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both obesity and low testosterone are linked with promotion of inflammatory pathways [70–72] and exert harmful actions on the central [73–75] and peripheral [29,76] nervous systems

In general, obesity-related changes were worsened by low testosterone and improved by testosterone treatment; however, this relationship was not statistically significant in several instances. Further, our data suggest that a common pathway that may contribute to obesity and testosterone effects is regulation of inflammation

fasting blood glucose levels were independently and additively increased by GDX-induced testosterone depletion and high-fat diet

testosterone treatment significantly reduced fasting glucose under both the normal and high-fat diets, demonstrating potential therapeutic efficacy of testosterone supplementation

fasting insulin, insulin resistance (HOMA index), and glucose tolerance, low testosterone tended to exacerbate and or testosterone treatment improved outcomes.

testosterone status did not significantly affect body weight

testosterone’s effects likely do not indicate an indirect result on adiposity but rather regulatory action(s) on other aspects of metabolic homeostasis

Prior work in rodents has shown diet-induced obesity induces insulin resistance in rat brain [63] and that testosterone replacement improves insulin sensitivity in obese rats [64]. Our findings are consistent with the human literature, which indicates that (i) testosterone levels are inversely correlated to insulin resistance and T2D in healthy [30,65] as well as obese men [66], and (ii) androgen therapy can improve some metabolic measures in overweight men with low testosterone

it has been shown that TNFα has inhibitory effects on neuron survival, differentiation, and neurite outgrowth

Our data demonstrate that low testosterone and obesity independently increased cerebrocortical mRNA levels of both TNFα and IL-1β

Testosterone status also affected metabolic and neural measures

many beneficial effects of testosterone, including inhibition of proinflammatory cytokine expression

neuroprotection [80,81], are dependent upon androgen receptors, the observed effects of testosterone in this study may involve androgen receptor activation

testosterone can be converted by the enzyme aromatase into estradiol, which is also known to exert anti-inflammatory [82] and neuroprotective [83] actions

glia are the primary sources of proinflammatory molecules in the CNS

poorer survival of neurons grown on glia from mice maintained on high-fat diet

Since testosterone can affect glial function [86] and improve neuronal growth and survival [87–89], it was unexpected that testosterone status exhibited rather modest effects on neural health indices with the only significant response being an increase in survival in the testosterone-treated, high-fat diet group

significantly increased expression of TNFα and IL-1β in glia cultures derived from obese mice

testosterone treatment significantly lowered TNFα and IL-1β expression to near basal levels even in obese mice, indicating a protective benefit of testosterone across diet conditions

IL-1β treatment has been shown to induce synapse loss and inhibit differentiation of neurons

Testosterone status and diet-induced obesity were associated with significant regulation of macrophage infiltration

testosterone prevented and/or restored thermal nociception in both diet groups

a possible mechanism by which obesity and testosterone levels may affect the health of both CNS and PNS

C. scindens and a small number of species belonging to the genus Clostridium are responsible for significant alterations in the human bile acid pool composition through bile acid 7α/β dehydroxylation

bile acids play an important role in maintaining intestinal barrier function as antimicrobial agents in the small bowel (37, 38) and inducers of antimicrobial peptides

Perturbations in the biliary bile acid pool composition can be indicative of hepatogastrointestinal diseases such as fat malabsorption (40), gallstones (3), gastrointestinal cancers (41), and possibly type II diabetes

On the whole, prospective epidemiological data do not support the hypothesis that the 2-hydroxyestrogen pathway is protective, and the 16α-hydroxyestrogen pathway harmful, in hormone-dependent cancers

Both 2- and 4-hydroxyestrogens are catecholestrogens, and it has been suggested that catecholestrogens increase risk of oestrogen-mediated cancers through direct genotoxic effects, rather than through stimulation of cell proliferation via binding to oestrogen receptors

the evidence is stronger for 4-hydroxyestrogens than for 2-hydroxyestrogens

a significant increase in risk of breast cancer with levels of 2-OHE1 has also been reported previously, although it was limited to hormone receptor-negative tumours

In the liver, fructose bypasses the two highly regulated steps of glycolysis, catalyzed by glucokinase/hexokinase and phosphofructokinase both of which are inhibited by increasing concentrations of their byproducts. Instead, fructose enters the pathway at a level that is not regulated and is metabolized to fructose-1-phosphate primarily by fructokinase or ketohexokinase

Fructokinase has no negative feedback system, and ATP is used for the phosphorylation process. As a result, continued fructose metabolism results in intracellular phosphate depletion, activation of AMP deaminase, and uric acid generation which is harmful at the cellular level

Uric acid, a byproduct of fructose degradation,

Uric acid inhibits endothelial NO both in vivo and in vitro, [15] and directly induces adipocyte dysfunction

Serum uric acid increases rapidly after ingestion of fructose, resulting in increases as high as 2 mg/dL within 1 hour

Uncontrolled fructose metabolism leads to postprandial hypertriglyceridemia, which increases visceral adipose deposition. Visceral adiposity contributes to hepatic triglyceride accumulation, protein kinase C activation, and hepatic insulin resistance by increasing the portal delivery of free fatty acids to the liver

Several reviews have concluded that intake of both fructose and HFCS by children and adults was associated with an increased risk of obesity and metabolic syndrome

Sucrose is a disaccharide that is comprised of fructose and glucose

Figure 2

Females suffering from breast cancer had significantly decreased Superoxide dismutase (SOD) and reduced glutathione (GSH) levels in comparison to normal females

ADA seems to be a promising marker of inflammation in breast cancer thereby suggesting that it can be used as a diagnostic tool to detect the stage of breast cancer along with cytopathological studies

In conclusion, our study confirmed the role of oxidative stress in the pathogenesis of breast cancer.

Another potent antioxidant molecule is reduced glutathione. It acts as reductant which converts hydrogen peroxide into water and reduces lipid peroxidation products into their corresponding alcohols and thus mediates protective action.

In the present study, significantly low SOD activity has been observed in female patients suffering from carcinoma breast both pre as well as post operative in comparison to healthy females.

We observed significantly decreased SOD activity and GSH levels in patients belonging to clinical stage 4 as compared to those having stages 1, 2 or 3 of breast cancer.

Increased ADA activity in breast cancer patients has also been reported

The compromised antioxidant defence system produces the oxidative stress which in turn creates the inflammatory response shown by concomitant increased adenosine deaminase (ADA) activity in female patients.

Experimental and epidemiological evidences implicate the involvement of oxygen derived free radical in the pathogenesis of breast cancer.

Antioxidant status was highly depressed in advanced stages of breast cancer as compared to initial stage.

In the present study, significantly low GSH levels were observed in female patients of carcinoma breast as compared to normal females

Walia et al. (1995) reported increased ADA activity in breast cancer patients as compared to age matched normal subjects.

These free radicals are able to cause damage to membrane, mitochondria and macromolecules including proteins, lipids and DNA and actively take part in cell proliferation. This cascade in turn generates the inflammatory response and causes the progression of the disease.

increased oxidative stress gives rise to inflammation which could further aggravates the disease

Breast carcinoma involves a cascade of events that are highly inflammatory.

Marked oxidative stress in stage 4 of breast cancer indicated advancement of the disease, hence checking oxidative stress at initial stage could be helpful for controlling the progression of the disease.

They concluded that ADA is a better probable parameter for detection of breast cancer

Adenosine deaminase enzyme (ADA) catalyzes the conversion of adenosine to inosine which finally gets converted to uric acid

serum ADA activity tends to increase with advancing age,

Prevalence of oxidative stress gives rise to inflammation.

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.

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.

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

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