CryoNet #32182 - #32184

CryoNet - Mon 30 Nov 2009

    #32182: "What's Really Wrong With Cryonics" [Mark Plus]
    #32183: cryoprotectant toxicity neutralization by quercetin I [oberon]
    #32184: cryoprotectant toxicity neutralization by quercetin II [oberon]

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Message #32182
From: Mark Plus <[email protected]>
Subject: "What's Really Wrong With Cryonics"
Date: Sun, 29 Nov 2009 06:28:01 -0800

http://econlog.econlib.org/archives/2009/11/whats_really_wr.html

NOVEMBER 29, 2009
What's Really Wrong With Cryonics
Bryan Caplan
    


"I don't want to achieve immortality through my work. I want to achieve it through not dying."
                                                          --Woody Allen

One of the most engaging after-lunch conversations of my life was when Robin Hanson sat me down and gave me the cryonics version of the Drake Equation.  The Drake Equation multiplies seven variables together in order to calculate the number of civilizations in our galaxy with which communication is possible.  The Hanson Equation, similarly, multiplies a bunch of factors together in order to calculate how many expected years of life you will gain by signing a contract to freeze your head when you die.

During his presentation, I noticed that Robin spent almost all of his time on various scientific sub-disciplines and the trajectory of their progress.  On these matters, I was fairly willing to defer to his superior knowledge (with the caveat that perhaps his enthusiasm was carrying him away).  What disturbed me was when I realized how low he set his threshold for success.  Robin didn't care about biological survival.  He didn't need his brain implanted in a cloned body.  He just wanted his neurons preserved well enough to "upload himself" into a computer.

To my mind, it was ridiculously easy to prove that "uploading yourself" isn't life extension.  "An upload is merely a simulation.  It wouldn't be you," I remarked.  "It would if the simulation were accurate enough," he told me. 

I thought I had him trapped.  "Suppose we uploaded you while you were still alive.  Are you saying that if someone blew your biological head off with a shotgun, you'd still be alive?!"  Robin didn't even blink: "I'd say that I just got smaller." 

The more I furrowed my brow, the more earnestly he spoke.  "It all depends on what you choose to define as you," he finally declared.  I said: "But that's a circular definition.  Illogical!"  He didn't much care.

Then I attacked him from a different angle.  If I'm whatever I define as me, why bother with cryonics?  Why not "define myself" as my Y-chromosome, or my writings, or the human race, or carbon?  By Robin's standard, all it takes to vastly extend your life is to identify yourself with something highly durable. 

His reply: "There are limits to what you can choose to identify with."  I was dumbstruck at the time.  But now I'd like to ask him, "OK, then why don't you spend more time trying to overcome your limited ability to identify with durable things?  Maybe psychiatric drugs or brain surgery would do the trick."

I'd like to think that Robin's an outlier among cryonics advocates, but in my experience, he's perfectly typical.  Fascination with technology crowds out not just philosophy of mind, but common sense.  My latest cryonics encounter was especially memorable.  When I repeated my standard objections, the advocate flatly replied, "Those aren't interesting questions."  Not interesting questions?!  They're common sense, and they go to the heart of the cryonic dream.

Personally, I'd really like to live forever - in the normal English sense of the phrase "live forever."  I wish cryonics could realistically offer me that.  Unfortunately, the sophistry of its advocates leaves me pessimistic.  If they had a ghost of a chance of giving me what I want, they wouldn't need to twist the English language.
 		 	   		  
_________________________________________________________________
Windows 7: It works the way you want. Learn more.
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Message #32183
Date: Sun, 29 Nov 2009 10:44:51 -0800 (PST)
From: [email protected]
Subject: cryoprotectant toxicity neutralization by quercetin I

[Quercetin eliminates DMSO induced toxicity, and greatly reduces glycerol
or ethanol induced damage. Quercetin also reduces cold storage-induced
renal injury, and possibly reduces ice crystal growth. However good
brain permeation would likely require liposome encapsulation. It is a
mystery why inexpensive quercetin does not see use in cryopreservation
solutions.]

Invest Ophthalmol Vis Sci. 2007 Aug;48(8):3714-8.
Responses of human lens epithelial cells to quercetin and DMSO.
Cao XG, Li XX, Bao YZ, Xing NZ, Chen Y. Department of Ophthalmology, People's Hospital of Peking University, Beijing, Peoples Republic of China.
    PURPOSE: Oxidative stress is an initiating factor in the development of maturity-onset cataract. Diet has a significant impact on cataract development, and individual dietary components responsible for the protective effect include flavonoids, of which quercetin is the most important. The purpose of this study was to investigate the protective effect of quercetin and its toxicity for human lens epithelial cells (HLECs). METHODS: HLECs in culture were incubated for 48 hours with either 1% (vol/vol) dimethyl sulfoxide (DMSO) alone or with this concentration of DMSO and between 0.1 and 100 microM of quercetin. Nonstimulated cells served as control cultures. The viability of HLECs was measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) colorimetric assay. Ge
 ne expression was assessed with reverse transcription-polymerase chain reaction (RT-PCR). Cellular apoptosis was examined by in situ immunocytochemistry using terminal deoxynucleotidyl transferase-mediated biotin-dUTP nicked labeling (TUNEL) and by flow cytometry, using annexin V-FITC apoptosis detection. RESULTS: DMSO (1% vol/vol) decreased cell viability, increased cellular apoptosis, and upregulated Bax in these cells; 0.1 microM quercetin inhibited these effects and protected HLECs from the toxicity of DMSO. Higher concentrations of quercetin the viability of HLECs decreased. In a dose-dependent response to quercetin, cellular apoptosis increased and the change correlated with upregulation of Bax and decreased cell viability. CONCLUSIONS: Quercetin, at a low concentration (0.1 microM
 ), protects HLECs and reverses the toxic effects of DMSO (1% vol/vol). However, at higher concentrations, quercetin is toxic to HLECs with an LD(50) of 90.85 microM. Quercetin induced apoptosis and upregulates apoptotic genes in HLECs in a dose-dependent manner.
PMID: 17652743

Brain Res. 1998 Jun 1;794(2):304-8.
Dimethyl sulfoxide, but not acidosis-induced metallothionein mRNA expression in neonatal rat primary astrocyte cultures is inhibited by the bioflavonoid, quercetin.
Conklin DR, Tan KH, Aschner M. Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
    Metallothionein (MT) mRNA levels were analyzed following exposure of neonatal rat primary astrocyte cultures to physiologic pH (7.4), acidosis (pH 6.5 and 6.0), and dimethyl sulfoxide (DMSO). Treatments were carried out both in the presence and absence of the bioflavonoid, quercetin. Total RNA was probed on northern blots with [alpha32P]dCTP-labeled synthetic cDNA probes specific for rat MT isoform mRNAs. MT-I and MT-II mRNA levels in astrocytes exposed to pH 6.5 or pH 6.0 were increased compared to controls (pH 7.4). Treatment with DMSO in the presence and absence of acidosis, also increased MT-I and MT-II mRNA levels compared to controls (pH 7.4). The DMSO-induced increase in MT mRNA expression was reversed by treatment of astrocytes with quercetin, such that MT-I and MT-II mRNA leve
 ls in DMSO plus quercetin-treated astrocytes were indistinguishable from mRNA levels in their respective controls at pH 7.4, pH 6.5, and pH 6.0. These findings suggest that both acidosis and DMSO exposure are associated with increased astrocytic MT synthesis at the mRNA level, and that quercetin, effectively blocks MT mRNA induction by DMSO. Copyright 1998 Elsevier Science B. V. All rights reserved.
PMID: 9622659

Pharmacology. 2005 Jan;73(1):49-56. Epub 2004 Sep 27.
Reversal of experimental myoglobinuric acute renal failure in rats by quercetin, a bioflavonoid.
Chander V, Singh D, Chopra K. Division of Pharmacology, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India.
    The occurrence of acute renal failure (ARF) following rhabdomyolysis has been put at between 10 and 40% of cases, and accounts for between 3 and 15% of all cases of ARF. Reactive oxygen intermediates have been demonstrated to play an etiological role in myoglobinuric renal failure. This study was performed to explore the protective effect of quercetin, a bioflavonoid, in an experimental model of myoglobinuric ARF in rats. Four groups of rats were employed in this study: group 1 served as control, group 2 was given 50% glycerol (8 ml/kg, i.m.), group 3 was given glycerol + quercetin (2 mg/kg, i.p.), and group 4 was given glycerol + DMSO (the solvent for quercetin, 5 ml/kg, i.p.). Renal injury was assessed by measuring serum creatinine, blood urea nitrogen, creatinine and urea clearance.
  The oxidative stress was measured by renal malondialdehyde levels, reduced glutathione levels and by enzymatic activity of catalase, glutathione reductase, and superoxide dismutase. Glycerol administration resulted in a marked renal oxidative stress, significantly deranged the renal functions as well as renal cytoarchitecture. All these factors were significantly improved by quercetin treatment. Because of its radical-scavenging and iron-chelating properties, quercetin protected the kidney against the glycerol-induced oxidative stress and resultant renal dysfunction. Based on these results, this study confirms the role of oxidative stress and demonstrates the renoprotective potential of quercetin in this rhabdomyolysis-mimicking model. 2005 S. Karger AG, Basel.
PMID: 15452363

Am J Physiol Gastrointest Liver Physiol. 2009 Jun;296(6):G1318-23. Epub 2009 Mar 26.
The protective role of HO-1 and its generated products (CO, bilirubin, and Fe) in ethanol-induced human hepatocyte damage.
Yao P, Hao L, Nussler N, Lehmann A, Song F, Zhao J, Neuhaus P, Liu L, Nussler A. Universitatsmedizin Berlin, Charite, Campus Virchow, Department of General, Visceral, and Transplantation Surgery, Berlin, Germany.
    It has been reported that naturally occurring quercetin exerts hepatoprotective effects through heme oxygenase-1 (HO-1) induction. However, the precise mechanism of how ethanol-associated liver damage is counteracted by quercetin-enhanced HO-1 metabolism still remains unclear. To further decipher the protective role of quercetin on ethanol-induced liver damage, we treated human hepatocytes with quercetin and various (end) products of the HO-1 pathway. Our data clearly showed that quercetin treatment attenuated ethanol-induced damage, whereas hemoglobin and zinc protoporphyrin 9 (ZnPP) abolished such effects. Iron-II aggravated ethanol toxicity and was only partially reduced by quercetin. In contrast, carbon monoxide (CO) dose dependently inhibited ethanol-induced cytochrome P450 2E1 (C
 YP 2E1) activity and hepatotoxicity but had no influence on CYP 2E1 protein expression. Similarly, hemoglobin dramatically stimulated CYP 2E1 activity but not the protein expression in quercetin- and ethanol-cotreated hepatocytes. ZnPP significantly promoted CYP 2E1 protein expression in the presence and absence of CO treatment but inhibited ethanol-induced CYP 2E1 activation following CO incubation in quercetin- and ethanol-cotreated hepatocytes. These results suggested that quercetin virtually attenuated ethanol-derived oxidative damage via HO-1 induction. Heme degradation and CO release may mediate the protective effects through inhibiting ethanol-induced CYP 2E1 synthesis and enzymatic activity, respectively.
PMID: 19325051

World J Gastroenterol. 2008 May 28;14(20):3242-8.
Effects of quercetin on hyper-proliferation of gastric mucosal cells in rats treated with chronic oral ethanol through the reactive oxygen species-nitric oxide pathway.
Liu JL, Du J, Fan LL, Liu XY, Gu L, Ge YB. Department of Physiology, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China.
    AIM: To investigate the effect of quercetin (3,3',4',5,7-pentahydroxy flavone), a major flavonoid in human diet, on hyper-proliferation of gastric mucosal cells in rats treated with chronic oral ethanol. METHODS: Forty male Sprague-Dawley rats, weighing 200-250 g, were randomly divided into control group (tap water ad libitum), ethanol treatment group (6 mL/L ethanol), quercetin treatment group (intragastric gavage with 100 mg/kg of quercetin per day), and ethanol plus quercetin treatment group (quercetin and 6 mL/L ethanol). Expression levels of proliferating cell nuclear antigen (PCNA) and Cyclin D1 were detected by Western blot to assay gastric mucosal cell proliferation in rats. To demonstrate the influence of quercetin on the production of extra-cellular reactive oxygen species/ni
 trogen species (ROS/RNS) in rats, changes in levels of thiobarbituric acid reactive substance (TBARS), protein carbonyl, nitrite and nitrate (NOx) and nitrotyrosine (NT) were determined. The activity of inducible nitric oxide synthase (NOS) including iNOS and nNOS was also detected by Western blot. RESULTS: Compared to control animals, cell proliferation in the gastric mucosa of animals subjected to ethanol treatment for 7 days was significant increased (increased to 290% for PCNA density P < 0.05, increased to 150 for Cyclin D1 density P < 0.05 and 21.6 +/- 0.8 vs 42.3 +/- 0.7 for PCNA positive cells per view field), accompanied by an increase in ROS generation (1.298 +/- 0.135 micromol vs 1.772 +/- 0.078 micromol for TBARS P < 0.05; 4.36 +/- 0.39 mmol vs 7.48 +/- 0.40 mmol for carbonyl
  contents P < 0.05) and decrease in NO generation (11.334 +/- 0.467 micromol vs 7.978 +/- 0.334 micromol P < 0.01 for NOx; 8.986 +/- 1.351 micromol vs 6.854 +/- 0.460 micromol for nitrotyrosine P < 0.01) and nNOS activity (decreased to 43% P<0.05). This function was abolished by the co-administration of quercetin. CONCLUSION: The antioxidant action of quercetin relies, in part, on its ability to stimulate nNOS and enhance production of NO that would interact with endogenously produced reactive oxygen to inhibit hyper-proliferation of gastric mucosal cells in rats treated with chronic oral ethanol.
PMID: 18506933

Biol Pharm Bull. 2003 Oct;26(10):1398-402.
Quercetin, a flavonoid antioxidant, prevents and protects against ethanol-induced oxidative stress in mouse liver.
Molina MF, Sanchez-Reus I, Iglesias I, Benedi J. Department of Pharmacology, Faculty of Pharmacy, UCM, Madrid, Spain.
    This study evaluates whether quercetin (25, 50 and 75 mg/kg body weight) treatment has a protective effect on the pro-oxidant-antioxidant state following chronic ethanol treatment in mice. Pretreatment (quercetin 25, 50 and 75 mg/kg body weight for 15 d+co-treatment of ethanol 18%+quercetin for 15 d and ethanol 18% for the 15 d) increased the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione (GSH) in comparison to the ethanol group. No significant differences from the ethanol group were observed in the group after post-treatment (ethanol 18% for 30 d+quercetin 25, 50 and 75 mg/kg body weight for 15 d) with quercetin. A significant increase in lipid peroxidation (malondialdehyde, MDA) products was observed
  in liver tissue after administration of ethanol, which was attenuated by pre- and post-treatment with a high dose of quercetin. GSH levels increased and oxidized glutathione (GSSG) levels decreased in groups of ethanol-exposed mice that received quercetin for 15 d prior to ethanol exposure. In conclusion, pre-treatment of quercetin may protect against ethanol-induced oxidative stress by directly quenching lipid peroxides and indirectly by enhancing the production of the endogenous antioxidant GSH. There was no protective effect on post-treatment with quercetin.
PMID: 14519943

Arch Toxicol. 2005 Jan;79(1):25-30. Epub 2004 Nov 4.
Oxidation of ethanol to acetaldehyde and free radicals by rat testicular microsomes.
Quintans LN, Castro GD, Castro JA. Centro de Investigaciones Toxicologicas (CEITOX) - CITEFA/CONICET, J.B. de La Salle 4397, B1603ALO Villa Martelli, Buenos Aires, Argentina.
    A large number of epidemiological studies evidencing that excessive alcohol consumption is associated with impaired testosterone production and testicular atrophy are available in the literature. One hypothesis to explain the deleterious action of alcohol involves the in situ biotransformation to acetaldehyde, but it strongly suggests the need to learn more about the enzymatic processes governing alcohol metabolism to acetaldehyde in different cellular fractions since limited information is available in the literature. In this article we report studies on the metabolic conversion of alcohol to acetaldehyde and to 1-hydroxyethyl radicals in rat testicular microsomal fractions. The oxidation of ethanol to acetaldehyde in rat testes microsomal fraction was mostly of enzymatic nature and s
 trongly dependent on the presence of NADPH and oxygen. Several compounds were able to significantly decrease the production of acetaldehyde: SKF 525A; diethyldithiocarbamate; esculetin; gossypol; curcumin; quercetin; dapsone; and diphenyleneiodonium. Microsomal preparations in the presence of NADPH were also able to produce both hydroxyl and 1-hydroxyethyl free radicals. Their generation was modulated by the presence of diphenyleneiodonium, gossypol, and deferoxamine. Results show that rat microsomal fractions are able to metabolize alcohol to deleterious chemicals, such as acetaldehyde and free radicals, that may be involved in ethanol toxic effects. Enzymes involved could include CYP2E1, P450 reductase, and other enzymes having lipoxygenase- /peroxidase-like behavior.
PMID: 15526191

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Message #32184
Date: Sun, 29 Nov 2009 10:47:49 -0800 (PST)
From: [email protected]
Subject: cryoprotectant toxicity neutralization by quercetin II

Transplantation. 2005 Dec 15;80(11):1556-9.
Beneficial effects of the bioflavonoids curcumin and quercetin on early function in cadaveric renal transplantation: a randomized placebo controlled trial.
Shoskes D, Lapierre C, Cruz-Correa M, Muruve N, Rosario R, Fromkin B, Braun M, Copley J. Department of Kidney Transplantation, Cleveland Clinic Florida, Weston, FL, USA.  Erratum in:  Transplantation. 2006 Sep 15;82(5):715. Cruz-Corerra, Marcia [corrected to Cruz-Correa, Marcia].
    BACKGROUND: The bioflavonoids quercetin and curcumin are renoprotective natural antioxidants. We wished to examine their effects on early graft function (EF). METHODS: Between September 2002 and August 2004, 43 dialysis dependent cadaveric kidney recipients were enrolled into a study using Oxy-Q which contains 480 mg of curcumin and 20 mg of quercetin, started after surgery and taken for 1 month. They were randomized into three groups: control (placebo), low dose (one capsule, one placebo) and high dose (two capsules). Delayed graft function (DGF) was defined as first week dialysis need and slow function (SGF) as Cr >2.5 mg/dl by day 10. Category variables were compared by chi squared and continuous variables by Kruskal-Wallis. RESULTS: There were four withdrawals: one by patient choic
 e and three for urine leak. The control group had 2/14 patients with DGF vs. none in either treatment group. Incidence of EF was control 43%, low dose 71% and high dose 93% (P=0.013). Serum creatinine was significantly lower at 2 days (control 7.6+/-2.1, low 5.4+/-0.6, high 3.96+/-.35 P=0.0001) and 30 days (control 1.82+/-.16, low 1.65+/-.09, high 1.33 +/-.1, P=0.03). Acute rejection incidence within 6 months was control 14.3%, low dose 14.3% and high dose 0%. Tremor was detected in 13% of high dose patients vs. 46% of others. Urinary HO-1 was higher in bioflavonoid groups. CONCLUSION: Bioflavonoid therapy improved early graft function. Acute rejection and neurotoxicity were lowest in the high dose group. These bioflavonoids improve early outcomes in cadaveric renal transplantation, poss
 ibly through HO-1 induction.
PMID: 16371925

Transplant Proc. 2001 Sep;33(6):2988.
Quercetin and curcumin up-regulate antioxidant gene expression in rat kidney after ureteral obstruction or ischemia/reperfusion injury.
Shahed AR, Jones E, Shoskes D. Harbor-UCLA Medical Center, Torrance, California, USA.
PMID: 11543823

Transplantation. 2006 Jan 27;81(2):231-9.
Improved cold preservation of kidney tubular cells by means of adding bioflavonoids to organ preservation solutions.
Ahlenstiel T, Burkhardt G, Kohler H, Kuhlmann MK. Department of Medicine, Division of Nephrology and Hypertension, University Hospital of Saarland, Homburg/Saar, Germany.
    BACKGROUND: Cold ischemia and reperfusion during renal transplantation result in release of reactive oxygen species. The aim of this study is to examine whether cold storage induced cell injury can be ameliorated by adding flavonoids directly to preservation solutions. METHODS: Cultured renal tubular epithelial cells (LLC-PK1) were stored in University of Wisconsin (UW) or Euro-Collins (EC) solution at 4 degrees C for 20 hours. Preservation solutions were supplemented with various flavonoids. After rewarming, structural and metabolic cell integrity was measured by lactate dehydrogenase (LDH) release and MTT-test, and lipid peroxidation was assessed from generation of thiobarbituric acid-reactive substances (TBARS). RESULTS: Twenty hours of cold storage resulted in a substantial loss of
  cell viability in both preservation solutions (in EC: LDH release 92.4+/-2.7%; MTT-test 0.5+/-0.7%). Addition of luteolin, quercetin, kempferol, fisetin, myricetin, morin, catechin, and silibinin significantly reduced cell injury (for luteolin in EC: LDH release 2.4+/-1.6%; MTT-test 110.3+/-10.4%, P<0.01; TBARS-production (related to cold stored control cells) 8.9+/-2.6%). No cytoprotection was found for apigenin, naringenin, and rutin. Protective potency of flavonoids depends on number of hydroxyl-substituents and lipophilicity of the diphenylpyran compounds. CONCLUSION: Cold storage induced injury of renal tubular cells was substantially ameliorated by adding selected flavonoids directly to preservation solutions.
PMID: 16436967

Kidney Int. 2003 Feb;63(2):554-63.
Bioflavonoids attenuate renal proximal tubular cell injury during cold preservation in Euro-Collins and University of Wisconsin solutions.
Ahlenstiel T, Burkhardt G, Kohler H, Kuhlmann MK. Department of Medicine, Division of Nephrology and Hypertension, University Hospital of Saarland, Homburg/Saar, Germany.
    BACKGROUND: Cold ischemia and reperfusion during kidney transplantation are associated with release of free oxygen radicals and damage of renal tubular cells. Bioflavonoids may diminish cold storage-induced injury due to antioxidant and iron chelating activities. This study was designed to delineate the renoprotective mechanisms of bioflavonoids and to define the structural features conferring cytoprotection from cold injury. METHODS: LLC-PK1 cells were preincubated for three hours with bioflavonoids and cold stored in University of Wisconsin (UW)- or Euro-Collins (EC)-solution for 20 hours. After rewarming, cell viability was assessed by the lactate dehydrogenase (LDH) release, MTT-test, and amino acid transport activity. Lipid peroxidation was assessed from the generation of thiobarb
 ituric acid-reactive substances. RESULTS: Twenty-hours of cold storage of LLC-PK1 cells resulted in a substantial loss of cell integrity that was more pronounced in the EC (LDH release, 93.6 +/- 1.6%) than the UW solution (67.2 +/- 6.9%; P < 0.0001). Pretreatment with quercetin significantly enhanced cell survival (LDH release, 5.4 +/- 2.7% for UW and 8.4 +/- 4.2% for EC) in a concentration dependent manner. Structure-activity studies revealed similar renoprotection for kaempferol, luteolin and fisetin, unlike myricetin, morin, apigenin, naringenin, catechin, silibinin and rutin. Lipid peroxidation was reduced (UW alone, 2.7 +/- 1.2 vs. UW+quercetin 0.5 +/- 0.2 nmol/mg protein, P < 0.01), and l-threonine uptake completely sustained by pretreatment with quercetin, kaempferol, luteolin, an
 d fisetin. However, renoprotection by fisetin was rapidly lost during rewarming. Protective properties of bioflavonoids were governed by the number and arrangement of hydroxyl substitutes, electron-delocalization, sterical planarity, and lipophilicity of the basic diphenylpyran skeleton. CONCLUSION: Cold storage-induced renal tubular cell injury is ameliorated by bioflavonoids. Renoprotective effects of bioflavonoids are defined by structure, suggesting that flavonoids are incorporated into membrane lipid bilayers and interfere with membrane lipid peroxidation.
PMID: 12631120

Skin Pharmacol Physiol. 2009 Sep 25;22(6):299-304. [Epub ahead of print]
Skin Penetration of Epigallocatechin-3-Gallate and Quercetin from Green Tea and Ginkgo biloba Extracts Vehiculated in Cosmetic Formulations.
Dal Belo SE, Gaspar LR, Maia Campos PM, Marty JP. Faculdade de Ciencias Farmaceuticas de Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil.
    Green tea (Camellia sinensis) and Ginkgo biloba extracts in cosmetic formulations have been suggested to protect the skin against UV-induced damage and skin ageing. Thus, it is very important to assess the human skin penetration of their major flavonoids to verify if they penetrate and remain in the skin to exert their proposed effects. The aim of this study was to evaluate the human skin penetration of epigallocatechin-3-gallate (EGCG) and quercetin from green tea and G. biloba extracts vehiculated in cosmetic formulations. This study was conducted with fresh dermatomed human Caucasian skin from abdominal surgery mounted on static Franz diffusion cells. Skin samples were mounted between two diffusion half-cells and 10 mg/cm(2) of formulations supplemented with 6% of green tea or G. bi
 loba extract were applied on the skin surface. The receptor fluid was removed after 6 and 24 h and analyzed by high-performance liquid chromatography for the quantification of the flavonoids. The stratum corneum was removed by tape stripping and immersed in methanol and the epidermis was mechanically separated from the dermis and triturated in methanol to extract EGCG and quercetin. The results showed that the flavonoids under study penetrated into the skin, without reaching the receptor fluid. The majority of EGCG was quantified in the stratum corneum (0.87 mug/cm(2)), which was statistically higher than the EGCG concentrations found in viable epidermis (0.54 mug/cm(2)) and in the dermis (0.38 mug/cm(2)). The majority of quercetin was quantified in the viable epidermis (0.23 mug/cm(2)),
  which was statistically higher than the EGCG concentration found in the stratum corneum layer (0.17 mug/cm(2)). Finally, it can be concluded that EGCG and quercetin from green tea and G. biloba extracts vehiculated in cosmetic formulations presented good skin penetration and retention, which can favor their skin effects. Copyright C 2009 S. Karger AG, Basel.
PMID: 19786823

Nanomedicine. 2008 Mar;4(1):70-8. Epub 2008 Jan 30.
Anxiety and cognitive effects of quercetin liposomes in rats.
Priprem A, Watanatorn J, Sutthiparinyanont S, Phachonpai W, Muchimapura S. Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen, Thailand. [email protected]
    Quercetin, an effective flavonol used as an antioxidant, was investigated for its anxiolytic and cognitive activities in male Wistar rats. Oral quercetin (300 mg/kg body weight/day) was compared with oral and intranasal quercetin liposomes (20 microg/day). Quercetin liposomes, in a mixture of egg phosphatidylcholine, cholesterol, and quercetin (2:1:1) and dispersed in 50% polyethylene glycol in water, were approximately 200 nm in mean particle diameter and negative surface charge with a range of encapsulation efficiency of 60% to 80%. Anxiolytic and cognitive-enhancing effects of quercetin, conventional and liposomal, were subjected to elevated plus maze and Morris water maze tests, respectively. Both conventional and quercetin liposomes showed anxiolytic and cognitive-enhancing effect
 s. A lower dose and a faster rate were observed with intranasal quercetin liposomes when compared with oral quercetin, conventional and liposomal. The intranasal quercetin liposomes are effective in the delivery of quercetin to the central nervous system.
PMID: 18249157

Clin Cancer Res. 2006 May 15;12(10):3193-9.
Liposomal quercetin efficiently suppresses growth of solid tumors in murine models.
Yuan ZP, Chen LJ, Fan LY, Tang MH, Yang GL, Yang HS, Du XB, Wang GQ, Yao WX, Zhao QM, Ye B, Wang R, Diao P, Zhang W, Wu HB, Zhao X, Wei YQ. State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, People's Republic of China.
    PURPOSE: Quercetin is a potent chemotherapeutic drug. Clinical trials exploring different schedules of administration of quercetin have been hampered by its extreme water insolubility. To overcome this limitation, this study is aimed to develop liposomal quercetin and investigate its distribution in vivo and antitumor efficacy in vivo and in vitro. EXPERIMENTAL DESIGN: Quercetin was encapsulated in polyethylene glycol 4000 liposomes. Biodistribution of liposomal quercetin i.v. at 50 mg/kg in tumor-bearing mice was detected by high-performance liquid chromatography. Induction of apoptosis by liposomal quercetin in vitro was tested. The antitumor activity of liposomal quercetin was evaluated in the immunocompetent C57BL/6N mice bearing LL/2 Lewis lung cancer and in BALB/c mice bearing CT
 26 colon adenocarcinoma and H22 hepatoma. Tumor volume and survival time were observed. The mechanisms underlying the antitumor effect of quercetin in vivo was investigated by detecting the microvessel density, apoptosis, and heat shock protein 70 expression in tumor tissues. RESULTS: Liposomal quercetin could be dissolved in i.v. injection and effectively accumulate in tumor tissues. The half-time of liposomal quercetin was 2 hours in plasma. The liposomal quercetin induced apoptosis in vitro and significantly inhibited tumor growth in vivo in a dose-dependent manner. The optimal dose of liposomal quercetin resulted in a 40-day survival rate of 40%. Quantitative real-time PCR showed that liposomal quercetin down-regulated the expression of heat shock protein 70 in tumor tissues. Immunoh
 istochemistry analysis showed that liposomal quercetin inhibited tumor angiogenesis as assessed by CD31 and induced tumor cell apoptosis. CONCLUSIONS: Our data indicated that pegylated liposomal quercetin can significantly improve the solubility and bioavailability of quercetin and can be a potential application in the treatment of tumor.
PMID: 16707620

[Quercetin -mediated cytoprotection is apparently maintained indefinitely in frozen cells.]

Mutagenesis. 2002 May;17(3):211-4.
Cryopreserved versus freshly isolated lymphocytes in human biomonitoring: endogenous and induced DNA damage, antioxidant status and repair capability.
Duthie SJ, Pirie L, Jenkinson AM, Narayanan S. Rowett Research Institute, Greenburn Road, Bucksburn, Aberdeen AB21 9SB, UK.
    Lymphocytes are routinely used in human biomonitoring to assess the potential toxic and cytoprotective effects of diet on both DNA damage and repair and, by implication, health. Logistically, samples may require to be cryopreserved and stored. How this affects cells used in human biomonitoring is often not considered. In this study we have evaluated the influence of cryopreservation on endogenous and induced DNA strand breakage, altered bases (oxidized purines, oxidized pyrimidines and misincorporated uracil), antioxidant capacity and DNA repair capability in human peripheral blood lymphocytes. Neither isolation nor freezing increased DNA strand breakage above endogenous levels found in freshly isolated human lymphocytes. Oxidized bases (both pyrimidines and purines) and misincorporate
 d uracil, were similar for fresh and frozen lymphocytes. Fresh and frozen lymphocytes responded almost identically to hydrogen peroxide. Quercetin-mediated cytoprotection against hydrogen peroxide-induced strand breakage was maintained in cryopreserved lymphocytes after short-term (24 h) and longer term (2 months) storage compared with freshly isolated and treated cells. Hydrogen peroxide-induced DNA strand breakage was repaired in fresh lymphocytes. Cryopreserved lymphocytes were unable to repair oxidant-induced DNA strand breaks. Frozen human lymphocytes can therefore be successfully used for most aspects of DNA damage biomonitoring, but not for repair.
PMID: 11971991

Plant Cell Environ. 2008 Sep;31(9):1335-48. Epub 2008 Jun 3.
Deep supercooling xylem parenchyma cells of katsura tree (Cercidiphyllum japonicum) contain flavonol glycosides exhibiting high anti-ice nucleation activity.
Kasuga J, Hashidoko Y, Nishioka A, Yoshiba M, Arakawa K, Fujikawa S. Research Faculty and Graduate School of Agriculture, Hokkaido University, Sapporo, Japan.
    Xylem parenchyma cells (XPCs) of boreal hardwood species adapt to sub-freezing temperatures by deep supercooling to maintain a liquid state of intracellular water near -40 degrees C. Our previous study found that crude xylem extracts from such tree species exhibited anti-ice nucleation activity to promote supercooling of water. In the present study, thus, we attempted to identify the causative substances of supercooling. Crude xylem extracts from katsura tree (Cercidiphyllum japonicum), of which XPCs exhibited deep supercooling to -40 degrees C, were prepared by methanol extraction. The crude extracts were purified by liquid-liquid extraction and then by silica gel column chromatography. Although all the fractions obtained after each purification step exhibited some levels of anti-ice 
 nucleation activity, only the most active fraction was retained to proceed to the subsequent level of purification. High-performance liquid chromatography (HPLC) analysis of a fraction with the highest level of activity revealed four peaks with high levels of anti-ice nucleation activity in the range of 2.8-9.0 degrees C. Ultraviolet (UV), mass and nuclear magnetic resonance (NMR) spectra revealed that these four peaks corresponded to quercetin-3-O-beta-glucoside (Q3G), kaempferol-7-O-beta-glucoside (K7G), 8-methoxykaempferol-3-O-beta-glucoside (8MK3G) and kaempferol-3-O-beta-glucoside (K3G). Microscopic observations confirmed the presence of flavonoids in cytoplasms of XPCs. These results suggest that diverse kinds of anti-ice nucleation substances, including flavonol glycosides, may ha
 ve important roles in deep supercooling of XPCs.
PMID: 18518920

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