review of SAMe, methylation, and Glutathione in the development of Nonalcoholic Steatohepatitis (NASH). This would serve as a potential treatment for those with NAFLD.
SAMe shown to be neuroprotective by increasing SOD activity, increasing glutathione production and decreasing homocysteine levels in Alzheimer's even in the presence of vitamin B deficiency.
SAMe show a decrease in gastric cell growth in vitro and in vivo studies. This appears to be secondary to the resolved hypomethylation status of the c-myc and the uPA genes.
Now this is an interesting study. In utero exposure to letrozole (femara) which is an aromatase inhibitor, is associated with same sex preference. Only abstract available, but this study points to environment, hormone effects in early development and future sexual preference. No difference in serum hormone levels were seen.
Recent reports indicate that a certain ROS concentration is required for high-dose vitamin C to induce cytotoxicity in cancer cells.
The generation of ascorbyl- and H2O2 radicals by PAA increases ROS stress in cancer cells
In this study, we report that PAA is efficacious in killing MM cells in vitro and in vivo models, which generated levels of 20–40 mM ascorbate and 500 nM ascorbyl radicals after intraperitoneal administration of 4 g ascorbate per kilogram of body weight (Chen et al., 2008Chen et al., 2008), in xenograft MM mice
These data suggest that PAA may show a therapeutic advantage to blood cancers vs solid tumors because of the communication between tumor cells and blood plasma
These results strongly suggest that the mechanism of PAA killing of MM cells is indeed iron-dependent
These results suggest that PAA administration in SMM may be able to prevent progression to symtomatic MM
A recent study by Yun and colleagues demonstrated that vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH, but spares normal cells
RAS family genes show the most frequent mutations in MM. KRAS, NRAS and BRAF are mutated in 22%, 20% and 7% of MM samples
the disease stage rather than the mutation of RAS and/or BRAF is the major predictive factor for PAA sensitivity in MM treatment
Other molecular mechanisms including ATP depletion and ATM-AMPK signaling have been reported to explain PAA-induced cell death
our pilot study also suggested that PAA could overcome drug resistance to bortezomib in MM cells
Our findings complement reported studies and further address the mechanism of action using clinical samples in which we observed that PAA killed tumor cells with high iron content, suggesting that iron might be the initiator of PAA cytotoxicity
combination of PAA with standard therapeutic drugs, such as melphalan, may significantly reduce the dose of melphalan needed
Combined treatment of reduced dose melphalan with PAA achieved a significantly longer progression-free survival than the same dose of melphalan alone.
These data also suggest that the bone marrow suppression induced by high-dose melphalan can be ameliorated by the combination of PAA with lower dose of melphalan because of the lack of toxicity of PAA on normal cells with low iron content.
if creatinine clearance is <30 mL/min, high dose ascorbic acid should be not administrated.
In MM preclinical and clinical studies, ascorbate was used as an adjunct drug and showed controversial results (Harvey et al., 2009, Perrone et al., 2009, Held et al., 2013, Sharma et al., 2012, Nakano et al., 2011, Takahashi, 2010, Sharma et al., 2009, Qazilbash et al., 2008). However, none of these tests used pharmacological doses of ascorbate and intravenous administration
Multiple myeloma (MM) is a plasma cell neoplasm.
Cameron and Pauling reported that high doses of vitamin C increased survival of patients with cancer
pharmacologically dosed ascorbic acid (PAA) 50–100 g (Chen et al., 2008, Padayatty et al., 2004, Hoffer et al., 2008, Padayatty et al., 2006, Welsh et al., 2013), administered intravenously, has potent anti-cancer activity and its role as anti-cancer therapy is being studied at the University of Iowa and in other centers
In the presence of catalytic metal ions like iron, PAA administered intravenously exerts pro-oxidant effects leading to the formation of highly reactive oxygen species (ROS), resulting in cell death
the labile iron pool (LIP) is significantly elevated in MM cells
The survival of CD138+ cells in vitro was significantly decreased following PAA treatment in all 9 MM
In contrast, no significant change of cell viability was observed in CD138− BM cells from the same patients
The same effect of PAA was also observed in the SMM patients
no response to PAA was detected in CD138+ cells from the 2 MGUS patients
the combination of melphalan plus PAA showed greater tumor burden reduction than each drug alone, suggesting a synergistic activity between these two drugs
Both catalase and NAC protect cells from oxidative damage
cells pretreated with NAC and catalase became resistant to PAA even at high doses
adding deferoxamine (DFO), an iron chelator, to OCI-MY5 cells before PAA treatment was also sufficient to prevent PAA-induced cellular death
iron is essential for PAA to achieve its anti-cancer activity
PAA induced early necrosis (Fig. 3Fig. 3A, 60 min) followed by late apoptosis
results further indicated that PAA induced mitochondria-mediated apoptosis
PAA by reacting with LIP and generating ROS induces mitochondria-mediated apoptosis in which AIF1 cleavage is important for cell death.
ROS and H2O2 are well known factors mediating PAA-induced cancer cell death
animal study finds high-dose, pharmacologic vitamin C found to kill multiple myeloma cells via pro-oxidant effect found in similar studies in dealing with different cancers.
Taken together, these data indicate that ascorbate at concentrations achieved
only by i.v. administration may be a pro-drug for formation of H2O2, and that blood can be a delivery system of the pro-drug to tissues.
These findings give plausibility to i.v. ascorbic acid
in cancer treatment, and have unexpected implications for treatment of infections where H2O2 may be beneficial
pharmacologic concentrations of ascorbate killed cancer but not normal cells, that cell death was
dependent only on extracellular but not intracellular ascorbate, and that killing was dependent on extracellular hydrogen
peroxide (H2O2) formation with ascorbate radical as an intermediate
Our data show that ascorbic acid selectively killed cancer but not normal cells, using concentrations that could only be achieved
by i.v. administration
Ascorbate-mediated cell death was due to protein-dependent
extracellular H2O2 generation, via ascorbate radical formation from ascorbate as the electron donor. Like glucose, when ascorbate is infused
i.v., the resulting pharmacologic concentrations should distribute rapidly in the extracellular water space (42). We showed that such pharmacologic ascorbate concentrations in media, as a surrogate for extracellular fluid, generated
ascorbate radical and H2O2. In contrast, the same pharmacologic ascorbate concentrations in whole blood generated little detectable ascorbate radical
and no detectable H2O2. These findings can be accounted for by efficient and redundant H2O2 catabolic pathways in whole blood (e.g., catalase and glutathione peroxidase) relative to those in media or extracellular
fluid
ascorbic acid administered i.v. in pharmacologic concentrations
may serve as a pro-drug for H2O2 delivery to the extracellular milieu
H2O2 generated in blood is normally removed by catalase and glutathione peroxidase within red blood cells, with internal glutathione
providing reducing equivalents
The electron source for glutathione is NADPH from the pentose shunt, via glucose-6-phosphate
dehydrogenase. If activity of this enzyme is diminished, the predicted outcome is impaired H2O2 removal causing intravascular hemolysis, the observed clinical finding.
The mechansism here is inadequate recycling of GSH due to lack of G6PD, build up of intracellular H2O2 and RBC lysis--hemolysis.
Only recently has it
been understood that the discordant clinical findings can be explained by previously unrecognized fundamental pharmacokinetics
properties of ascorbate
Intracellular transport of ascorbate is tightly controlled in relation to extracellular concentration
Intravenous ascorbate infusion is expected to drastically change extracellular but not intracellular concentrations
For i.v. ascorbate to be clinically useful in killing cancer cells, pharmacologic but not physiologic extracellular concentrations
should be effective, independent of intracellular ascorbate concentrations.
accumulation of extracellular vitamin C is the effect.
It is unknown why ascorbate, via H2O2, killed some cancer cells but not normal cells.
There was no correlation with ascorbate-induced cell death and glutathione,
catalase activity, or glutathione peroxidase activity.
H2O2, as the product of pharmacologic ascorbate concentrations, has potential therapeutic uses in addition to cancer treatment,
especially in infections
Neutrophils generate H2O2 from superoxide,
i.v. ascorbate is effective in some viral infections
H2O2 is toxic to hepatitis C
Use of ascorbate as an H2O2-delivery system against sensitive pathogens, viral or bacterial, has substantial clinical implications that deserve rapid
exploration.
Recent pharmacokinetics studies in men and women show that 10 g of ascorbate given i.v. is expected to produce plasma concentrations of nearly 6 mM, which are >25-fold higher than those concentrations from the same oral dose
As much as a 70-fold difference in plasma concentrations is expected between oral and i.v. administration,
Complementary and alternative medicine practitioners worldwide currently use ascorbate i.v. in some patients, in part because there is no apparent harm
Human Burkitt's lymphoma cells
We first investigated whether ascorbate in pharmacologic concentrations selectively affected the survival of cancer cells by studying nine cancer cell lines
Clinical pharmacokinetics analyses show that pharmacologic concentrations of plasma ascorbate, from 0.3 to 15 mM, are achievable only from i.v. administration
plasma ascorbate concentrations from maximum possible oral doses cannot exceed 0.22 mM because of limited intestinal absorption
For five of the nine cancer cell lines, ascorbate concentrations causing a 50% decrease in cell survival (EC50 values) were less than 5 mM, a concentration easily achievable from i.v. infusion
All tested normal cells were insensitive to 20 mM ascorbate.
Lymphoma cells were selected because of their sensitivity to ascorbate
As ascorbate concentration increased, the pattern of death changed from apoptosis to pyknosis/necrosis, a pattern suggestive of H2O2-mediated cell death
Apoptosis occurred by 6 h after exposure, and cell death by pyknosis was ≈90% at 14 h after exposure
In contrast to lymphoma cells, there was little or no killing of normal lymphocytes and monocytes by ascorbate
Ascorbate is transported into cells as such by sodium-dependent transporters, whereas dehydroascorbic acid is transported into cells by glucose transporters and then immediately reduced internally to ascorbate
Whether or not intracellular ascorbate was preloaded, extracellular ascorbate induced the same amount and type of death.
extracellular ascorbate in pharmacologic concentrations mediates death of lymphoma cells by apoptosis and pyknosis/necrosis, independently of intracellular ascorbate.
H2O2 as the effector species mediating pharmacologic ascorbate-induced cell death
Superoxide dismutase was not protective
Because these data implicated H2O2 in cell killing, we added H2O2 to lymphoma cells and studied death patterns using nuclear staining (19, 28). The death patterns found with exogenous H2O2 exposure were similar to those found with ascorbate
For both ascorbate and H2O2, death changed from apoptosis to pyknosis/necrosis as concentrations increased
Sensitivity to direct exposure to H2O2 was greater in lymphoma cells compared with normal lymphocytes and normal monocytes
There was no association between the EC50 for ascorbate-mediated cell death and intracellular glutathione concentrations, catalase activity, or glutathione peroxidase activity
H2O2 generation was dependent on time, ascorbate concentration, and the presence of trace amounts of serum in media
ascorbate radical is a surrogate marker for H2O2 formation.
whatever H2O2 is generated should be removed by glutathione peroxidase and catalase within red blood cells, because H2O2 is membrane permeable
The data are consistent with the hypothesis that ascorbate in pharmacologic concentrations is a pro-drug for H2O2 generation in the extracellular milieu but not in blood.
The occurrence of one predicted complication, oxalate kidney stones, is controversial
In patients with glucose-6-phosphate dehydrogenase deficiency, i.v. ascorbate is contraindicated because it causes intravascular hemolysis
ascorbate at pharmacologic concentrations in blood is a pro-drug for H2O2 delivery to tissues.
ascorbate, an electron-donor in such reactions, ironically initiates pro-oxidant chemistry and H2O2 formation
data here showed that ascorbate initiated H2O2 formation extracellularly, but H2O2 targets could be either intracellular or extracellular, because H2O2 is membrane permeant
the conversion of ascorbate to H2O2 occurs extracellular
More than 100 patients have been described, presumably without glucose-6-phosphate dehydrogenase deficiency, who received 10 g or more of i.v. ascorbate with no reported adverse effects other than tumor lysis
study shows that mice lacking PR-A and PR-B (progesterone receptors) have increased uterine inflammation. Again, the inflammatory/pro-inflammatory effects of hormones may be regulated through receptors. This may be the reason that different stages of life elicit a different response with the same hormone.
Estrogen receptors alpha and beta show dominance in the proliferative phases, with alpha isoform predominating. In the secretory phase, less expression of ER was present.
ER alpha was predominantly expressed in the epithelial and stromal cells in the proliferative phase. ER beta was predominantly expressed in glandular cells in the same proliferative phase.
in the luteal phase, ER alpha expression declined in the funtionalis layers. ER alpha in the basalis remained unchanged. ER beta in the functionalis layers also declined in the luteal phase.
No relative change was found in the weak expression of ER alpha/beta in the myometrium.
SHBG decreased in hyperinsulinemic states, such as in metabolic syndrome. Low Testosterone has proven to be the same, though not looked at in this study.
Also, in this study, low SHBG is associated with increased cardiovascular mortality.
Good non biased look at heavy metals, particularly Hg, and autism. The authors of this study found the same neurologic pathology biochemically in Hg poisoning as in autism.
The androgens testosterone and DHT elicit vasodilation via calcium and potassium channel activation. The vasodilatory effect of the androgens is through, in part, due to K activated Ca channels. Also of note, DHT had the same effect and DHT cannot be aromatized to estrogen.
Physiologic levels of testosterone shown to induce Calcium channel blockade. This induces the beneficial cardiovascular vasodilation. It is known that testosterone binds to the same receptor as the common calcium channel blocker nifedipine.
No surprise, testosterone in men and women have different effects. I just wrote a post on this. Testosterone is positively associated with increased risk of diabetes in women, but inversely with men. That is increased T in women equals increased Diabetes in women; contrast with increased T associated with decreased Diabetes in men.
But the interesting point is SHBG. This study found a strong inverse association between SHBG with diabetes in women when compared to men. Meaning: low SHBG is associated with an increased risk of type II Diabetes. This is at the same time that testosterone is associated with an increased risk.
estrogen receptors are transported to the cell membrane after production in the rat hippocampus. The membrane receptors have the same origin as the intracellular receptors.