Ascorbic acid-independent synthesis of collagen in mice

The mouse has become the most important model organism for the study of human physiology and disease. However, until the recent generation of mice lacking the enzyme gulanolactone oxidase (Gulo), the final enzyme in the ascorbic acid biosynthesis pathway, examination of the role of ascorbic acid in various biochemical processes using this model organism has not been possible. In the mouse, similar to most mammals but unlike humans who carry a mutant copy of this gene, Gulo produces ascorbic acid from glucose. We report here that, although ascorbic acid is essential for survival, its absence does not lead to measurable changes in proline hydroxylation. Vitamin C deficiency had no significant effect on the hydroxylation of proline and collagen production during tumor growth or in angiogenesis associated with tumor or mammary gland growth. This suggests that factors other than ascorbic acid can support proline hydroxylation and collagen synthesis in vivo. Furthermore, the failure of Gulo−/− mice to thrive on a vitamin C-deficient diet therefore suggests that ascorbic acid plays a critical role in survival other than the maintenance of the vasculature.

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In Vitro and in Vivo Imaging of Nitroxyl with Copper Fluorescent Probe in Living Cells and Zebrafish

Molecules ◽

10.3390/molecules23102551 ◽

2018 ◽

Vol 23 (10) ◽

pp. 2551 ◽

Cited By ~ 3

Author(s):

Sathyadevi Palanisamy ◽

Yu-Liang Wang ◽

Yu-Jen Chen ◽

Chiao-Yun Chen ◽

Fu-Te Tsai ◽

...

Keyword(s):

Critical Role ◽

Model Organism ◽

Living Cells ◽

Biological Species ◽

Zebrafish Model ◽

Physiological Processes ◽

Collective Data ◽

Angeli's Salt

Nitroxyl (HNO) plays a critical role in many physiological processes which includes vasorelaxation in heart failure, neuroregulation, and myocardial contractility. Powerful imaging tools are required to obtain information for understanding the mechanisms involved in these in vivo processes. In order to develop a rapid and high sensitive probe for HNO detection in living cells and the zebrafish model organism, 2-((2-(benzothiazole-2yl)benzylidene) amino)benzoic acid (AbTCA) as a ligand, and its corresponding copper(II) complex Cu(II)-AbTCA were synthesized. The reaction results of Cu(II)-AbTCA with Angeli’s salt showed that Cu(II)-AbTCA could detect HNO quantitatively in a range of 40–360 µM with a detection limit of 9.05 µM. Furthermore, Cu(II)-AbTCA is more selective towards HNO over other biological species including thiols, reactive nitrogen, and reactive oxygen species. Importantly, Cu(II)-AbTCA was successfully applied to detect HNO in living cells and zebrafish. The collective data reveals that Cu(II)-AbTCA could be used as a potential probe for HNO detection in living systems.

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Inactivation of Diphtheria Toxin in vivo and in vitro by Crystalline Vitamin C (Ascorbic Acid).

Experimental Biology and Medicine ◽

10.3181/00379727-32-8039c ◽

1935 ◽

Vol 32 (8) ◽

pp. 1229-1234 ◽

Cited By ~ 25

Author(s):

C. W. Jungeblut ◽

R. L. Zwemer

Keyword(s):

Ascorbic Acid ◽

Vitamin C ◽

Diphtheria Toxin

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Ascorbic acid in epigenetic reprogramming

Current Stem Cell Research & Therapy ◽

10.2174/1574888x16666210714152730 ◽

2021 ◽

Vol 16 ◽

Author(s):

Xinhui Liu ◽

Aamir Khan ◽

Huan Li ◽

Shensen Wang ◽

Xuechai Chen ◽

...

Keyword(s):

Ascorbic Acid ◽

Vitamin C ◽

Somatic Cell ◽

Epigenetic Modification ◽

Critical Role ◽

Cellular Reprogramming ◽

Epigenetic Reprogramming ◽

Cell Reprogramming ◽

Histone Demethylases ◽

Somatic Cell Reprogramming

: Emerging evidence suggests that ascorbic acid (vitamin C) enhances the reprogramming process by multiple mechanisms. This is primarily due to its cofactor role in Fe(II) and 2-oxoglutarate-dependent dioxygenases, including the DNA demethylases Ten Eleven Translocase (TET) and histone demethylases. Epigenetic variations have been shown to play a critical role in somatic cell reprogramming. DNA methylation and histone methylation are extensively recognized as barriers to somatic cell reprogramming. N6-methyladenosine (m6A), known as RNA methylation, is an epigenetic modification of mRNAs and has also been shown to play a role in regulating cellular reprogramming. Multiple cofactors are reported to promote the activity of demethylases, including vitamin C. This review focuses on examining the evidence and mechanism of vitamin C in DNA and histone demethylation and highlights its potential involvement in regulating m6A demethylation. It also shows the significant contribution of vitamin C in epigenetic regulation and the affiliation of demethylases with vitamin C-facilitated epigenetic reprogramming.

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A Multicenter Phase II Study of Combination Treatment with Melphalan, Arsenic Trioxide and Vitamin C (MAC) for Patients with Relapsed or Refractory Multiple Myeloma.

Blood ◽

10.1182/blood.v106.11.2564.2564 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2564-2564 ◽

Cited By ~ 1

Author(s):

James Berenson ◽

Ralph Boccia ◽

David Siegel ◽

Marek Bozdech ◽

Alberto Bessudo ◽

...

Keyword(s):

Multiple Myeloma ◽

Ascorbic Acid ◽

Vitamin C ◽

Arsenic Trioxide ◽

Phase Ii ◽

Stable Disease ◽

Objective Response ◽

In Vivo Studies

Abstract Background: Despite the recent increase in treatment options for patients with multiple myeloma (MM), the disease remains largely incurable. Both arsenic trioxide (ATO) and melphalan have shown clinical activity in MM. Recent in vitro and in vivo studies in our laboratory have shown that arsenic trioxide sensitizes chemoresistant MM cells to melphalan-induced cytotoxicity; the addition of ascorbic acid (AA) further improves this effect. We conducted a multi-center clinical trial to evaluate the safety and efficacy of this steroid-free combination, melphalan, ATO and vitamin C (MAC), for patients with relapsed/refractory MM. Methods: MM pts who relapsed after responding to 1st-line therapy and/or were refractory to prior treatment were enrolled. During week 1 of each 6-week cycle, pts received ATO, 0.25 mg/kg IV, followed by ascorbic acid (AA), 1 g IV, days 1–4. ATO followed by AA was given twice-weekly for the next 4 weeks of each cycle. Low-dose melphalan (0.10 mg/kg) was administered orally for the first 4 days of each cycle. Pts received a maximum of 6 cycles followed by weekly maintenance treatment with ATO and AA. The primary objectives of this study were to determine response rate and safety and tolerability of MAC therapy. Results: 65 patients have been enrolled and 51 are currently evaluable for response. 26 (1 CR, 10 PR, 15 MR) of the 51 evaluable patients (51%) had an objective response and an additional 14 patients achieved stable disease, resulting in a total of 40 patients (78%) with disease control. Among patients with elevated serum creatinine levels at baseline, renal function improved for those with responsive or stable disease. 20 of the 26 responding patients had failed ≥ 2 prior therapies: 19 pts had received prior thalidomide or lenalidomide therapy and 8 pts had received prior bortezomib. The regimen was well-tolerated with few significant side effects reported. Mild cytopenias occurred infrequently and were reversible. Conclusions: The results from this large multi-center phase II trial show that the MAC regimen is active in a group of MM patients who had either relapsed or were refractory to standard and/or investigational MM treatments. The regimen was well-tolerated even in this heavily pre-treated patient population. These findings are consistent with preclinical studies that showed the efficacy of this combination from both in vitro and in vivo studies.

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Ascorbic acid (vitamin C) modulates the mutagenic effects produced by an alkylating agent in vivo

Environmental and Molecular Mutagenesis ◽

10.1002/em.2850240311 ◽

1994 ◽

Vol 24 (3) ◽

pp. 220-228 ◽

Cited By ~ 18

Author(s):

Anane Aidoo ◽

Lascelles E. Lyn-Cook ◽

Shelly Lensing ◽

Wayne Wamer

Keyword(s):

Ascorbic Acid ◽

Vitamin C ◽

Alkylating Agent ◽

Mutagenic Effects

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Nrf2 activation induces mitophagy and reverses Parkin/Pink1 knock down-mediated neuronal and muscle degeneration phenotypes

Cell Death and Disease ◽

10.1038/s41419-021-03952-w ◽

2021 ◽

Vol 12 (7) ◽

Author(s):

Sentiljana Gumeni ◽

Eleni-Dimitra Papanagnou ◽

Maria S. Manola ◽

Ioannis P. Trougakos

Keyword(s):

Critical Role ◽

Model Organism ◽

Dependent Manner ◽

Degenerative Diseases ◽

Knock Down ◽

Age Related ◽

Degenerative Disorders ◽

Pathway Activation

AbstractThe balanced functionality of cellular proteostatic modules is central to both proteome stability and mitochondrial physiology; thus, the age-related decline of proteostasis also triggers mitochondrial dysfunction, which marks multiple degenerative disorders. Non-functional mitochondria are removed by mitophagy, including Parkin/Pink1-mediated mitophagy. A common feature of neuronal or muscle degenerative diseases, is the accumulation of damaged mitochondria due to disrupted mitophagy rates. Here, we exploit Drosophila as a model organism to investigate the functional role of Parkin/Pink1 in regulating mitophagy and proteostatic responses, as well as in suppressing degenerative phenotypes at the whole organism level. We found that Parkin or Pink1 knock down in young flies modulated proteostatic components in a tissue-dependent manner, increased cell oxidative load, and suppressed mitophagy in neuronal and muscle tissues, causing mitochondrial aggregation and neuromuscular degeneration. Concomitant to Parkin or Pink1 knock down cncC/Nrf2 overexpression, induced the proteostasis network, suppressed oxidative stress, restored mitochondrial function, and elevated mitophagy rates in flies’ tissues; it also, largely rescued Parkin or Pink1 knock down-mediated neuromuscular degenerative phenotypes. Our in vivo findings highlight the critical role of the Parkin/Pink1 pathway in mitophagy, and support the therapeutic potency of Nrf2 (a druggable pathway) activation in age-related degenerative diseases.

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Targeting the Redox Balance Pathway Using Ascorbic Acid in sdhb Zebrafish Mutant Larvae

Cancers ◽

10.3390/cancers13205124 ◽

2021 ◽

Vol 13 (20) ◽

pp. 5124

Author(s):

Margo Dona ◽

Maaike Lamers ◽

Svenja Rohde ◽

Marnix Gorissen ◽

Henri J. L. M. Timmers

Keyword(s):

Ascorbic Acid ◽

Vitamin C ◽

Drug Screening ◽

Redox Balance ◽

Wild Type ◽

Zebrafish Model ◽

High Throughput Drug Screening ◽

Anti Cancer ◽

Cancer Agent

Patients with mutations in the β-subunit of the succinate dehydrogenase (SDHB) have the highest risk to develop incurable malignant phaeochromocytomas and paragangliomas (PPGLs). Therapy development is hindered by limited possibilities to test new therapeutic strategies in vivo. One possible molecular mechanism of SDHB-associated tumorigenesis originates in an overproduction of reactive oxygen species (ROS) due to mitochondrial dysfunction. Ascorbic acid (Vitamin C) has already been shown to act as anti-cancer agent in several clinical trials for various types of cancer. In this study, the potential of the sdhbrmc200 zebrafish model to study SDHB-associated PPGLs using a drug screening approach was investigated. First, we identified increased basal ROS levels in homozygous sdhb larvae compared to heterozygous and wild-type siblings. Using a semi high-throughput drug screening, the effectiveness of different dosages of anti- and pro-oxidant Vitamin C were assessed to evaluate differences in survival, ROS levels, and locomotor activity. Low-dosage levels of Vitamin C induced a decrease of ROS levels but no significant effects on lifespan. In contrast, high-dosage levels of Vitamin C shortened the lifespan of the homozygous sdhbrmc200 larvae while not affecting the lifespan of heterozygous and wild-type siblings. These results validated the sdhbrmc200 zebrafish model as a powerful drug screening tool that may be used to identify novel therapeutic targets for SDHB-associated PPGLs.

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Effect of Lipopolysaccharide and TNFα on Neuronal Ascorbic Acid Uptake

Mediators of Inflammation ◽

10.1155/2021/4157132 ◽

2021 ◽

Vol 2021 ◽

pp. 1-11

Author(s):

Veedamali S. Subramanian ◽

Trevor Teafatiller ◽

Anshu Agrawal ◽

Masashi Kitazawa ◽

Jonathan S. Marchant

Keyword(s):

Ascorbic Acid ◽

Vitamin C ◽

Inhibitory Effect ◽

Acid Uptake ◽

Mrna Levels ◽

The Central Nervous System ◽

Factor Α ◽

And Function

Vitamin C (ascorbic acid: AA) uptake in neurons occurs via the sodium-dependent vitamin C transporter-2 (SVCT2), which is highly expressed in the central nervous system (CNS). During chronic neuroinflammation or infection, CNS levels of lipopolysaccharide (LPS) and LPS-induced tumor necrosis factor-α (TNFα) are increased. Elevated levels of LPS and TNFα have been associated with neurodegenerative diseases together with reduced levels of AA. However, little is known about the impacts of LPS and TNFα on neuronal AA uptake. The objective of this study was to examine the effect of LPS and TNFα on SVCT2 expression and function using in vitro and in vivo approaches. Treatment of SH-SY5Y cells with either LPS or TNFα inhibited AA uptake. This reduced uptake was associated with a significant decrease in SVCT2 protein and mRNA levels. In vivo exposure to LPS or TNFα also decreased SVCT2 protein and mRNA levels in mouse brains. Both LPS and TNFα decreased SLC23A2 promoter activity. Further, the inhibitory effect of LPS on a minimal SLC23A2 promoter was attenuated when either the binding site for the transcription factor Sp1 was mutated or cells were treated with the NF-κB inhibitor, celastrol. We conclude that inflammatory signals suppress AA uptake by impairing SLC23A2 transcription through opposing regulation of Sp1 and NF-κB factors.

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On the Stability of Vitamin C Radicals

Zeitschrift für Naturforschung A ◽

10.1515/zna-1986-1109 ◽

1986 ◽

Vol 41 (11) ◽

pp. 1315-1318 ◽

Cited By ~ 1

Author(s):

M. Eckert-Maksić ◽

P. Bischof ◽

Z. B. Maksić

Keyword(s):

Ascorbic Acid ◽

Vitamin C ◽

Energy Partitioning ◽

Mndo Method ◽

Biochemical Processes ◽

Stable Species ◽

The Stability ◽

Semiempirical Mndo ◽

Partitioning Technique

Stability of vitamin C (ascorbic acid - AA) radicals is considered by the semiempirical MNDO method. It is found that AA⨪ is thermodynamically the most stable species. Interestingly, the AA⨪ radical is more stable than the parent AA. This finding is of great importance in view of omnipresence and versatility of the vitamin C in biochemical processes. The origin of the pronounced stability of AA⨪ is elucidated by a particular form of the energy partitioning technique.

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