- 10-25-2011, 11:19 AM
- 10-25-2011, 11:49 AM
Ursolic Acid suppresses T-Cell Activation, not stimulates it PA!
Chin J Integr Med. 2011 Oct 12.
Ursolic acid inhibits T-cell activation through modulating nuclear factor-κ B signaling.
Zeng G, Chen J, Liang QH, You WH, Wu HJ, Xiong XG.
Institute of Integrative Medicine, Xiangya Hospital, Central South University, Changsha, 410008, China.
To investigate the effects of ursolic acid (UA) on T-cell proliferation and activation, as well as to examine its effect on nuclear factor-κB (NF-κB) signaling pathway in T cells.
T-cells isolated from BALB/c mice were incubated with UA at concentrations ranging from 5-30 μmol/L in the presence of phorbol 12-myristate 13-acetate (PMA) or PMA plus ionomycin. The proliferation of T cells was measured by the MTT assay. The expressions of CD69, CD25, and CD71 on T-cell surface were analyzed using flow cytometry. The level of interleukin-2 (IL-2) in the culture supernatant of activated T cells was quantified by enzyme-linked immunosorbent assay (ELISA). The level of phosphorylated IκB-α (p-IκB-α) in total protein and p65, a subunit of NF-κB, nuclear translocation were measured by Western blot analysis.
UA in a dose-dependent manner significantly decreased the proliferation and inhibited the surface expressions of CD69, CD25, and CD71 in murine T lymphocytes upon in vitro activation (P <0.01). Significant reduction of IL-2 production was found in activated T cells treated with UA (P<0.01). The PMA-induced increase in p-IκB-α protein was inhibited, and nuclear translocation of p65 from the cytoplasm was blocked by UA.
UA is a potent inhibitor for T cell activation and proliferation; these effects are associated with the inhibition of NF-κB signaling pathway.
J Altern Complement Med. 2004 Jun;10(3):519-26.
Yin zi huang, an injectable multicomponent chinese herbal medicine, is a potent inhibitor of T-cell activation.
Chen X, Krakauer T, Oppenheim JJ, Howard OM.
Basic Research Program, SAIC-Frederick, Inc., National Cancer Institute-Frederick, Frederick, MD 21702-1201, USA.
The clinical efficacy of many multiherbal Traditional Chinese Medicines (TCM) is partially attributable to their immunoregulatory properties. In this study we evaluated the effect of eight commonly used, commercially available multiherbal Chinese medicines on T-cell activation. We focused on Yin Zhi Huang (YZH, an injectable herbal medicine commonly used for the treatment of liver diseases in China), because it was the most potent inhibitor of T-cell activation in our experimental system. The effects of 10 ingredient components of YZH were also evaluated.
[3H] thymidine incorporation assay was used to assess mouse T-cell proliferation after stimulation with latex beads coated with anti-CD3/CD28 antibodies. CD25, CD69, PD-1, and I-COS expression by purified mouse CD4+ T cells treated with plate-bound anti-CD3 antibody and soluble anti-CD28 antibody was analyzed by fluorescent-activated cell sorter (FACS). Cytokine/chemokine production by human peripheral blood mononuclear cells (PBMC) stimulated with staphylococcal enterotoxin B (SEB) was determined by enzyme-linked immunosorbent assay (ELISA).
Among tested herbal medicines, YZH was the most potent inhibitor of T-cell activation. In splenocyte proliferation assays, the inhibitory effect of YZH was dose-dependent, with a 50% inhibition concentration (IC50) of 1:3200-1:1600. Ten (10) purified compounds found in YZH were evaluated for their activity. Among them, ursolic acid (1-10 micromol), luteolin (1-10 micromol), baicalein (1-10 micromol), scopran (5-50 micromol), and crocin (5-50 micromol), exhibited dose-dependent inhibition. YZH also inhibited CD25, CD69, PD-1, and ICOS expression by stimulated mouse CD4+ T cells. In human PBMCs, YZH inhibited SEB-stimulated cytokine (interleukin [IL]-1, IL-2, IL-6, tumor necrosis factor[TNF]-alpha, interferon [IFN]-gamma) and chemokine (IP-10, MCP-1, MIP-1alpha and MIP-1beta) production in a dose-dependent manner.
Our data show for the first time that YZH is a potent inhibitor of T-cell activation, and this property may be the major mechanism underlying the clinical efficacy of YZH. Our experimental results pave the way for identification of active component(s) and/or analysis of synergistic/additive effect of a YZH ingredient in future studies.
Now these were in vitro studies using mice T-cells so people should not automatically assume this will happen in humans. The second study also has multiple components used and not just Ursolic Acid. However, it is a red flag and something that should make people ask more questions.
The study below also seems to show some different, undesirable potential side effects concerning Ursolic Acid.
Ursolic Acid also seems to be an atherosclerotic in vitro at least as well as toxic to endothelial cells, damaging DNA.
Atherosclerosis. 2011 Jun 22.
Ursolic acid causes DNA-damage, P53-mediated, mitochondria- and caspase-dependent human endothelial cell apoptosis, and accelerates atherosclerotic plaque formation in vivo.
Messner B, Zeller I, Ploner C, Frotschnig S, Ringer T, Steinacher-Nigisch A, Ritsch A, Laufer G, Huck C, Bernhard D.
Cardiac Surgery, Research Laboratories, Department of Surgery, Medical University of Vienna, Vienna, Austria.
The plant derived triterpene ursolic acid (UA) has been intensively studied in the past; mainly as an anti-cancer compound and for its cardiovascular protective properties. Based on the controversy of reports suggesting anti-angiogenic and cytotoxic effects of UA on one side and cardiovascular and endothelial protective effects on the other side, we decided to assess UA effects on primary human endothelial cells in vitro and atherosclerotic plaque formation in vivo.
METHODS AND RESULTS:
Our in vitro analyses clearly show that UA inhibits endothelial proliferation and is a potent inducer of endothelial cell death. UA causes DNA-damage, followed by the activation of a P53-, BAK-, and caspase-dependent cell-death pathway. Oral application of UA in APO E knockout mice potently stimulated atherosclerotic plaque formation in vivo, which was correlated with decreased serum levels of the athero-protective cytokine IL-5.
Due the potent endothelial cell death inducing activity of UA, a systemic application of UA in the treatment of cardiovascular diseases seems unfavourable. UA as an anti-angiogenesis, anti-cancer and - locally applied - cardiovascular drug may be helpful. The DNA damaging activity of UA may however constitute a serious problem.
Again, this is in vitro. But this time human endothelial cells were used. That's a little more damning. Endothelial cells line blood vessels but also your intestines, skin, etc. The potential DNA damaging aspects are also worrisome, PA. Especially the authors conclusion of, "The DNA damaging activity of UA may however constitute a serious problem."
VEGF is important in angiogenesis. Maybe this is important if you grow new muscle tissue? Wouldn't you need new capillaries to feed the new muscles oxygen and other nutrients?
Integr Cancer Ther. 2010 Jun;9(2):224-35.
Antiangiogenic activity of ursolic acid.
Kanjoormana M, Kuttan G.
Department of Immunology, Amala Cancer Research Centre, Amala Nagar, Thrissur, Kerala, India. [email protected]
Angiogenesis, the formation of new capillaries from preexisting vessels, is essential for tumor progression. Ursolic acid inhibited the tumor-associated capillary formation in C57BL/6 mice induced by highly metastatic B16F-10 melanoma cells. The levels of serum vascular endothelial growth factor (VEGF), NO, and proinflammatory cytokines were significantly reduced in ursolic acid-treated animals compared with those in control animals. The diminished expressions of VEGF and iNOS genes in B16F-10 melanoma cells treated with nontoxic concentrations of ursolic acid support these observations; the serum TIMP-1 (tissue inhibitor of metalloproteinase-1) and IL-2 (interleukin-2) levels were significantly elevated after the ursolic acid treatment. Nontoxic concentrations of ursolic acid toward human umbilical vein endothelial cells (HUVEC) were determined by MTT (methylthiazol tetrazolium) assay, and these nontoxic concentrations were selected for the in vitro studies. Nontoxic concentrations of ursolic acid inhibited vessel growth from the rat aortic ring. (3)H-thymidine proliferation assay clearly showed the inhibitory effect of ursolic acid on the proliferation of HUVECs in vitro. Ursolic acid significantly inhibited endothelial cell migration and invasion. The role of metalloproteinases has been shown to be important in angiogenesis; therefore, gelatin zymography was performed to determine whether ursolic acid affected protease activity. Gelatin zymographic analysis showed the inhibitory effect of ursolic acid on the protein expression of matrix metalloproteinases MMP-2 and MMP-9. The above observation shows the antiangiogenic activity of ursolic acid.
I am not sure inhibiting MMP's are a good thing like you wrote, PA. If they are needed to form new blood vessels wouldn't
inhibiting them possibly inhibit the growth of new blood vessels. How is this a good thing?
The above study was also in vitro but it also used human endothelial cells as did the one below.
Biochem Biophys Res Commun. 2004 Jul 23;320(2):402-8.
Effects of ursolic acid on different steps of the angiogenic process.
Cárdenas C, Quesada AR, Medina MA.
Central Culture Cell Service, University of Málaga, Spain.
Ursolic acid is a triterpenoid with pleiotropic biological effects. In this report, we study the effects of ursolic acid on different key steps of angiogenesis. Our results show that ursolic acid is able to inhibit key steps of angiogenesis in vitro, including endothelial cell proliferation, migration, and differentiation. At the same time, it seems to stimulate other key steps of angiogenesis, such as extracellular matrix degradation by MMP-2 and urokinase. Although ursolic acid can inhibit in vivo angiogenesis in the CAM assay, the different signs of the effects it causes on different steps of angiogenesis force one to be cautious concerning its anti-angiogenic potential.
None of this means Ursolic Acid is dangerous for people to use. To me it means Ursolic Acid needs more clinical studies conducted on it. Then we can see what it really does for muscle growth as well as inhibiting blood vessels growth and possible DNA damage.
But people should be made aware of the potential negative studies regarding it as well as the potential positive studies. This allows people to make a more educated choice before deciding to use or not use a product.
I am sure you would agree with this sentiment.
- 10-25-2011, 11:53 AM
10-25-2011, 11:55 AM
yes it all has to do with inhibiting NF-kappa beta signalling. reseveratrol does that too, as do the dhea metabolites, zingerone, pentoxyfylline, and a million other wonderful thing. It is an excellent property and part of what makes ursolic acid very cool
I dont understand if you thought this was some kind of negative. If you did you really blew it
Anabolicminds.com Featured Author
10-25-2011, 12:00 PM
Anabolicminds.com Featured Author
10-25-2011, 12:06 PM
you chose to ignore a NEWER article published in the EXACT SAME JOURNAL which shows CONTRADICTORY evidence in regards to atherosclerosis. I dont think it was an innocent oversight either.
Atherosclerosis. 2011 Jun 17. [Epub ahead of print]
Ursolic acid protects diabetic mice against monocyte dysfunction and accelerated atherosclerosis.
Ullevig SL, Zhao Q, Zamora D, Asmis R.
Department of Biochemistry, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3900, United States.
Accelerated atherosclerosis is a major diabetic complication initiated by the enhanced recruitment of monocytes into the vasculature. In this study, we examined the therapeutic potential of the phytonutrients ursolic acid (UA) and resveratrol (RES) in preventing monocyte recruitment and accelerated atherosclerosis.
METHODS AND RESULTS:
Dietary supplementation with either RES or UA (0.2%) protected against accelerated atherosclerosis induced by streptozotocin in high-fat diet-fed LDL receptor-deficient mice. However, mice that received dietary UA for 11 weeks were significantly better protected and showed a 53% reduction in lesion formation while mice fed a RES-supplemented diet showed only a 31% reduction in lesion size. Importantly, UA was also significantly more effective in preventing the appearance of proinflammatory GR-1(high) monocytes induced by these diabetic conditions and reducing monocyte recruitment into MCP-1-loaded Matrigel plugs implanted into these diabetic mice. Oxidatively stressed THP-1 monocytes mimicked the behavior of blood monocytes in diabetic mice and showed enhanced responsiveness to monocyte chemoattractant protein-1 (MCP-1) without changing MCP-1 receptor (CCR2) surface expression. Pretreatment of THP-1 monocytes with RES or UA (0.3-10μM) for 15h resulted in the dose-dependent inhibition of H(2)O(2)-accelerated chemotaxis in response to MCP-1, but with an IC(50) of 0.4μM, UA was 2.7-fold more potent than RES.
Dietary UA is a potent inhibitor of monocyte dysfunction and accelerated atherosclerosis induced by diabetes. These studies identify ursolic acid as a potential therapeutic agent for the treatment of diabetic complications, including accelerated atherosclerosis, and provide a novel mechanism for the anti-atherogenic properties of ursolic acid.
Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
Anabolicminds.com Featured Author
10-25-2011, 12:25 PM
Ac guy chose to ignore an article which shows pro angiogenic effects of ursolic acid in muscle. and another one that talks about how it upregulates angiogenic factors
J Agric Food Chem. 2010 Dec 22;58(24):12941-9. Epub 2010 Nov 12.
Ursolic acid induces allograft inflammatory factor-1 expression via a nitric oxide-related mechanism and increases neovascularization.
Lee AW, Chen TL, Shih CM, Huang CY, Tsao NW, Chang NC, Chen YH, Fong TH, Lin FY.
Graduate Institute of Medical Sciences and Department of Anatomy, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Ursolic acid (UA), a triterpenoid compound found in plants, is used in the human diet and in medicinal herbs and possesses a wide range of biological benefits including antioxidative, anti-inflammatory, and anticarcinogenic effects. Endothelial expression of allograft inflammatory factor-1 (AIF-1) mediates vasculogenesis, and nitric oxide (NO) produced by endothelial NO (eNOS) represents a mechanism of vascular protection. It is unclear whether UA affects the neovascularization mediated by AIF-1 and eNOS expression. This study investigated the effects and mechanisms of UA on angiogenesis in vivo in hind limb ischemic animal models and in vitro in human coronary artery endothelial cells (HCECs). This study explored the impact of UA on endothelial cell (EC) activities in vitro in HCECs, vascular neovasculogenesis in vivo in a mouse hind limb ischemia model, and the possible role of AIF-1 in vasculogenesis. The results demonstrate that UA enhances collateral blood flow recovery through induction of neovascularization in a hind limb ischemia mouse model. In vitro data showed that UA increases tube formation and migration capacities in human endothelial cells, and exposing HCECs to UA increased AIF-1 expression through a NO-related mechanism. Moreover, UA administration increased capillary density and eNOS and AIF-1 expression in ischemic muscle. These findings suggest that UA may be a potential therapeutic agent in the induction of neovascularization and provide a novel mechanistic insight into the potential effects of UA on ischemic vascular diseases.
Biochem Biophys Res Commun. 2008 Jul 4;371(3):556-60. Epub 2008 Apr 28.
Modulation of angiogenic factors by ursolic acid.
Kiran MS, Viji RI, Sameer Kumar VB, Sudhakaran PR.
Department of Biochemistry, University of Kerala, Thiruvananthapuram, Kerala 695 581, India. [email protected]
Investigations were carried out to understand the molecular basis of the effect of ursolic acid on angiogenesis by analysing its effects on the expression of modulators of angiogenesis by HUVECs in culture. Treatment with ursolic acid increased the expression of adhesion molecules such as E-selectin, CD-31 and I-CAM, upregulated angiogenic growth factors such as VEGF and FGF-2 and their receptors and caused increase in the ratio of PGE(2) to PGD(2). Reversal of the effect of ursolic acid by inhibition of PI3K-Akt pathway and increase in the level of phospho Akt suggest that the ursolic acid effect is mediated through PI3K-Akt pathway.
Anabolicminds.com Featured Author
10-25-2011, 12:27 PM
if you want to discuss ursolic anymore Ac guy start a new thread. This has gone off topic long enough. thank you
Anabolicminds.com Featured Author
10-25-2011, 12:35 PM
And I disagree with your broad statement that "...obviously the findings on VEGF dont have much relevance to healthy organisms and muscle tissue." You do not know this. Many of the studies were conducted using ursolic acid were done on healthy cells which became quite unhealthy when exposed to ursolic acid.
Mice are not always great models for what happens in people, good or bad, but I see you use that as a marketing tool anyhow too. People should be made aware of all the data concerning it. More research is clearly needed. The two studies you cited would have been better if the scientists looked into interleukin and cytokine expression and MMP-2/MMP-8 levels. The effects on VEGF and angiogenesis should have been looked at and noted in the publication.
Curiously absent from those two studies were androgenic hormone level assays. You reference ursolic acid as an aromatase inhibitor which it is weakly in vitro. I think its about forty times less potent than formestane?
If this were true and there was an aromatase inhibiting effect then its a good thing for men and an added benefit to ursolic acid for men. Just seems very odd that none of this or the angiogenic markers were assayed.
Look PA, your goal is to make people think ursolic acid is a great compound for a dietary supplement because you have a product with ursolic acid in it. I'd say you have a conflict there and a motivation to suppress any potentially negative findings concerning ursolic acid rather than elucidating any truth, PA. Not the other way around. Cherry picking? It's just as easy for someone to say that you cherry picked the two studies on mice that support your product purpose.
DNA damage is not something that might be seen immediately either but certainly is concerning. T-cell suppression is not a good thing either.
The verdict is still out on ursolic acid. I'm sorry that this makes you upset and unhappy. But it is still factual.
10-25-2011, 12:37 PM
10-25-2011, 12:42 PM
PA, did you know this plant has been used to increase and maintain energy levels, especially post-coital energy levels in people? It also has shown some neuroprotective effects in mammals and some positive effects regarding memory.
I'd say this has at least some potential based on these findings and indications. Certainly as a pre-workout stimulant. Sex could be equated to working out!
10-25-2011, 01:03 PM
His track record and history cannot be ignored...but if your skeptical its your right to be so, unless you have your own personal agenda..really, nobody knows who you are, do we?
나는 2000년 10월 매들린 올브라이트 전 미 국무장관 매들린 사랑, 그 중 한 뜨거운 젠장!
10-25-2011, 01:12 PM
10-25-2011, 01:12 PM
If my direct and cynical approach bothers you, just ignore it. I'm just saying what you need to hear ;).
10-25-2011, 04:13 PM
10-25-2011, 04:14 PM
10-25-2011, 04:19 PM
10-25-2011, 04:22 PM
10-25-2011, 10:43 PM
10-26-2011, 12:51 AM
I'll set you up for a great reply here to. The authors studied a "decoction" of Dendrobium nobile Lindl stems [来源] 为兰科植物石斛 and concluded basically that this may help guys "keep it up longer." Wouldn't you think something called a "decoction" would have the opposite type of effect?
These compounds also seem to prevent guys from falling asleep after sex and made some of the guys more talkative and animated.
I bet these compounds are naturally found in women's brains but not men's...
10-26-2011, 12:56 AM
a lot more that can be done with PEA's - realizing of course that a PEA "backbone" is found in the tryptamines, ecgonines and opiates too - I mean the more simple PEA homologs.
Then again with the right MAOi and in combination with a few other goodies? You may find pure bliss. Or not.
10-26-2011, 08:24 AM
"Well at least dendramine is potentially compliant with DHSEA 1994 while geranamine clearly
ain't. No clue what dendramine does or why its in Driven's PWO but nice to see they did not
just go the geranamine route."
i dont appreciate games on my board here. if you have information then share it. dont play stupid just for an opportunity to be a smart ass and annoy me. If it were my choice right now I would ban you. Its not completely my choice though.
if you do stick around then act normal please. dont play any more games
Anabolicminds.com Featured Author
10-26-2011, 08:26 AM
10-26-2011, 05:28 PM
10-26-2011, 06:30 PM
10-26-2011, 07:02 PM
10-26-2011, 07:26 PM
10-26-2011, 08:39 PM
10-26-2011, 08:51 PM
10-26-2011, 09:28 PM