X-Message-Number: 32923
Date: Mon, 11 Oct 2010 06:40:36 -0700 (PDT)
From: 
Subject: silymarin may prove to be an effective antiaging drug


[While Rapamycin extends rodent lifespan, rodents do not age the same way humans
do. Unlike rodents, human aging is characterized by significantly shortened 
telomeres, which rapamycin can shorten even more. In contrast, silymarin 
increases telomerase activity in EPCs, while lowering it in cancer cells. 
Silymarin might prove to be an effective anti-aging drug in humans, by 
selectively modulating telomerase.]

J Cardiovasc Pharmacol. 2010 Aug 31. [Epub ahead of print]

Silymarin Inhibits Endothelial Progenitor Cells Senescence and Protects Against 
the Antiproliferative Activity of Rapamycin. Preliminary Study. Parzonko A, 
Naruszewicz M. Department of Pharmacognosy and Molecular Basis of Phytotherapy, 
Medical University of Warsaw, Poland.
Abstract

    Rapamycin, an antiproliferative agent used on drug-eluting stents, induces 
    endothelial progenitor cells senescence through telomerase inactivation, and
    may impair the re-endothelisation of an injured arterial wall, leading to 
    thrombosis. We examined whether silymarin, a complex of flavonolignans with 
    hepatoprotective and antioxidative properties, can protect EPCs against 
    rapamycin-induced senescence. Mononuclear cells were isolated from 
    peripheral blood of healthy volunteers. EPCs were cultured in endothelial 
    cell growth medium-2 in the presence or absence of rapamycin (0.1 ng/mL) 
    and/or silymarin (12.5 to 50 I g/mL). EPCs senescence associated I 
    -galactosidase activity, telomerase activity and prolifertive activity were 
    measured. The influence on tubular-like structure formation in vitro was 
    investigated and colony forming assay on methylcellulose plates was 
    performed. Silymarin increased telomerase activity threefold, reduced the 
    number of senescent cells and increased EPC proliferative activity (up to 
    64%) in comparison with cells cultured with rapamycin alone. Moreover, 
    silymarin partially prevented impairment of tubular-like structure formation
    in Matrigel by rapamycin. These findings suggests, that silymarin 
    counteracts the inhibitory effects of rapamycin in EPCs. Silymarin may 
    protect EPCs against the anti-proliferative effects of rapamycin and restore
    their reconstructive ability.
PMID: 20838231

Iran J Immunol. 2009 Mar;6(1):33-9.

The influence of iron loading and iron chelation on the proliferation and 
telomerase activity of human peripheral blood mononuclear cells.

Bagherpour B, Gharagozloo M, Moayedi B. Department of Immunology, School of 
Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
Abstract

BACKGROUND: Iron is an essential trace element in cell proliferation. Several 
investigations demonstrate that iron deprivation inhibits cell proliferation. 
However, the impact of iron on telomerase activity of activated lymphocytes 
remains unexplained to date.

OBJECTIVE: In this study, the effect of iron on the proliferation and telomerase
activity of lymphocytes stimulated by phytohemagglutinin (PHA) were 
investigated.

METHODS: Iron loading was performed by incubating peripheral blood mononuclear 
cells in 500microM FeSO4.7H2O for 24 h and iron chelation was done by exposing 
cells to desferrioxamine, a potent iron chelator. The effects of silymarin, a 
flavonoid with both antioxidant and iron chelating activities, on the 
proliferation and telomerase activity of PHA-activated lymphocytes were also 
compared with desferrioxamine. Proliferation and telomerase activity were 
assessed using BrdU incorporation assay and Telomeric Repeat Amplification 
Protocol (TRAP), respectively.

RESULTS: The proliferations of lymphocytes were significantly inhibited by 10 
and 20 microg/ml desferrioxamine in a dose dependent manner, while iron loading 
recovered suppressed cell proliferation to the normal level. Silymarin at 20 
microg/ml significantly increased the proliferation of lymphocytes in both 
normal and iron-treated conditions. Telomerase activity of lymphocytes was 
markedly increased by iron treatment and suppressed by desferrioxamine. 
Conversely, iron treatment had no effect on the telomerase activity of 
lymphocytes incubated with silymarin.

CONCLUSION: Iron plays a significant role in the proliferation and telomerase 
activity of lymphocytes. The effects of silymarin on the proliferation and 
telomerase activity of lymphocytes were completely different from those of 
desferrioxamine, suggesting that the immunomodulatory effect of silymarin is 
probably not associated with its iron chelating activity.
PMID: 19293476


[Activating telomerase in cancer cells, could be expected to increase cancer 
mortality. Fortunately silibinin, which is the active main ingredient in 
silymarin, actually lowers telomerase activity in cancer cells.]

J Urol. 2004 May;171(5):1934-8.

Inhibition of telomerase activity and secretion of prostate specific antigen by 
silibinin in prostate cancer cells.

Thelen P, Wuttke W, Jarry H, Grzmil M, Ringert RH. Department of Urology, 
Institute of Human Genetics, Georg-August-University, GA ttingen, Germany.
Abstract

PURPOSE: The androgen sensitive prostate cancer cell line LNCaP is strongly 
positive for dihydrotestosterone (DHT) dependent telomerase activity, which is 
an important factor in cellular immortality and carcinogenesis. In this study we
determined the potential of silibinin as an anticancer drug that down-regulates
telomerase activity and prostate specific antigen (PSA) together with the 
co-activator of the androgen receptor prostate epithelium specific Ets 
transcription factor.

MATERIALS AND METHODS: LNCaP cells were treated with various concentrations of 
silibinin in the presence or absence of 5alpha-DHT. We used real-time reverse 
transcriptase-polymerase chain reaction to quantify mRNA expression of PSA, 
prostate epithelium specific Ets transcription factor and the catalytic subunit 
of telomerase vs the housekeeping gene porphobilinogen deaminase with gene 
specific, dual labeled fluorescence probes. PSA secretion from LNCaP cells in 
conditioned medium was measured with an Elecsys System 2010 (Roche Diagnostics, 
Mannheim, Germany) and telomerase activity in extracts from LNCaP cells was 
measured with a TRAP (telomeric repeat amplification protocol) assay.

RESULTS: Silibinin down-regulated PSA mRNA expression and PSA secretion in 
conditioned medium. Simultaneous stimulation with silibinin and 10(-8) M DHT 
also resulted in PSA down-regulation, whereas DHT alone increased PSA secretion.
Telomerase catalytic subunit mRNA decreased significantly after silibinin 
stimulation. Telomerase activity was down-regulated by silibinin and stimulated 
by DHT. The 2 agents in combination resulted in telomerase down-regulation.

CONCLUSIONS: The down-regulation of PSA by silibinin and its counteraction on 
DHT effects indicate that this compound can interact with the expression of 
genes that are regulated through the androgen receptor. Silibinin can also 
inhibit the telomerase activity that mediates cell immortality and 
carcinogenesis. The 2 effects underline the possible therapeutic use of 
silibinin as an antiproliferative agent in intervention for prostate cancer.
PMID: 15076315


[Silymarin may offer additional benefits against some of the diseases associated
with human aging.]

Br J Pharmacol. 2009 Aug;157(7):1270-7. Epub 2009 Jun 22.

Silibinin prevents amyloid beta peptide-induced memory impairment and oxidative 
stress in mice.

Lu P, Mamiya T, Lu LL, Mouri A, Zou L, Nagai T, Hiramatsu M, Ikejima T, 
Nabeshima T. Department of Chemical Pharmacology, Graduate School of 
Pharmaceutical Sciences, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya, 
Japan.
Abstract

BACKGROUND AND PURPOSE: Accumulated evidence suggests that oxidative stress is 
involved in amyloid beta (Abeta)-induced cognitive dysfunction. Silibinin 
(silybin), a flavonoid derived from the herb milk thistle (Silybum marianum), 
has been shown to have antioxidative properties; however, it remains unclear 
whether silibinin improves Abeta-induced neurotoxicity. In the present study, we
examined the effect of silibinin on the memory impairment and accumulation of 
oxidative stress induced by Abeta(25-35) in mice.

EXPERIMENTAL APPROACH: Aggregated Abeta(25-35) (3 nmol) was 
intracerebroventricularly administered to mice. Treatment with silibinin (2, 20 
and 200 mg.kg(-1), once a day, p.o.) was started immediately after the injection
of Abeta(25-35). Locomotor activity was evaluated 6 days after the Abeta(25-35)
treatment, and cognitive function was evaluated in a Y-maze and novel object 
recognition tests 6-11 days after the Abeta(25-35) treatment. The levels of 
lipid peroxidation (malondialdehyde) and antioxidant (glutathione) in the 
hippocampus were measured 7 days after the Abeta(25-35) injection.

KEY RESULTS: Silibinin prevented the memory impairment induced by Abeta(25-35) 
in the Y-maze and novel object recognition tests. Repeated treatment with 
silibinin attenuated the Abeta(25-35)-induced accumulation of malondialdehyde 
and depletion of glutathione in the hippocampus.

CONCLUSIONS AND IMPLICATIONS: Silibinin prevents memory impairment and oxidative
damage induced by Abeta(25-35) and may be a potential therapeutic agent for 
Alzheimer's disease.
PMID: 19552690
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2743846/pdf/bph0157-1270.pdf

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