PMID: 

Nature. 2019 Sep ;573(7773):271-275. Epub 2019 Sep 4. PMID: 31485074

Abstract Title: 

Maternal vitamin C regulates reprogramming of DNA methylation and germline development.

Abstract: 

Development is often assumed to be hardwired in the genome, but several lines of evidence indicate that it is susceptible to environmental modulation with potential long-term consequences, including in mammals. The embryonic germline is of particular interest because of the potential for intergenerational epigenetic effects. The mammalian germline undergoes extensive DNA demethylationthat occurs in large part by passive dilution of methylation over successive cell divisions, accompanied by active DNA demethylation by TET enzymes. TET activity has been shown to be modulated by nutrients and metabolites, such as vitamin C. Here we show that maternal vitamin C is required for proper DNA demethylation and the development of female fetal germ cells in a mouse model. Maternal vitamin C deficiency does not affect overall embryonic development but leads to reduced numbers of germ cells, delayed meiosis and reduced fecundity in adult offspring. The transcriptome of germ cells from vitamin-C-deficient embryos is remarkably similar to that of embryos carrying a null mutation in Tet1. Vitamin C deficiency leads to an aberrant DNA methylation profile that includes incomplete demethylation of key regulators of meiosis and transposable elements. These findings reveal that deficiency in vitamin C during gestation partially recapitulates loss of TET1, and provide a potential intergenerational mechanism for adjusting fecundity to environmental conditions.

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PMID: 

Oxid Med Cell Longev. 2019 ;2019:4517091. Epub 2019 Jun 2. PMID: 31281576

Abstract Title: 

Cucurbitacin B Exerts Antiaging Effects in Yeast by Regulating Autophagy and Oxidative Stress.

Abstract: 

The budding yeasthas been used as a model organism for the basic mechanism of aging, which provides useful assay systems for measuring both replicative and chronological lifespans. In the course of our screening program for substances that extend replicative lifespan, cucurbitacin B (CuB) was found as a hit compound from a compound library, which contains cerebrosides, phenols, sesquiterpenoid, triterpenoids, and sterols isolated from natural products by our research group. Importantly, it prolonged not only the replicative lifespan but also the chronological lifespan in yeast. CuB increasedgene expression, suggesting that CuB induces autophagy. Indeed, the GFP signal generated from the cleavage of GFP-Atg8, which is a signature of autophagy, was increased upon CuB treatment. On the other hand, CuB failed to increase the chronological lifespans when eitheror, essential autophagy genes, was deleted, indicating that the lifespan extension by CuB depends on autophagy induction. Furthermore, CuB significantly increased superoxide dismutase (Sod) activity and the survival rate of yeast under oxidative stress, while it decreased the amount of reactive oxygen species (ROS) and malondialdehyde (MDA) production, indicating that CuB has activity to antagonize oxidative stress. Additionally, CuB did not affect replicative lifespans of,,, andmutants with the K6001 background, indicating that aging-related genes including,,, andparticipate in the antiaging effect of CuB. These results suggest that CuB exerts antiaging activity by regulating autophagy, ROS, antioxidative ability, and aging-related genes. Finally, we discuss the possible intracellular targets of CuB based on the phenotypic comparison between the CuB and global gene deletion databases.

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PMID: 

Connect Tissue Res. 2019 Sep 5:1-11. Epub 2019 Sep 5. PMID: 31488012

Abstract Title: 

Ascorbic acid mitigates the deleterious effects of nicotine on tendon stem cells.

Abstract: 

: Nicotine causes tendon degeneration, whereas ascorbic acid imparts beneficial effects on tendon cells. Tendon stem cells (TSCs) play a vital role in maintaining tissue integrity and promoting restoration of structure and function after tendon injury. In the present study, cell culture experiments were performed to determine the effects of nicotine on TSCs and whether ascorbic acid supplementation could antagonize the action of high concentration nicotine.: After treatment with nicotine and ascorbic acid, TSC proliferation, migration, stemness, apoptosis, and differentiation were analyzed.: TSC proliferation and expression of stem cell markers were significantly impaired by a high concentration of nicotine (1000 ng/mL), but a lower concentration (100 ng/mL) induced proliferative effects in TSCs. Moreover, the highest concentration of nicotine tested (1000 ng/mL) significantly inhibited the migratory ability of TSCs, while relatively high concentrations (100 and 1000 ng/mL) significantly (

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PMID: 

Zhejiang Da Xue Xue Bao Yi Xue Ban. 2019 May 25 ;48(3):296-302. PMID: 31496162

Abstract Title: 

[High dose vitamin C inhibits proliferation of breast cancer cells through reducing glycolysis and protein synthesis].

Abstract: 

OBJECTIVE: To investigate the effects of high dose vitamin C (VC) on proliferation of breast cancer cells and to explore its mechanisms.METHODS: Human breast cancer cells Bcap37 and MDA-MB-453 were treated with VC at low dose (0.01 mmol/L), medium dose (0.10 mmol/L) and high dose (2.00 mmol/L). Cell proliferation was determined with CCK-8 assay, protein expression was evaluated by Western blot, and the secretion of lactic acid in tumor cells was detected by colorimetric method. Bcap37 cells were inoculated in nude mice, and tumor baring nude mice were intraperitoneally injected with high VC(4 g/kg, VC group,=5)or normal saline (control group,=5) for 24 d. Tumor weight and body weight were calculated.RESULTS: experiments demonstrated that high dose VC significantly inhibited cell proliferation in Bcap37 and MDA-MB-453 cells (all

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PMID: 

Epigenetics. 2019 Sep 11. Epub 2019 Sep 11. PMID: 31505989

Abstract Title: 

Vitamin C in combination with inhibition of mutant IDH1 synergistically activates TET enzymes and epigenetically modulates gene silencing in colon cancer cells.

Abstract: 

Mutations in the enzyme isocitrate dehydrogenase 1 (IDH1) lead to metabolic alterations and a sustained formation of 2-hydroxyglutarate (2-HG). 2-HG is an oncometabolite as it inhibits the activity ofα-ketoglutarate-dependent dioxygenases such as ten-eleven translocation (TET) enzymes. Inhibitors of mutant IDH enzymes, like ML309, are currently tested in order to lower the levels of 2-HG. Vitamin C (VC) is an inducer of TET enzymes. To test a new therapeutic avenue of synergistic effects, the anti-neoplastic activity of inhibition of mutant IDH1 via ML309 in the presence of VC was investigated in the colon cancer cell line HCT116(harboring a mutatedallele) and the parental cells HCT116(wild type). Measurement of the oncometabolite indicated a 56-fold higher content of 2-HG in mutated cells compared to wild type cells. A significant reduction of 2-HG was observed in mutated cells after treatment with ML 309, whereas VC produced only minimally changes of the oncometabolite. However, combinatorial treatment with both, ML309 and VC, in mutated cells induced pronounced reduction of 2-HG leading to levels comparable to those in wild type cells. The decreased level of 2-HG in mutated cells after combinatorial treatment was accompanied by an enhanced global DNA hydroxymethylation and an increased gene expression of certain tumor suppressors. Moreover, mutated cells showed an increased percentage of apoptotic cells after treatment with non-cytotoxic concentrations of ML309 and VC. These results suggest that combinatorial therapy is of interest for further investigation to rescue TET activity and treatment ofmutated cancers.

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PMID: 

Heart Vessels. 2016 Jun ;31(6):990-5. Epub 2015 Mar 21. PMID: 25794983

Abstract Title: 

Late gadolinium enhancement in cardiac amyloidosis: attributable both to interstitial amyloid deposition and subendocardial fibrosis caused by ischemia.

Abstract: 

Gadolinium contrast agents used for late gadolinium enhancement (LGE) distribute in the extracellular space. Global diffuse myocardial LGE pronounced in the subendocardial layers is common in cardiac amyloidosis. However, the pathophysiological basis of these findings has not been sufficiently explained. A 64-year-old man was admitted to our hospital with leg edema and nocturnal dyspnea. Bence Jones protein was positive in the urine, and an endomyocardial and skin biopsy showed light-chain (AL) amyloidosis. He died of ventricular fibrillation 3 months later. 9 days before death, the patient was examined by cardiac magnetic resonance (CMR) imaging on a 3-T system. We acquired LGE data at 2, 5, 10, and 20 min after the injection of gadolinium contrast agents, with a fixed inversion time of 350 ms. Myocardial LGE developed sequentially.The myocardium was diffusely enhanced at 2 min, except for the subendocardium, but LGE had extended to almost the entire left ventricle at 5 min and predominantly localized to the subendocardial region at 10 and 20 min. An autopsy revealed massive and diffused amyloid deposits in perimyocytes throughout the myocardium. Old and recent ischemic findings, such as replacement fibrosis and coagulative myocyte necrosis, were evident in the subendocardium. In the intramural coronary arteries, mild amyloid deposits were present within the subepicardial to the mid layer of the left ventricle, but nostenotic lesions were evident. However, capillaries were obstructed by amyloid deposits in the subendocardium. In conclusion, the late phase of dynamic LGE (at 10 and 20 min) visualized in the subendocardium corresponded to the interstitial amyloid deposition and subendocardial fibrosis caused byischemia in our patient.

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PMID: 

Magn Reson Imaging. 2016 Dec ;34(10):1383-1390. Epub 2016 Aug 13. PMID: 27530966

Abstract Title: 

Gadolinium deposition disease: Initial description of a disease that has been around for a while.

Abstract: 

PURPOSE: To describe the clinical manifestations of presumed gadolinium toxicity in patients with normal renal function.MATERIALS AND METHODS: Participants were recruited from two online gadolinium toxicity support groups. The survey was anonymous and individuals were instructed to respond to the survey only if they had evidence of normal renal function, evidence of gadolinium in their system beyond 30days of this MRI, and no pre-existent clinical symptoms and/or signs of this type.RESULTS: 42 subjects responded to the survey (age: 28-69, mean 49.1±22.4years). The most common findings were: central pain (n=15), peripheral pain (n=26), headache (n=28), and bone pain (n=26). Only subjects with distal leg and arm distribution described skin thickening (n=22). Clouded mentation and headache were the symptoms described as persistent beyond 3months in 29 subjects. Residual disease was present in all patients. Twenty-eight patients described symptoms following administration of one brand of Gadolinium-Based Contrast Agent (GBCA), 21 after a single GBCA administration and 7 after multiple GBCA administrations, including: gadopentetate dimeglumine, n=9; gadodiamide, n=4; gadoversetamide, n=4; gadobenate dimeglumine, n=4; gadobutrol, n=1; gadoteridol, n=2; and unknown, n=4.CONCLUSIONS: Gadolinium toxicity appears to arise following GBCA administration, which appears to contain clinical features seen in Nephrogenic Systemic Fibrosis, but also features not observed in that condition.

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PMID: 

Toxicol Lett. 2019 Feb ;301:157-167. Epub 2018 Nov 23. PMID: 30476537

Abstract Title: 

Gadolinium tissue deposition in the periodontal ligament of mice with reduced renal function exposed to Gd-based contrast agents.

Abstract: 

Gadolinium deposition in tissue is linked to nephrogenic systemic fibrosis (NSF): a rare disorder occurring in patients with severe chronic kidney disease and associated with administration of Gd-based contrast agents (GBCAs) for Magnetic Resonance Imaging (MRI). It is suggested that the GBCAs prolonged permanence in blood in these patients may result in a Gd precipitation in peripheral or central organs, where it initiates a fibrotic process. In this study we investigated new sites of retention/precipitation of Gd in a mouse model of renal disease (5/6 nephrectomy) receiving two doses (closely after each other) of a linear GBCA. Two commercial GBCAs (Omniscan® and Magnevist®) were administered at doses slightly higher than those used in clinical practice (0.7 mmol/kg body weight, each). The animals were sacrificed one month after the last administration and the explanted organs (kidney, liver, femur, dorsal skin, teeth) were analysed by X-ray fluorescence (XRF) at two synchrotron facilities. The XRF analysis with a millimetre-sized beam at the SYRMEP beamline (Elettra, Italy) produced no detectable levels of Gd in the examined tissues, with the notable exception of the incisors of the nephrectomised mice. The XRF analyses at sub-micron resolution performed at ID21 (ESRF, France) allowed to clearly localize Gd in the periodontal ligaments of teeth both from Omniscan® and Magnevist® treated nephrectomised mice. The latter results were further confirmed by laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS). The studyprompts that prolonged permanence of GBCAs in blood may result in Gd retention in this particular muscular tissue, opening possibilities for diagnostic applications at this level when investigating Gd-related toxicities.

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PMID: 

Invest Radiol. 2019 04 ;54(4):191-197. PMID: 30379729

Abstract Title: 

A Structured Survey on Adverse Events Occurring Within 24 Hours After Intravenous Exposure to Gadodiamide or Gadoterate Meglumine: A Controlled Prospective Comparison Study.

Abstract: 

OBJECTIVE: This study compares the incidence of new-onset symptoms within 24 hours after enhanced magnetic resonance imaging (eMRI) with intravenous administration of gadodiamide or gadoterate meglumine compared with a control group undergoing unenhanced MRI (uMRI).MATERIALS AND METHODS: A prospective cohort study (n = 1088 patients) was designed to assess the incidence of symptoms within 24 hours after administration of gadodiamide or gadoterate meglumine. The participants underwent a structured questionnaire by phone call before and 24 hours after the MRI scan to check for symptoms that were not present before the scan. The questionnaire included a list of active questions aimed to test the prevalence of symptoms that have been proposed in the debated definition of gadolinium deposition disease (GDD) and that we recorded in this study as GDD-like. In particular, the following symptoms and signs were tested: central torso pain, arm or leg pain, bone pain, headache, skin redness (any site of the body), fatigue, and mental confusion.Fisher exact test was used to test differences between groups with significance threshold set at P

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PMID: 

Neurology. 2019 Aug 6 ;93(6):e611-e623. Epub 2019 Jul 8. PMID: 31285398

Abstract Title: 

Cumulative gadodiamide administration leads to brain gadolinium deposition in early MS.

Abstract: 

OBJECTIVE: Frequent administration of gadolinium-based contrast agents in multiple sclerosis (MS) may increase signal intensity (SI) unenhanced T1-weighted imaging MRI throughout the brain. We evaluated the association between lifetime cumulative doses of gadodiamide administration and increased SI within the dentate nucleus (DN), globus pallidus (GP), and thalamus in patients with early MS.METHODS: A total of 203 patients with MS (107 with baseline and follow-up MRI assessments) and 262 age- and sex-matched controls were included in this retrospective, longitudinal, 3T MRI-reader-blinded study. Patients with MS had disease duration

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