X-Message-Number: 32184
Date: Sun, 29 Nov 2009 10:47:49 -0800 (PST)
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 choice 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, possibly through HO-1 
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,
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 thiobarbituric 
    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, and 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. biloba 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. 

    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 effects. 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 

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 CT26 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. 
    Immunohistochemistry 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 misincorporated 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 

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 have important roles in deep supercooling of XPCs.
PMID: 18518920

Rate This Message: http://www.cryonet.org/cgi-bin/rate.cgi?msg=32184