-suppression and phase II metabolism, and upregulated oncogenes. Gene expression changes mediated by ascorbate-stabilized quercetin were concordant with those occurring in human colorectal carcinogenesis (â 80-90%), but were opposite to those previously described for Caco-2 cells exposed to quercetin in the absence of ascorbate (â 75-90%). In conclusion, gene expression among Caco-2 cells exposed to ascorbate-stabilized quercetin showed mechanisms contrary to what is expected for a cancer-preventive agent. Whether this unexpected in vitro effect is relevant in vivo, remains to be elucidated. Experiment Overall Design: Caco-2 cells were harvested on days 5 and 10 post-confluency. Per day, fold changes were calculated as quercetin vs. control.
2008-06-15 | E-GEOD-7259 | biostudies-arrayexpress
Project description:The aim was to investigate mechanisms contributing to quercetin’s previously described effects on cell-proliferation and -differentiation, which contradicted its proposed anti-carcinogenic potency. In a 10-day experiment, 40 µM quercetin stabilized by 1mM ascorbate reduced Caco-2 differentiation up to 50% (P<0.001). Caco-2 RNA from days 5 and 10, hybridized on HG-U133A2.0 Affymetrix® GeneChips®, showed 1,743 affected genes on both days (P<0.01). All 14 Caco-2 differentiation-associated genes showed decreased expression (P<0.01), including intestinal alkaline phosphatase that was confirmed technically (qRT-PCR) and functionally (enzyme-activity). The 1,743 genes contributed to 27 affected pathways (P<0.05) categorized under 6 gene ontology (GO) processes, including apoptosis and cell-cycle. Genes within these GO-processes showed fold changes that suggest increased cell-survival and -proliferation. Furthermore, quercetin downregulated expression of genes involved in tumor-suppression and phase II metabolism, and upregulated oncogenes. Gene expression changes mediated by ascorbate-stabilized quercetin were concordant with those occurring in human colorectal carcinogenesis (≈ 80-90%), but were opposite to those previously described for Caco-2 cells exposed to quercetin in the absence of ascorbate (≈ 75-90%). In conclusion, gene expression among Caco-2 cells exposed to ascorbate-stabilized quercetin showed mechanisms contrary to what is expected for a cancer-preventive agent. Whether this unexpected in vitro effect is relevant in vivo, remains to be elucidated. Keywords: Colon cancer; Caco-2; quercetin; differentiation
2007-06-01 | GSE7259 | GEO
Project description:Zingerone, a component of dried ginger, has known anti-ulcer and bone growth-promoting effects, but its impact on postmenopausal osteoporosis (PO) is unclear. This study investigates the therapeutic potential and underlying mechanisms of zingerone in PO. A concentration-dependent effect identified on osteoclast precursors: at low concentrations, zingerone maintains low ROS levels, enhance proliferation, and facilitates bone remodelling; at high concentrations, it elevates ROS levels, enhances ferroptosis sensitivity, and suppresses osteoclast formation. Zingerone significantly improves bone mass in an ovariectomised mouse model of PO. Metabolomics identifies 869 differential metabolites linked to glutathione and purine metabolism. Transcriptomics highlights pathways including ferroptosis, leukocyte migration, and cell adhesion. In RAW264.7 cells, zingerone modulates p53, enhances ferroptosis sensitivity, increasing ROS and Fe2+, upregulates Sat1, and downregulates Gpx4, suggesting that zingerone may act via p53-mediated ferroptosis, indicating potential clinical utility. Before clinical application, the dose-dependent effects of zingerone on bone remodelling and its underlying mechanisms warrant further investigation.
2025-08-11 | GSE304652 | GEO
Project description:Ascorbate (vitamin C) is an important antioxidant in leaves with multiple functions in photosynthesis and its levels are tightly regulated by light quality. The majority of work to date has focussed on regulation of ascorbate levels via biosynthesis. However, the pathway of ascorbate degradation, which is localised in the apoplast may additionally play a significant role. The degradative pathway begins with ascorbate oxidation by the enzyme ascorbate oxidase (AO) and hence we have examined the impact of manipulation of ascorbate oxidase activity on the content of ascorbate and the acclimation of photosynthesis to changing light levels. Leaf ascorbate content was highly light dependent in Nicotiana tobaccum being double in high compared with low light conditions. In contrast ascorbate oxidase activity was not altered by changing light levels. Transgenic tobacco lines with reduced or enhanced AO activity exhibited no morphological phenotype and photosynthesis under high light was similarly impaired irrespective of the measured AO activity. However further investigation between AO activity and leaf acclimation to changing light intensity revealed a suite of metabolic and transcriptome changes indicating a role for the apoplastic ascorbate pool in chloroplast to nucleus communication. In all genotypes, transcripts associated with ascorbate synthesis and recycling were less abundant following transition from high to low light. However transcripts associated with glutathione recycling, light harvesting, reaction centre function and the Calvin cycle were all increased in abundance. Following the transition from high to low light increases in leaf threonate, an ascorbate degradation product, were proportional to AO activity. A number of chloroplast synthesised amino acids were significantly increased both during high light and following transfer back to LL for 12 h. Similarly, several primary carbohydrates and TCA intermediates were significantly enhanced following high light treatment. In addition to light effects, AO activity had a significant impact on ï¢-alanine, aspartate and threonine. Intriguingly, a large number of fatty acids were reduced in antisense AO and wild-type plants immediately after high light stress however the content of these compounds were significantly increased in overexpressing sense lines. We conclude that AO mediated turnover plays an important role in adjusting cellular ascorbate content to photosynthetic need in a fluctuating light environment and that light mediated signals rapidly adjust that the apoplastic ascorbate pool.
2017-03-01 | E-MTAB-4816 | biostudies-arrayexpress
Project description:Zingerone (Z) is a phenolic alkanone derived from natural sources with anti-inflammatory and antioxidant effects. Acetyl zingerone (AZ) is a newly designed molecule that shares structural features with Z but is expected to have improved stability and antioxidant function. This study utilized microarrays to compare effects of Z and AZ on gene expression in reconstituted human epidermis. Both Z and AZ increased Notch pathway gene expression (NOTCH1, MAML3) and decreased expression of genes linked to extracellular matrix disassembly (MMP3, CTSV) and reactive oxygen species metabolism (PMAIP1, ARG2). Although Z and AZ each inhibited in vitro MMP-1, MMP-3 and MMP-12 activity, inhibition of MMP-3 and MMP-12 was greater with AZ. Moreover, AZ led to more consistent increases in the expression of genes encoding collagens (COL11A2), proteoglycans (VCAN) and ECM glycoproteins (SPARC). Finally, AZ opposed gene expression patterns associated with fibroblast senescence, keratinocyte differentiation, and IL-17A stimulation. These effects were AZ-specific and not replicated by Z. These results show that AZ improves extracellular matrix integrity with retinoid-like effects on differentiation and inflammation. Our findings provide rationale for clinical studies to understand benefits of AZ in the treatment or prevention of skin aging, or potentially, as a treatment for other human skin diseases. Microarray analyses was performed to characterize global gene expression responses to zingerone (Z) (50 μg/ml) in EpiDerm FT (RHE) tissue cultures.
2019-09-26 | GSE133338 | GEO
Project description:Zingerone (Z) is a phenolic alkanone derived from natural sources with anti-inflammatory and antioxidant effects. Acetyl zingerone (AZ) is a newly designed molecule that shares structural features with Z but is expected to have improved stability and antioxidant function. This study utilized microarrays to compare effects of Z and AZ on gene expression in reconstituted human epidermis. Both Z and AZ increased Notch pathway gene expression (NOTCH1, MAML3) and decreased expression of genes linked to extracellular matrix disassembly (MMP3, CTSV) and reactive oxygen species metabolism (PMAIP1, ARG2). Although Z and AZ each inhibited in vitro MMP-1, MMP-3 and MMP-12 activity, inhibition of MMP-3 and MMP-12 was greater with AZ. Moreover, AZ led to more consistent increases in the expression of genes encoding collagens (COL11A2), proteoglycans (VCAN) and ECM glycoproteins (SPARC). Finally, AZ opposed gene expression patterns associated with fibroblast senescence, keratinocyte differentiation, and IL-17A stimulation. These effects were AZ-specific and not replicated by Z. These results show that AZ improves extracellular matrix integrity with retinoid-like effects on differentiation and inflammation. Our findings provide rationale for clinical studies to understand benefits of AZ in the treatment or prevention of skin aging, or potentially, as a treatment for other human skin diseases. Microarray analyses was performed to characterize global gene expression responses to acetyl zingerone (AZ) (50 μg/ml) in EpiDerm FT (RHE) tissue cultures.
2019-09-26 | GSE133339 | GEO
Project description:Ascorbate is the most abundant water-soluble antioxidant in plants, and it is an essential molecule for normal plant development. It is present in all green plants, with very different concentrations in different plant species. While ascorbate accumulation is a trait of nutritional, and therefore, agronomical interest, the impact of different concentrations over cellular homeostasis remains elusive. In order to shed light over this question, we leveraged Arabidopsis lines with very low ascorbate (vtc2 mutant with 20% of WT ascorbate levels), and low ascorbate concentration (vtc4 mutant with 65% of WT levels), and we generated a line that accumulates 165% of WT levels (vtc2/OE-VTC2). An 80% reduction of ascorbate increased the expression of genes implicated in defense against pathogens, but repressed genes associated with abiotic stress responses. Unexpectedly, lines with increased (165% of WT) and decreased (65% of WT) ascorbate levels shared 85% of induced transcription factors and the GO terms associated with their transcriptional programs. Among the group of genes whose expression is positively correlated with ascorbate content, we identified TAA1/WEI8, a gene encoding a tryptophan aminotransferase that catalyzes the first step of auxin biosynthesis. Using a combination of genetic and pharmacological approaches in fluorescent and histochemical reporter lines for auxin biosynthesis and signaling activity, we revealed that TAA1- and TAA1-RELATED2 (TAR2)-mediated auxin biosynthesis is necessary for plants to cope with increased ascorbate concentration in a light-dependent manner, revealing a new layer of complexity in the regulatory landscape of redox homeostasis.
2025-05-17 | GSE296827 | GEO
Project description:The zingerone analog, acetyl zingerone, bolsters matrisome synthesis, inhibits MMPs, and represses IL-17A target gene expression
| PRJNA551204 | ENA