August 2014 Blog with Durk and Sandy

APPETIZERS

All men dream, but not equally. Those who dream by night in the dusty recesses of their mind wake in the day to find that it was vanity; but the dreamers of the day are dangerous men, for they may act their dreams with open eyes, to make it possible. 
— T. E. Lawrence 
(“Lawrence of Arabia”) 
Seven Pillars of Wisdom (1926)

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Everything is Different This Time... NOT

The Gods of the Copybook Headings

AS I PASS through my incarnations in every age and race,
I make my proper prostrations to the Gods of the Market Place.
Peering through reverent fingers I watch them flourish and fall,
And the Gods of the Copybook Headings, I notice, outlast them all.

We were living in trees when they met us. They showed us each in turn
That Water would certainly wet us, as Fire would certainly burn:
But we found them lacking in Uplift, Vision and Breadth of Mind,
So we left them to teach the Gorillas while we followed the March of Mankind.

We moved as the Spirit listed. They never altered their pace,
Being neither cloud nor wind-borne like the Gods of the Market Place,
But they always caught up with our progress, and presently word would come
That a tribe had been wiped off its icefield, or the lights had gone out in Rome.

With the Hopes that our World is built on they were utterly out of touch,
They denied that the Moon was Stilton; they denied she was even Dutch;
They denied that Wishes were Horses; they denied that a Pig had Wings;
So we worshipped the Gods of the Market Who promised these beautiful things.

When the Cambrian measures were forming, They promised perpetual peace.
They swore, if we gave them our weapons, that the wars of the tribes would cease.
But when we disarmed They sold us and delivered us bound to our foe,
And the Gods of the Copybook Headings said: “Stick to the Devil you know.”

On the first Feminian Sandstones we were promised the Fuller Life
(Which started by loving our neighbour and ended by loving his wife)
Till our women had no more children and the men lost reason and faith,
And the Gods of the Copybook Headings said: “The Wages of Sin is Death.”

In the Carboniferous Epoch we were promised abundance for all,
By robbing selected Peter to pay for collective Paul;
But, though we had plenty of money, there was nothing our money could buy,
And the Gods of the Copybook Headings said: “If you don’t work you die.”

Then the Gods of the Market tumbled, and their smooth-tongued wizards withdrew
And the hearts of the meanest were humbled and began to believe it was true
That All is not Gold that Glitters, and Two and Two make Four
And the Gods of the Copybook Headings limped up to explain it once more.

As it will be in the future, it was at the birth of Man
There are only four things certain since Social Progress began.
That the Dog returns to his Vomit and the Sow returns to her Mire,
And the burnt Fool’s bandaged finger goes wabbling back to the Fire;

And that after this is accomplished, and the brave new world begins
When all men are paid for existing and no man must pay for his sins,
As surely as Water will wet us, as surely as Fire will burn,
The Gods of the Copybook Headings with terror and slaughter return!

— Rudyard Kipling

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Throughout history, poverty is the normal condition of man. Advances which permit this norm to be exceeded — here and there, now and then — are the work of an extremely small minority, frequently despised, often condemned, and almost always opposed by all right-thinking people. Whenever this tiny minority is kept from creating, or (as sometimes happens) is driven out of a society, the people then slip back into abject poverty. This is known as “bad luck.” 
— Robert A. Heinlein, Time Enough for Love

When all government, in little as in great things, shall be drawn to Washington as the Center of all power, it will render powerless the checks provided of one government on another and will become as venal and oppressive as the government from which we separated. 
— Thomas Jefferson

(D&S: Jefferson’s genius here displayed — perhaps he was a closet anti-Federalist.)

Doing well is the result of doing good.
That’s what capitalism is all about. 
— Ralph Waldo Emerson

With socialized medicine, the trick is not to die while waiting for treatment. 
— James Cook

(D&S: You do this “trick” by developing your own resources: how to research the prevention and treatment of disease and the availability of alternative medications as well as alternative sources for conventional medicines. Add guns, encryption systems, moving to a location with fewer regulations and taxes, and learning how to live the life you want despite living in the midst of enemies. With politicized reality, the trick is to look like everyone else while living a much freer life.)

The worship of the state is the worship of force. 
— Ludwig von Mises, economist

THE HELPFUL DICTIONARY OF SCIENTIFIC LINGO, 
SLANG, AND OFFHAND REMARKS

What IS Understood When Something Is Not FULLY Understood

 

CAUTION: 
“process x is not fully understood” might mean 
“process x is hardly understood at all.”

FIGHTING THE BLAHS

DHA AND EPA—OMEGA-3 FATTY ACIDS WHICH INCREASE GRAY MATTER IN HUMAN BRAIN AREAS THAT REGULATE EMOTIONS

Decreases in the brain’s gray matter takes place in various areas during aging. These decreases are associated with cognitive decline. A 2007 paper¹ reported the results of an examination via magnetic resonance imaging of gray matter volume in 55 middle aged male and female subjects (mean age = 44.7) and related the decreased gray matter to the dietary intake of long chain omega-3 fatty acids (DHA and EPA). The subjects were divided into three groups based on long chain omega-3 intake: low 0-20 mg/day, n=16; medium (25–70 mg/day, n=21; and high 80-1600 mg/day, n=18.

The authors hypothesized that reduced gray matter volume in certain brain areas involved in regulating emotion might be causative factors in depression. They noted that (1) low levels of long chain omega-3 fatty acids are inversely associated with depressive behavior; (2) treatment of animals or humans that exhibit depressive behavior with long chain omega-3 fatty acids has been reported to have beneficial effects; and (3) reduced gray matter volume in nodes of corticolimbic brain circuitry observed in major depressive disorder may result from reduced neurogenesis and increased neuronal apoptosis that could result from the elevation in circulating glucocorticoids associated with depression.

Deficiency of long chain omega-3 fatty acids has been associated with increased circulating levels of glucocorticoids, which the authors attribute to HPA (hypothalamic-pituitary axis) hyperactivity.

The results showed that a higher intake of the long chain omega-3 fatty acids was associated with increased gray matter volume in the subgenual ACC (anterior cingulate cortex) and in an overlapping region of the right amygdala and right hippocampus, areas important for emotion arousal and regulation.

The authors cautioned that the study included only a small number of subjects and that the intake of EPA and DHA was estimated from dietary recall rather than actual measurements of blood fatty acid composition. Nevertheless, the data are consistent with animal studies in which DHA supplementation, for example, has been shown to increase neurite growth and c-Fos containing neurons (indicating neuronal activity) in the hippocampal CA1 field of the rat brain.

Reference

1. Conklin, Gianaros, Brown, et al. Long-chain omega-3 fatty acid intake is associated positively with corticolimbic gray matter volume in healthy adults. Neurosci Lett. 421:209-12 (2007).

IGF-1 IS IMPORTANT TO PREVENT FRAILTY

Selenium, Magnesium, and Zinc Appear to Be 
Important Determinants of IGF-1 Bioactivity

A point where several elements involved in human aging seem to come together is the IGF-1 (insulin-like growth factor-1) pathway, where its decline is associated with frailty.¹A very recent review paper explored this subject, noting that the minerals selenium, magnesium, and zinc appear to be important determinants of IGF-1 bioactivity. In the papers we discussed in an earlier newsletter on senescence, deficiencies of selenium and magnesium are shown to be important in the senescence of cells in age-associated sarcopenia (loss of muscle mass). The authors of the paper describe frailty as the result of an interplay of multiple factors including hormones, pro-inflammatory status, oxidative stress, and nutrition and explain that “frailty is a geriatric syndrome occurring in the early stages of mobility impairment and is not a synonymous or consequence of co-morbidity or disability.”

Reference

1. Maggio et al. IGF-1, the crossroad of the nutritional, inflammatory, and hormonal pathways to frailty. Nutrients. 5:4184-205 (2013).

LYCOPENE-CONTAINING TOMATO EXTRACT 
EFFECTS ON BLOOD PRESSURE — A META-ANALYSIS

Reduced Systolic Blood Pressure (BP) With Tomato Extract Supplementation, Especially for Those with Baseline Systolic BP > 120 mm Hg

A recent meta-analysis that examined the effect of tomato extract supplementation on blood pressure included 241 subjects in six studies. One limit of the meta-analysis was that, although the amount of lycopene that was contained in the supplement ingested by subjects was known, the authors could not ascribe the results only to lycopene, since tomato extract contains many other bioactive components than just lycopene. The results, therefore, can be ascribed to tomato extract, but are not all necessarily due to lycopene.

The researchers reported that the tomato extract supplementation showed a significant reduction of systolic blood pressure, with subgroup analysis finding that a higher dosage of lycopene (>12 mg/day) derived from the supplement lowered systolic blood pressure more significantly, especially for participants whose baseline systolic blood pressure was greater than 120 mm Hg, such as Asians.

Midlife Blood Pressure Is a Significant Predictor of Reduced Cognitive Function in Later Life

An earlier paper² reported that, among 3735 Japanese-American subjects (surviving cohort members of the prospective Honolulu Heart Program that began in 1965 – 68) living in Hawaii with an average age of 78 years (at the time of their examination for this study), there was a progressive increase in the risk of intermediate and poor cognitive function with increasing level of midlife systolic blood pressure. For every 10 mm. Hg increase in systolic blood pressure, the authors calculated an increase of 7% (95% confidence interval, 3% to 11%) in the risk for intermediate cognitive function and an increase of 9% (95% confidence interval, 3% to 16%) in the risk for poor cognitive function. The researchers reported finding no association between later cognitive function and midlife diastolic blood pressure.

The results suggest that a relatively small reduction in systolic blood pressure in middle age can provide physiologically important protection against age-associated cognitive decline.

References

1. Li and Xu. Lycopene supplement and blood pressure: an updated meta-analysis of intervention trials. Nutrients. 5:3696-712 (2013).
2. Launer, Masaki, Petrovitch, et al. The association between midlife blood pressure levels and late-life cognitive function. JAMA. 274(23):1846-51 (1995).

HYPOCHLOROUS ACID — POTENT OXIDANT PRODUCT OF MYELOPEROXIDASE— IS IMPLICATED IN ATHEROSCLEROSIS, CANCER, DNA DAMAGE, EVEN OOCYTE (EGG CELL) AGING

The Tomato Carotenoid LYCOPENE is a Powerful Scavenger of Hypochlorous Acid (HOCl)

Protects Against Inflammation

Considerable evidence supports the involvement of the enzyme myeloperoxidase(MPO) in inflammatory processes. Indeed, a very recent paper^A notes that “[t]he serum levels of MPO and its by-products have potential as predictors of outcome in patients with severe inflammation.” For example, in atherosclerosis, the enzyme promotes the oxidation of LDL¹—and oxidized LDL causes macrophages to turn into foam cells in atherosclerotic plaques. MPO has also been reported to cause extensive damage to double stranded DNA, and to attack the double bonds of unsaturated fatty acids and cholesterol (where it has been reported to function as a major enzymatic catalyst for initiation of lipid peroxidation at sites of inflammation).² Hypochlorous acid (HOCl)—released by MPO—can react with superoxide to generate highly toxic hydroxyl radicals.³

MPO Accelerates the Aging of Oocytes (Mammalian Egg Cells)

Interestingly, MPO has been shown to play an important role in accelerating the aging of mouse oocytes through a mechanism that appears to involve oocyte fragmentation and degradation.⁶ (Paper #6 was an earlier one published by the group that published paper #3.) This could be of particular importance in the case of women wanting to conceive at a relatively late age because of the increased potential for birth defects in offspring derived from older, more-likely-to-be-damaged oocytes. The researchers⁶ explain: “[a]ging of the unfertilized oocyte inevitably occurs following ovulation, limiting its fertilizable life span.” They studied the effects of major reactive oxygen species (superoxide, hydrogen peroxide, and hypochlorous acid) on the aging of young and of relatively old mouse oocytes. They report that their “results clearly demonstrate that HOCl [hypochlorous acid] produced by mammalian peroxidases [including myeloperoxidase] is a much more powerful oxidant in accelerating oocyte aging than either [superoxide] or H2O2 [hydrogen peroxide] and may easily be formed internally in oocytes or provided by the neighboring follicular cells through the reaction of MPO with H2O2 in the presence of chloride ions. Indeed, young oocytes exposed to lower concentrations (1 – 10uM) accelerate aging phenomena, while higher concentrations (0.1 – 1mM) caused lysis of the cell membrane and death of the oocyte. In contrast, the older oocytes underwent lysis even on exposure to 1 μM HOCl.”⁶

MPO and Stroke

MPO is also widely distributed in ischemic tissues, as occurs in stroke or heart attack, where it was shown to correlate positively with infarct size (the volume of cells killed in a stroke).⁴

MPO and Neurodegenerative Diseases

A recent hypothesis⁵ proposed a model in which the interaction of microglia (immune cells in the brain) and MPO may be important in the generation of inflammatory cytokines as seen in neurodegenerative diseases.

Lycopene Identified as Potential Scavenger of HOCl (an MPO end product) 

Multiple Molecules of HOCl May Be Consumed Per Molecule of Lycopene

A recent paper reviewed extensive evidence and results of experiments performed by the authors supporting a role for lycopene to act as a potent scavenger of HOCl.³ The researchers found that “[t]he degree of degradation of lycopene (as assessed by the number and chain lengths of the different oxidative metabolites of lycopene) depends mainly on the ratio between HOCl to lycopene, suggesting that multiple molecules of HOCl are consumed per molecule of lycopene.” This points to a superior protective effect of lycopene in comparison to other agents reportedly able to protect against MPO and its end product HOCl.³ In its interaction with HOCl, lycopene can be attacked at its many double bonds, resulting in degradation into a variety of breakdown products, of which a number have been identified to have biological activity.³

The authors’ experiments show that “lycopene can function as a potent scavenger of HOCl at a wide range of concentrations that span various pathophysiological and supplemental ranges.”

The researchers interpreted the disappearance of the red lycopene color as an indication of the oxidation of lycopene in interactions with HOCl. “The oxidation of lycopene by a slight excess of HOCl was accompanied by a marked change from red color to colorless.”

As the authors explain, “[i]ncreased levels of HOCl, a potent oxidant, are typically observed in the plasma and tissues of individuals with inflammatory diseases … a functional deficiency of taurine, a potent HOCl scavenger, is a defining feature of diabetes, obesity, depression, hypertension, gout, kidney failure, and autism, among other conditions.” The need for additional protection against HOCl is indicated. The authors conclude: “[i]n summary, inhibition of MPO or removing its downstream final product, HOCl, is an attractive target for preventing HOCl-mediated tissue injury and progression of inflammatory diseases. In this study we … show for the first time that lycopene may serve as a potent scavenger of HOCl. The interplay between lycopene and HOCl may have a broad implication in the function of inflammatory biological systems throughout the body.” The authors propose that lycopene “could represent an interventional approach to minimize the deleterious effects associated with inflammation.”

We take 20 mg (Sandy) or 40 mg (Durk) of lycopene a day as a dietary supplement.

References

1. Patterson, Fraser, Capretta, et al. Carbon monoxide-releasing molecule 3 inhibits myeloperoxidase (MPO) and protects against MPO-induced vascular endothelial cell activation/dysfunction.Free Radic Biol Med.70:167-73 (2014). 
   1. Van Antwerpen, Boudjeltia, Babar, et al. Thiol-containing molecules interact with the myeloperoxidase/H2O2/chloride system to inhibit LDL oxidation. Biochem Biophys Res Commun. 337:82-8 (2005). 
   2. Zhang, Brennan, Shen, et al. Myeloperoxidase functions as a major enzymatic catalyst for initiation of lipid peroxidation at sites of inflammation. J Biol Chem.277(48):46116-22 (2002). 
   3. Pennathur, Maitra, Byun, et al. Potent antioxidative activity of lycopene: a potential role in scavenging hypochlorous acid. Free Radic Biol Med. 49(2):205-13 (2010). 
   4. Breckwoldt, Chen, Stangenberg, et al. Tracking the inflammatory response in stroke in vivo by sensing the enzyme myeloperoxidase. Proc Natl Acad Sci USA.105(47):18584-9 (2008). 
   5. Lefkowitz and Lefkowitz. Microglia and myeloperoxidase: a deadly partnership in neurodegenerative diseases. Free Radic Biol Med. 45:726-31 (2008). 
   6. Goud, Goud, Diamond, et al. Reactive oxygen species and oocyte aging: role of superoxide, hydrogen peroxide, and hypochlorous acid. Free Radic Biol Med. 44:1295-304 (2008).

LYCOPENE — FOLLOWING THE TRAIL TO SIRT1, A PUTATIVE LONGEVITY GENE

Apo-10’-Lycopenoic Acid, a Lycopene Metabolite, Increases Sirtuin 1 (SIRT1) mRNA and Protein Levels and Decreases Liver Fat Accumulation in Mice

Here we describe recent research on a lycopene metabolite (one of the “lycopenoids”), apo-10’-lycopenoic acid.¹ There are a lot of metabolites, but only a limited amount of research has been done in this area so far. Like so many other nutrients, including vitamin E,^A metabolites may play a far larger role in the biological effects of these substances than has been previously realized. Conversion of the parent molecules to metabolites is likely to play an important role in determining how long the parent compounds can be detected in the bloodstream and their peak concentrations.

In one paper,^1B researchers noted that “[a]n indication of how essential these secondary metabolites are to plants’ survival can be seen in the energy invested in their synthesis, which is usually far in excess of that required to synthesize primary metabolites.”

Take apo-10’-lycopenoic acid, for example. The recent discovery of carotene 9,10-oxygenase, a mammalian enzyme that catalyzes the cleavage of lycopene (and other carotenoids) into metabolites has opened the door to a larger world of hitherto unknown effects of lycopene. “A series of apo-lycopenals, including apo-10’-lycopenal, has recently been identified in human plasma.”¹ The researchers¹ decided that there might be something important going on here and have followed up on it. The work was supported by grants from the NIH, the USDA, and from Kyung Hee University in Korea.

The researchers first calculated a dose of the apo-10’-lycopenoic acid (synthesized at BASF, it had a purity of >99%) based on a number of factors to be approximately equivalent to 14.4 mg lycopene/day in a 60 kg. adult male human and, therefore, the authors concluded, to be “physiologically relevant.” The apo-10’-lycopenoic acid was used to treat ob/ob mice, a strain susceptible to the development of obesity and fatty liver on a high fat diet. The authors¹ cited two studies (one of which their group published), that had found lycopene to reduce these adverse effects in rodents on a high fat diet. They wondered whether apo-10’-lycopenal was wholly or partially responsible for that effect.

The results showed, first, that apo-10’-lycopenal accumulated in the liver and decreased the fatty liver seen in the untreated controls on the high fat diet. Previous work cited in the paper¹ reported that suppression of or knockout of SIRT1 resulted in the accumulation of fat in mouse livers in mice on a high fat diet as a result of changes in lipid metabolism. In this study,¹ the authors report that not only did ALA decrease fat accumulation in the liver but the liver expression of SIRT1 was “greatly induced by ALA [apo-10’-lycopenoic acid] supplementation.”

SIRT1 May Be a Longevity Gene

The increased expression of SIRT1 with apo-10’-lycopenal supplementation is of interest beyond the prevention of fatty liver because SIRT1 is a gene that has been extensively studied and found to have life-extending effects in animal models of aging.^2–4 A human study⁵ reported that a single nucleotide polymorphism (SNP) of the SIRT1 gene was associated with better cognitive functioning.

References

1. Jiang, Yin, Lill, et al. Long-chain carboxychromanols, metabolites of vitamin E, are potent inhibitors of cyclooxygenases.Proc Natl Acad Sci USA.105(51):20464-9 (2008).
   1. Chung, Koo, Lian, et al. Apo-10’-Lycopenoic acid, a lycopene metabolite, increases sirtuin 1 mRNA and protein levels and decreases hepatic fat accumulation in ob/ob mice. J Nutr. 142:405-10 (2012).
   1B. Kennedy and Wightman. Herbal extracts and phytochemicals: plant secondary metabolites and the enhancement of human brain function. Adv Nutr. 2:32-50 (2011).
   2. Milne, Lambert, Schenk, et al. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature. 450(7170):712-6 (2007).
   3. Morselli, Maiuri, Markaki, et al. The life span-prolonging effect of sirtuin-1 is mediated by autophagy. Autophagy. 6(2);186-8 (Jan, 2010).
   4. Smith, Kenney, Gagne, et al. Small molecule activators of SIRT1 replicate signaling pathways triggered by calorie restriction in vivo. BMC Syst Biol. 3:31 (March 2009) doi:10.1186/1752-0509-3-31.
   5. Kuningas, Putters, Westendorp, et al. SIRT1 gene, age-related diseases, and mortality: the Leiden 85-Plus Study. J Gerontol A Biol Sci Med Sci. 62(9):960-5 (2007).

LYCOPENE’S ANTICANCER MECHANISM—IT 
INHIBITS HMG-CoA REDUCTASE, THE ENZYME 
THAT CATALYZES THE SYNTHESIS OF CHOLESTEROL

Mechanisms of Cell Growth Inhibition That May Be Involved in Lycopene’s Anticancer Effects

A number of mechanisms through which lycopene and tomato products providing lycopene might reduce the risk of developing various types of cancer include (as found in in vitro and some in vivo animal models) were reviewed in a recent paper:¹“upregulation of connexin 43 and consequent enhancement of gap junction communication; modulation of growth factors and growth factor receptors, including insulin-like growth factor-1 and platelet-derived growth factor; immunoenhancement and decrease in inflammation; modulation of cyclo-oxygenase pathways and xenobiotic metabolism and gene methylation.” A year later, however, another paper found that lycopene and apo-10’-lycopenal did not alter DNA methylation of the gene for GSTP1 (a selenoprotein) in cancer cell lines as reported in the paper cited in reference #1.²

In the prostatic LNCaP carcinoma cells, total cholesterol was progressively decreased by adding increasing concentrations of lycopene (2.5 – 10 μM) to the culture media. At concentrations below 2.5 μM, lycopene had no effect in reducing cholesterol levels or inhibiting HMG-CoA reductase expression. Interestingly, lycopene reduced Ras activity (as indicated by markedly decreased translocation from the cytosol to cell membranes). At concentrations above 2.5 μM, lycopene inhibited cancer cell growth, by decreasing cell proliferation and by increasing apoptosis (programmed cell death).The researchers¹ sought to further investigate the inhibitory effect of lycopene on the synthesis of cholesterol, which is increased in many types of cancer cells. This inhibitory effect is produced by lycopene’s interference in the Mevanolate Pathway by inhibition of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. (See Fig. 1.) HMG-CoA reductase catalyzes the synthesis of cholesterol production. (Statins work, in a major—but not the only—way by inhibiting HMG-CoA reductase.) The scientists treated cancer cell lines with lycopene in which the oncogene ras was activated (including LNCaP prostatic carcinoma and colon carcinoma HT-29) as well as squamous carcinoma BEN cells and other cell lines in which ras was not activated.

The researchers also tested the effect of mevalonate on lycopene’s ability to inhibit cancer cell growth by adding mevalonate to the cell culture medium. Mevalonate is a fatty acid derivative that results from the conversion of HMG-CoA into cholesterol via the Mevalonate Pathway. With the addition of 100 μM mevalonate to the culture medium, even 10 μM of lycopene was ineffective in inhibiting cancer cell growth. This strongly suggests that the effect of lycopene on the mevalonate pathway (via inhibition of HMG-CoA reductase) was responsible for the reduced cancer cell growth in these lines of cancer cells.

Why Do Data for Lycopene Treatment of Cancer Show Inconsistent Results?

Despite strong support for important anti-cancer effects of lycopene, the totality of the evidence for in vitro and in vivo studies with lycopene treatment is not consistent though, overall, supporting anticancer activity. There are several reasons: There is not just one mechanism causing cancer. Cancer is a complex FAMILY of diseases where many pathways are dysfunctional, where each cancer differs from another (in fact, the cancer cells change from one stage of growth to another and what therapy works at one stage may not work at another). Hence, it is unrealistic to expect any single agent to be effective for all cancers at all times in all individuals. That is one reason cancer still remains a challenging disease to treat and why it is also challenging to dissect the results of clinical studies to determine what caused beneficial effects when they are observed, as well as determining why beneficial effects of treatment often do not persist, allowing cancer cells to become resistant and cancers to recur.³ (And be sure to keep in mind that the cancer that recurs is not quite the same cancer that you had in the first place …)

As the authors³ pointed out, “[w]e now know that cellular functions are regulated by a network of effector pathways. These pathways interact with each other and maintain cellular stability, but also trigger proliferation, differentiation, migration, and survival.” “The acquired resistance of cancer cells has to be approached from a signaling network perspective and take into account the insights into the regulatory mechanisms which establish interconnections and adaptations between effector pathways.”

A key insight from the study of the regulatory networks of cancer cells is that a single agent is generally inadequate to restore a cancer cell to normality or to kill it without also doing irreparable damage to a large number of normal cells. (As an extreme example, you could certainly destroy every cancer cell in your body by a high enough dose of whole body irradiation, but guess what? It wouldn’t do you any good because you’d also have killed every normal cell in your body.) You need to simultaneously target as many known cancer-supporting pathways as you can. That is one reason why it is important to identify particular mechanisms by which a substance with substantial anticancer properties such as lycopene can block a cancer-inducing pathway.

The breakthrough in treating AIDS came about when it was realized that if you treat somebody infected with HIV with a single drug they might respond for a period of time but would eventually stop responding. You might even get a second remission using a second rank drug—but people died because the HIV virus was very good at mutating and, hence, adapting, to treatment with a single drug. Nowadays they use a few to several different drugs to hit the virus at different targets. A person infected with HIV can typically live for 20 years or more. That’s what happens when you go from an acute disease that is likely to kill you within a few years to one that is a chronic disease that probably won’t kill you at all because you will live long enough to die from something else.

We suggest including lycopene in your cancer prevention kit. You don’t need a magic (and nonexistent) silver bullet if you have enough bullets of different types. As a BONUS, you get the lycopene metabolites at NO EXTRA CHARGE!!

Lycopene Metabolites May Have Anti-Cancer Activity

A group that has done quite a bit of work on lycopene metabolites reported a recent paper of theirs⁴ in which they found that apo-10’-lycopenal and apo-12’-lycopenal treatment reduced the proliferation of DU145 prostate cancer cells in a dose-dependent manner in part by affecting the cell cycle. A study⁵ by a different group found apo-10’-lycopenoic acid reduced the proliferation of a human bronchial epithelial cell line as well as tumor promotion of an in vivo lung tumor mouse model by inducing Nrf2-mediated induction of protective phase II detoxifying/antioxidant enzymes. In the latter paper, the researchers found ALA to increase expression of enzymes that included heme oxygenase-1, glutathione-S-transferases, NAD(P)H:quinone oxidoreductase 1, and glutamate-cysteine ligases in the bronchial (BEAS-2B) cells. Moreover, apo-10’-lycopenoic acid treatment was reported to increase total intracellular glutathione levels as well as to reduce reactive oxygen species generation and hydrogen peroxide-mediated cell damage.

We wondered whether the stock solutions of lycopenoids that were prepared in tetrahydrofuran that contained 0.025% BHT (butylated hydroxytoluene) were affected in the experiments reported in paper #5 by the included BHT, which is a powerful antioxidant (probably added to prevent autooxidation). That appears not to be a problem as it was reported in a later paper by a different group⁶ that also used tetrahydrofuran containing 0.025% BHT that the vehicles had no effect on the parameters measured in that study, which examined the effect of oxidized lycopenoids in the activation of phase II enzymes.

Interestingly, the last paper⁶ reported that the apo­carotenals (oxidized derivatives of lycopene) “inhibited breast and prostate cancer cell growth with a similar order of potency to the activation of EpRE/ARE [electrophile/antioxidant response element].” The researchers suggested that this “may provide a mechanistic explanation for the cancer preventive effect of carotenoids.” EpRE/ARE regulates a system of protective antioxidant defenses including phase II detoxifying enzymes, “a major cellular strategy for reducing the risk of cancer, inflammation, and other chronic degenerative diseases.”⁶In that same paper, the researchers mention that “lycopene is more active than beta carotene in stimulating the EkpRE/ARE activity and thus may be more effective in cancer prevention.” [Emphasis added.]

A Message to Those Who Have Read This Far

We include these detailed descriptions of how scientists follow the pathways from starting material (lycopene) to metabolites (lycopenoids) and the intercommunication with other pathways along the way to show how complex it is to unravel something as seemingly “simple” as lycopene, a tomato carotenoid that makes tomatoes red, and to get a grasp on why the tomato plant bothers to make it in the first place. A wondrous story and a true inspiration to those with a love for solving/understanding the many mysteries of life.

References

1. Palozza et al. Lycopene induces cell growth inhibition by altering mevalonate pathway and Ras signaling in cancer cell lines. Carcinogenesis. 31(10):1813-21 (2010).
2. Liu and Erdman. Lycopene and apo-10’-lycopenal do not alter DNA methylation of GSTP1 in LNCaP cells. Biochem Biophys Res Commun. 412:479-82 (2011).
3. von Manstein, Yang, Richter, et al. Resistance of cancer cells to targeted therapies through the activation of compensating signaling loops. Curr Sig Transduction Therapy. 8:193-202 (2013).
4. Ford, Elsen, Zunga, Lindshield, Erdman. Lycopene and apo-12’-lycopenal reduce cell proliferation and alter cell cycle progression in human prostate cancer cells. NUTRI CANCER. 63:256-63 (2011).
5. Lian and Wang. Enzymatic metabolites of lycopene induce Nrf2-mediated expression of phase II detoxifying/antioxidant enzymes in human bronchial epithelial cells. Int J Cancer. 123(6):1262-8 (2008).
6. Linnewiel, Ernst, Caris-Veyrat, et al. Structure-activity relationship of carotenoid derivatives in activation of the electrophile/antioxidant response element transcription system. Free Radic Biol Med. 47:659-67 (2009).

The Safety of Lycopene Depends, Like That of All 
Natural Substances, on the Dose

As a rule of thumb, “the dose makes the poison” can hardly be beat. It provides the basic guidance to the safe use of a natural substance, which, at amounts found in a diet, are quite safe—but at high doses (more than you could get in a diet even highly enriched in the substance) could have adverse effects.

With respect to carotenoids, taking the data all together, you generally observe protection against cancer at low doses, with sometimes increased risk of cancer at high doses. Beta carotene surprised many when it increased the risk of lung cancer in smokers in a large intervention trial. Scientists who published on this effect¹ explained it this way:

… we have shown that high doses of beta carotene in an oxidative environment (such as the lungs of smokers) may result in excess levels of polar metabolites, which can promote carcinogenesis, whereas lower doses of beta carotene have been shown to be protective.

In a very recent study,² we observed that high dose lycopene supplementation in the presence of alcohol* ingestion increased hepatic [liver] inflammation and TNFalpha [tumor necrosis factor alpha, an inflammatory cytokine]. While no apparent adverse effects—such as a decrease in body weight or tissue damage—were observed in our recent study of apo-10’-lycopenoic acid-supplemented NNK-treated A/J mice, an earlier study showed enhancement of benzo[a]pyrene [a polynuclear aromatic hydrocarbon constituent of smoke]-induced mutagenesis in mouse lung and colon tissues after lycopene supplementation.

* In the experiment referred to here (involving high dose lycopene in the presence of alcohol), the alcohol dose amounted to 36% of the caloric intake. This is roughly equivalent to a human on a 2400 kcal/day diet (including the alcohol) consuming 120 grams of pure ethanol per day or about 1½ bottles of 12% alcohol-containing wine per day. The lower dose of lycopene was roughly equivalent to 15 mg per day while the high dose was roughly equivalent to 45 mg per day for a 70 kg adult human.

Further research is needed to determine the mechanisms involved in whether a carotenoid will, at a particular dose, act to protect against cancer or to increase the risk of cancer—particularly under conditions involving smoke exposure and/or alcohol ingestion.

Taking lycopene at an amount that could be ingested by people eating a diet enriched in tomato products would, therefore, likely, be safe and reduce the risk of cancer, while it would be unclear how safe it would be to take a lot more than this.

The principle is the same with other dietary supplements. You see a similar effect with turmeric, a spice used in fairly large amounts on a daily basis in Indian food. Taking turmeric root as a supplement in amounts that are consumed by Indians eating a traditional turmeric-spiced diet is associated with a reduced risk of Alzheimer’s disease (though this is an association, not proof of cause and effect) and has not been associated with increased risk of diseases. On the other hand, taking very large doses of turmeric might not be safe for some people, though turmeric and its contained curcumin and curcuminoids are remarkably safe and are being used experimentally to try to prevent Alzheimer’s disease.³

References

1. Mein, Lian, Wang. Biological activity of lycopene metabolites: implications for cancer prevention. Nutr Rev. 66(12):667-83 (2008).
2. Veeramachaneni, Ausman, Choi, Russell, Wang. High dose lycopene supplementation increases hepatic cytochrome P4502E1 protein and inflammation in alcohol-fed rats. J Nutr. 138:1329-35 (2008).
3. Frautschy, Hu, Kim, et al. Phenolic anti-inflammatory antioxidant reversal of amyloid beta-induced cognitive deficits and neuropathology. Neurobiol Aging. 22:993 – 1005 (2001). In this study, one experiment involved 22 month old Sprague-Dawley female rats; a group of these rats were treated with 500 ppm dietary curcumin, which prevented amyloid beta-infusion induced spatial memory deficits in the Morris Water Maze and post-synaptic density (PSD)-95 loss and reduced amyloid beta deposits.

A UNIQUE CAROTENOID PLAYS AN IMPORTANT ROLE IN THE RADIATION RESISTANCE OF RADIODURANS

Famous Radiation-Resistant Bacterium Relies on Defensive System That Includes Potent Carotenoid

Deinococcus radiodurans, the famously radiation resistant bacterium, is able to tolerate gamma-ray and UV radiation, cold, vacuum, acid, oxidants and desiccation. Versions of it were even produced by genetic engineering to recover radionuclides/heavy metals from nuclear wastes! Radiodurans can survive radiation doses 2,000 times what would fry a human being, and is reportedly even better at resisting radiation than cockroaches. (The bacterium was actually discovered in a batch of irradiated meat.) Radiodurans is even listed as the world’s toughest bacterium in “The Guinness Book of World Records!”^A Here is a bug whose ability to thrive under hostile conditions would be nice to emulate!

Carotenoid Protection Against Protein Oxidation in radiodurans

Substantial Protection by Lycopene as Compared to Deinoxanthin in Chemical Assay

Just for fun, we report here that a study of carotenoids in D. radiodurans¹ found that the bug synthesizes a unique carotenoid, deinoxanthin, as its major carotenoid and that the compound “was shown to protect DNA against damage as it is a more efficient scavenger of H2O2 [hydrogen peroxide] and singlet oxygen than lycopene, beta carotene, and lutein.”¹ At a concentration of 0.05 mmol/liter, deinoxanthin inhibited protein oxidation by 29.7% as compared to 16.8% for lycopene, 14.3% for beta carotene, and 6.59% for lutein. At 0.1 mmol/liter, protein oxidation was inhibited by 45.1% by deinoxanthin, 37.6% by lycopene, 22.7% by lutein, and 50.3% by beta carotene (not significantly different from deinoxanthin).

The numbers above were obtained in an experimental system in which oxidative damage to bovine serum albumin was determined in the presence or absence of carotenoids.¹ As protein oxidation is believed to be an important part of the aging process, preventing this (especially in long-lived proteins) is a desirable part of any longevity regimen. Another paper^1B proposes that it is the oxidation of protein, rather than DNA, that is the principal target of ionizing radiation in bacteria, and resistance to that oxidation is the basis for radioresistance in bugs such as radiodurans.

The authors of another paper² on the properties of deinoxanthin conclude that the ROS-scavenging ability of radiodurans “plays an important role in the radioresistance of D. radiodurans.”

Keeping in mind that D. radiodurans has a lot more in its damage resistance tool kit than just carotenoids and/or ROS-scavenging,³ the numbers above from paper #1 are still pretty impressive. It would be interesting to see what deinoxanthin would do in mammalian cells.

References

A. “Deinococcus radiodurans,” WIKIPEDIA (In their writeup here, it is said that the bug has been nicknamed “Conan the Bacterium.”)
1. Tian, Sun, Shen, et al. Effects of carotenoids from Deinococcus radiodurans on protein oxidation. Lett Appl Microbiol. 49:689-94 (2009).
1B. Daly, Gaidamakova, Matrosova, et al. Protein oxidation implicated as the primary determinant of bacterial radioresistance. PLoS Biol. 5(4):e92 (Apr 2007).
2. Hong-Fang Ji. Insight into the strong antioxidant activity of deinoxanthin, a unique carotenoid in Deinococcus radiodurans. Int J Mol Sci. 11:4506-10 (2010).
3. Slade and Radman. Oxidative stress resistace in Deinococcus radiodurans. Microbiol Mol Biol Rev. 75(1):133-91 (Mar. 2011).

Methods for Reducing the Damage Resulting from a Heart Attack 

Modification of Intestinal Microbiota for the Treatment of Disease: Cardioprotection in Rats Experiencing a Heart Attack

 

With the discovery of the importance of the resident intestinal microbes (microbiota) in the maintenance of normal host physiology, researchers are now beginning to publish work on how modification of the intestinal microbiota can be used to promote improved health or amelioration of disease states. A new (2012) paper¹ is of considerable interest in this regard. The researchers reported that treatment of Dahl S rats with a minimally absorbed antibiotic vancomycin in their drinking water resulted in decreased circulating leptin levels by 38%, 27% smaller myocardial infarcts (death of heart cells as a result of an experimental occlusion of the left anterior descending coronary artery), and improved recovery of postischemic mechanical function (35%) in treated as compared to untreated control rats.

The Dahl S rat “is an established model of increased susceptibility to injury from myocardial ischemia/reperfusion injury.”¹ Vancomycin was used because it is minimally absorbed by the GI tract, and thereby specifically modifies the makeup of the resident intestinal bacteria, without systemic antibiotic effects. Nevertheless, vancomycin administration resulted in a reduction of infarct size despite the absence of the antibiotic in the coronary perfusate at the time of ischemia/reperfusion. This suggests that a direct effect of the antibiotic on the heart is not responsible for the decrease in IS [infarct size].”¹ In fact, the authors reported that, “when administered directly into the coronary circulation, [vancomycin] had no effect on severity of myocardial infarction.”¹ The rats were treated with vancomycin for its effects on the resident intestinal microbes, decreasing the total numbers while altering the abundance of individual groups of the gut microbiota.¹

“The minimum treatment time vancomycin needed to decrease IS was 48 h.”¹ One of the effects of vancomycin was to decrease circulating leptin levels by 38%. Conversely, the researchers found that administration of leptin to the vancomycin treated rats beforeischemia/reperfusion abolished the decrease in IS.

Additional studies were performed by the researchers in which the rats were fed a commercial blend (Goodbelly^®) of two probiotics, Lactobacillus plantarum (Lp299v) and Bifidobacterium lactis (Bi-07) for 14 days before receiving ischemia/reperfusion treatment. This resulted in a 29% decrease in infarct size in the probiotic supplemented rats as compared to the rats subject to the ischemia/reperfusion procedure but without probiotics pretreatment. Treatment with the two probiotics also decreased leptin levels in blood by 41% and, like vancomycin, pretreatment with leptin abolished the cardioprotection by the two probiotics.

The authors explain that leptin is synthesized and secreted into the circulation largely by white adipocytes (fat cells), but that the heart also produces and is responsive to leptin. They suggest that thedata support a model of leptin resistance in the heart in which persistently high levels of leptin desensitizes the heart to leptin signaling. Conversely, reduced levels of leptin in circulation increase the sensitivity of the heart to leptin. They suggest that the probiotics may have a cardioprotective effect by decreasing circulating leptin levels.

Interestingly, the researchers compared the protective effects of vancomycin or probiotics to that of other widely used medical therapies. For example, they noted that the vancomycin resulted in a 27% reduction in IS, while the two probiotics reduced IS by 29%. Early ischemic preconditioning, on the other hand, can cause an 86% reduction in IS, while late ischemic preconditioning can reduce IS by 66%.

Remote preconditioning (where transient periods of nonlethal ischemia and reperfusion, such as can be produced by a short period of on and off by a blood pressure gauge cuff on a limb — see our newsletter of April 2014 for details on this simple, safe procedure) can also provide substantial cardioprotection of 52% reduction in IS.

The protection resulting from vancomycin or the two probiotics was much less than these other methods. However, the authors also noted that the results with these agents are similar to the protection resulting from treatment with erythopoietin (39% reduction in IS) or thrombopoietin (34% reduction in IS). These are encouraging results. Supplementation with the two identified probiotics is likely to be safer and cheaper than the use of an antibiotic drug. It must be remembered that the experimental investigation of probiotics for medical therapy has barely begun.

Reference

1. Lam et al. Intestinal microbiota determine severity of myocardial infarction in rats,” FASEB J. 26:1727-35 (2012).

HERBAL ANTIBIOTICS 
A USEFUL BOOK IN A TIME OF ANTIBIOTIC RESISTANT MICROBES

Recommended Book: Herbal Antibiotics by Stephen Harrod Buhner (foreword by James A. Duke, Ph.D.)

Herbal Antibiotics is a handy book to have around during a time of an increasing incidence of antibiotic-resistant bacteria. It provides information on safe and effective (to one degree or another) antibacterial herbs, including Ashwaghanda (Withania somnifera), Astragalus membranaceus, ginger, garlic, sage, and many others. We were not familiar with the author, but have read considerable work of Dr. James A. Duke, a world-famous expert on herbal medicine. In his foreword, Dr. Duke notes, “[t]he polychemical synergistic mix, concentrating the powers already evolved in medicinal plants, may be our best hope for confronting drug resistant bacteria.”

The book contains preparation for use and dose information, plus contraindications and adverse effects, as well as references to scientific papers. It even includes some recipes for eating the herbal medicines for those herbs that are not too bitter.

STATE NULLIFICATION OF UNCONSTITUTIONAL FEDERAL LAW 
How to Resist Federal Tyranny in the 21st Century 

A Book Review

This book, written by Thomas E. Woods, Jr., Senior Fellow at the Ludwig von Mises Institute (Regnery Publishing, 2010) is a very good introduction to the subject of nullification, a mechanism whereby unconstitutional federal laws are voided by a state within its borders by simply refusing to comply with or enforce them. A contemporary ruling on this issue is New York v. United States,^A decided June 19, 1992, in which the U.S. Supreme Court found that the federal government cannot commandeer the resources or personnel of a state to enforce any federal law within its borders.

Another more recent ruling from the U.S. Supreme Court is Printz v. United States,decided June 27, 1997,^B in which the court ruled that states and county sheriffs could not be required to perform Brady checks on firearms purchases to enforce Federal law.

Though these decisions do not rule that a state can actually nullify a federal law, they clearly uphold the right of a state to withhold any and all of its resources from the enforcement of a federal law within its borders.^A,B As the court put it in New York v. United States (pg. 188): “States are not mere political subdivisions of the United States. State governments are neither regional offices nor administrative agencies of the Federal Government. … The Constitution instead ‘leaves to the several States a residuary and inviolable sovereignty.’ The Federalist No. 39, p. 245 (C. Rossiter ed. 1961), reserved explicitly to the States by the Tenth Amendment.”

“Whatever the outer limit of that sovereignty may be, one thing is clear: The Federal Government may not compel the States to enact or administer a federal regulatory program.”^A

“We held in New York [v. United States] that Congress can not compel the States to enact or enforce a federal regulatory program. Today we hold that Congress cannot circumvent that prohibition by conscripting the States’ officers directly. The Federal Government may neither issue directives requiring the States to address particular problems, nor command the States’ officers, or those of their political subdivisions, to administer or enforce a federal regulatory program.”^B

“… the Federal Government’s authority under the Commerce Clause, which merely allocates to Congress the power ‘to regulate Commerce … among the several States,’ does not extend to the regulation of wholly intrastate point-of-sale transactions. See United States v. Lopez, 514 U.S. 549, 584 (1995) (concurring opinion). Absent the underlying authority to regulate the intrastate transfer of firearms, Congress surely lacks the corollary power to impress state law enforcement officers into administering and enforcing such regulations.” (Thomas, J., concurring, Printz v. United States)

Lest anybody believe that this would not be a severe hindrance to the enforcement of federal law, remember that medical marijuana is still illegal at the federal level, but is legal at the state level in 18 states (as of Dec. 12, 2012), and there is indeed legal state commerce in medical marijuana going on in defiance of the federals.¹ “State exemptions remain enforceable …” and “… are not merely symbolic gestures.”¹ “… the federal government lacks the resources needed to enforce its own ban … Only 1 percent of the roughly 800,000 marijuana cases generated every year are handled by federal authorities.”¹

“Nullification begins with the axiomatic point that a federal law that violates the Constitution is no law at all. It is void and of no effect. Nullification simply pushes this uncontroversial point a step further: … it is up to the states, the parties to the federal compact, to declare it so [unconstitutional] and thus refuse to enforce it.” (pg. 3)

“The central point behind nullification is that the federal government cannot be permitted to hold a monopoly on constitutional interpretation. If the federal government has the exclusive right to judge the extent of its own powers, warned James Madison and Thomas Jefferson in 1798, it will continue to grow — regardless of elections, the separation of powers, and other much touted limits on government power.” Indeed, Jefferson warned William Branch Giles that this was already happening in 1825: “It is but too evident, that the three ruling branches of [the Federal government] are in combination to strip their colleagues, the State authorities, of the powers reserved by them, and to exercise themselves all functions foreign and domestic.”

The Failure of Representative Government

A key problem in a representative government is when a country becomes so large that those at the top become remote from popular control and oversight, so that the government can routinely act in open defiance of public opinion. The book notes that in 1920 (when the population of the U.S. was 90,000,000), the size of the House of Representatives was capped at 435 members. “By 2010 the population was nearly 309 million. That’s one representative per 710,345 people. Had this ratio been observed in 1790, there would have been about four people in the House of Representatives. Were the old ratio observed today, there would be 10,300 members in the House.” What this means is that you, as an individual, are virtually powerless to affect the actions of the federal government through the mechanism of “representation” in the Congress.

There can be no surprise, then, that what passes for rules and regulations these days is totally out of control (follows no lawful process) and that a Constitutional rule of law is perilously close to being no longer in existence. A good example of this is that last year some 72 bills were passed by the Congress and signed into law by the President, while 3,659 regulations were issued (as “regulations”) by regulatory agencies,³ showing how the U.S. has become an administrative state in which Constitutional protections are exceedingly weakened.

These regulations have the force of law and take effect by mere publication in the Federal Register. Article I Section 1 of the U.S. Constitution vests all legislative power in Congress and does NOT authorize its delegation to an Executive Branch administrative agency. The “laws” derived from administrative agencies are NOT voted into law by the House and Senate. Moreover, your Constitutional rights have been severely weakened in relation to administrative law. For example, you have no right to a jury trial, as provided for in the Sixth Amendment, when you are accused of violating an administrative rule, even when you face a year in prison and/or large penalties. Moreover, courts routinely defer to the regulatory agencies’ claimed limits of their own powers, which has resulted in — surprise, surprise — dramatic agency expansion of their jurisdiction far beyond Constitutional limits by self-proclamation with little or no oversight by Congress or the Courts.

We are aware (and so is the book’s author) that nullification is hardly a perfect solution. Any state might have a different interpretation of the Constitution from any other and act accordingly. One has to compare the risks of state nullification to what we have now, which is dangerously out of control federal government self-empowerment. As Thomas Jefferson noted, “I would rather be exposed to the inconveniences attending too much liberty than to those attending too small a degree of it.” (pg. 19) Of course, Jefferson had a very expansive view of liberty, which may not be shared by a large number of other people, some of whom may prefer the inconveniences of too little liberty. That is the basis of the war of all against all that is currently raging in America and destabilizing civil society.

The Understanding of the States Forming the Federal Union Was That It Was a Federal Government of Limited Powers

What Would Today Be Considered Laughable — That the Federal Government Is Limited to Its Delegated Powers — Was Taken Seriously by the Founding Generation

The Kentucky Resolutions of 1798, approved by the Kentucky House and Senate in November 1798, included the following:

“1. Resolved. That the several states composing the United States of America are not united on the principle of unlimited submission to their general government, but that, by compact, under the style and title of a Constitution for the United States, and of amendments thereto, they constituted a general government for special purposes, delegated to that government certain definite powers, reserving, each state to itself, the residuary mass of right to their own self-government, and that whensoever the general government assumes undelegated powers, its acts are unauthoritative, void, and of no force; that to this compact each state acceded as a state, and is an integral party; that this government, created by this compact, was not made the exclusive or final judge of the extent of the powers delegated to itself, since that would have made its discretion, and not the Constitution, the measure of its powers …”

“2. Resolved, That the Constitution of the United States having delegated to Congress a power to punish treason, counterfeiting the securities and current coin of the United States, piracies and felonies committed on the high seas, and offences against the law of nations, and no other crimes, whatsoever, and it being true, as a general principle, and one of the amendments to the Constitution having also declared, that ‘the powers not delegated to the United States by the Constitution, nor prohibited by it to the states, are reserved to the states respectively, or to the people,’ — therefore, also, the same act of Congress, passed on the 14th day of July, 1798, and entitled ‘An Act in Addition to the Act entitled “An Act for the Punishment of Certain Crimes Against the United States” as also the act passed by them on the 27th day of June, 1798, “An Act to Punish Frauds Committed on the Bank of the United States” (and all other their acts which assume to create, define, or punish crimes other than those so enumerated in the Constitution,) are altogether void, and of no force, and that the power to create, define, and punish, such other crimes is reserved, and of right pertains, solely and exclusively, to the respective states, each within its own territory.”

“4. Resolved, That alien friends are under the jurisdiction and protection of the laws of the state wherein they are; that no power over them has been delegated to the United States, nor prohibited to the individual states … the act of the Congress of the United States, passed on the 22d day of July, 1798, entitled ‘An Act Concerning Aliens’ [Alien and Sedition Act], which assumes powers over alien friends not delegated by the Constitution, is not law, but is altogether void and of no force.”

“6. Resolved, … transferring the power of judging any person who is under the protection of the law, from the courts to the President of the United States, as is undertaken by the same act concerning aliens, is against the article of the Constitution which provides, that ‘the judicial power of the United States shall be vested in the courts, the judges of which shall hold their offices during good behavior,’ and that the said act is void for that reason also …”

“9. Resolved, lastly, … that if the acts before specified should stand, these conclusions would flow from them — that the general government may place any act they think proper on the list of crimes, and punish it themselves, whether enumerated or not enumerated by the Constitution as cognizable by them; that they may transfer its cognizance to the President, or any other person, who may himself be the accuser, counsel, judge, and jury, whose suspicions may be the evidence, his order the sentence, his officer the executioner, and his breast the sole record of the transaction … and the barriers of the Constitution thus swept from us all …”

All That Was Foreseen in Resolution #9 Has Come to Pass

It is remarkable, indeed, how all of what was described in resolution #9 has come to pass and is now accepted by most Americans as legitimate powers of the federal government, with “the barriers of the Constitution thus swept from us all.”

Example of Actual State Nullification Occurring in Response to Slavery

On pp. 261 – 263, the book reports the Joint Resolution of the legislature of Wisconsin March 19, 1859, which contained the following:

“And whereas, such assumption of power and authority by the supreme court of the United States, to become the final arbiter of the liberty of the citizen, and to override and nullify the judgments of the state courts’ declaration thereof, is in direct conflict with that provision of the constitution of the United States which secures to the people the benefits of the writ of habeus corpus:

“…

“Therefore, Resolved, That the government formed by the Constitution of the United States was not the exclusive or final judge of the extent of the powers delegated to itself, but that, as in all other cases of compact among parties having no common judge, each party has an equal right to judge for itself, as well of infractions as of the mode and measure of redress.

“…

“… that the several States which formed that instrument, being sovereign and independent, have the unquestionable right to judge of its infractions, and that a positive defiance of those sovereignties, of all unauthorized acts done or attempted to be done under color of that instrument, is the rightful remedy.”

State Nullification of the Fugitive Slave Act of 1850

Shall a man be dragged back to Slavery from our Free Soil, without an open trial of his right to Liberty? 
— Sherman Booth, protesting the seizure of 
a free black man residing in Wisconsin to 
return him to his “master” in St. Louis

Another example of state nullification took place in Wisconsin. During a prolonged legal battle between the state of Wisconsin and the federal government over the attempt of the federals to seize a black man to return him to slavery, the Wisconsin Supreme Court ruled that the Fugitive Slave Act was unconstitutional. The U.S. Supreme Court unanimously overturned the Wisconsin decision. “When the Wisconsin Supreme Court received the request to file the U.S. Supreme Court’s ruling reversing the state court’s decisions and dismissals in the Booth case, it refused. To this day, those mandates have not been filed, and the U.S. Supreme Court’s decision has never been officially recognized by the state of Wisconsin.”²

References

1. New York v. United States, 505 U.S. 144, 188 (1992) (holding that Congress may not order state legislature to enact Federal laws).
   B. Printz v. United States, 521 U.S. 898 (1997).
   1. Robert A. Mikos, Policy Analysis No. 714: “On the limits of federal supremacy: when states relax (or abandon) marijuana bans,” CATO Institute, Dec. 12, 2012.
   2. It is quite a story and well worth reading, if you are interested in state nullification of federal laws. See “Glover, Booth and Paine: Over 150 years of nullification” at the Tenth Amendment Center:
   [http://tenthamendmentcenter.com/2014/04/13/glover-booth-and-paine-over-150-years-of-nullification/].
   3. Wayne Crews, author of the annual report on federal regulation, “Ten Thousand Commandments” (Competitive Enterprise Institute) in the Spring 2014 CEI PLANET (CEI.org).