Posts

Are New Blood Vessels A Good Thing?

blood-vesselsAngiogenesis is the creation of new blood vessels, a process that occurs in both health and disease. When new tissue is formed, as in the healing of a wound or the creation of the placenta, blood vessel formation must occur as well. The body is awash in factors that act to signal the growth and differentiation of various cells, including those of the arteries and veins, and the arterioles, venules, and capillaries. The control of angiogenesis operates through a series of “on” and “off” switches that either stimulate or inhibit the formation of new vessels. If there are too many “ons” and insufficient “offs,” the upset of balance favors the growth of new blood vessels. The opposite also holds true. If a person is healthy, the balance is easily maintained, but in some disease states things get out of hand, in either direction—too many or too few new vessels. You see, tumors also need a blood supply. The nutrients and growth factors supplied by the new blood vessels allow tumors to grow. Because of this, the search for ways to destroy cancer cells is partly focused on anti-angiogenesis. But having too many blood vessels is not limited to tumors. Diseases of the eye (macular degeneration, for example) and chronic inflammatory diseases, such as rheumatoid arthritis, psoriasis, and periodontal disease are also characterized by proliferation of vascular tissue. (Polverini. 1995) And researchers at the University of British Columbia believe that Alzheimer’s disease may be related to hypervascularization. (Biron. 2011)

Substances that prevent the formation of new blood vessels have been around for awhile. Thalidomide is one of them. This drug caused quite a stir in the 1950’s and 60‘s, after it was found to cause skeletal birth defects. Prescribed as a sedative to prevent morning sickness, thalidomide caused thousands of congenital disorders before it was reined in. Because it has benefits for leprosy patients and some inflammatory and autoimmune disorders, it’s still available. Additionally, its antiangiogenic character makes it an appropriate choice for the treatment of multiple myeloma, a primary tumor of bone marrow. (Singhal. 1999) (Bamias. 2003) If thalidomide is able to interrupt the formation of new blood vessels, you can easily see how the development of a neonate can be disrupted.

To study the effects of antiangiogenic substances, some scientists have chosen fat as the experimental system because of its remodeling capacity. Here they have learned that the manufacture of new blood vessels is important to the viability of adipose tissue, and that if the neovascularization were halted, so would be the proliferation of fat cells. (Rupnick. 2002) This transfer of concept to tumor cells is encouraging. A signaling protein termed VEGF (vascular endothelial growth factor) stimulates the growth of new blood vessels, and it helps to restore the oxygen supply to tissues when blood circulation is inadequate. Its importance in embryonic development is obvious, but its overexpression can be problematic. Solid tumors need VEGF to grow beyond their normally limited size, so they make their own. On the other hand, the body makes angiogenic inhibitors, such as thrombospondin and angiostatin to keep tumors dormant. ( Huang. 2004) Besides thalidomide, there are numerous pharmaceuticals available to interrupt angiogenesis, including bevacizumab (Avastin®) and other monoclonal antibodies, the side effects of which offer a laundry list of ills, including cancer. (Hansel. 2010) How ironic! The majority of these drugs block the activity of VEGF, but there may be other angiogenic factors about which less is known.

Working on the antiangiogenesis strategy proposed by renowned cancer researcher, Judah Folkman, Dr. William Li, of the Angiogenesis Foundation in New York, looked beyond drugs and their costs and toxicity, and identified powerful antiangiogenic molecules in dietary sources. This suggests that dietary enlightenment could offer a safe, readily available, novel strategy for preventing cancer. (Folkman. 2006) (Li. 2012)

Dr. Li discovered that nature has loaded a number of foods, beverages and herbs with naturally occurring inhibitors of angiogenesis: berries, citrus fruits, cruciferous vegetables, mushrooms, tomatoes, red wine, green tea, parsley, garlic, turmeric and dark chocolate, among others. The laboratory names extracted from these foods include brassanin, curcumin, genistein, N-acetylcysteine, resveratrol, silymarin, and selenium. The last-named is the only antioxidant mineral. ( Li. 2012)

A study in India, at the Himalayan Institute of Medical Sciences, found aberrant angiogenesis to be factored in Alzheimer’s disease and AIDS, comparing the modulation of angiogenesis in this century to the antibiotics of the twentieth century. (Bisht. 2010) Sagar, Yance and Wong, working at the McMaster University Department of Medicine, in Ontario, added a litany of herbs to Dr. Li’s initial list, citing their antiangiogenic behavior as being engaged through several interdependent processes that include effects on gene expression and enzyme activities. Besides inhibiting the formation of new vascular tissue, these may directly hinder tumor progression and reduce metastasis by way of other actions, including the interruption of epidermal growth factor reception, the blocking of the cyclooxygenase-2 enzyme, and the obstruction of nuclear factor kappa-B transcription. The herbals, artemisia annua (Chinese wormwood), viscum album (European mistletoe), curcuma longa (curcumin), resveratrol, quercitin, ginger, Panax ginseng, and proanthocyanidin (grape seed extract) are among them. (Sagar, Yance and Wang. 2006)

Not only has a soy-based diet, but also the isolated soy isoflavone, genistein, exhibited anti-cancer properties, particularly in lines of melanoma and mammary carcinoma. As is the case with most non-drug treatments, effect is dose-dependent. Its behavior suggests interference with tumor cell migration. (Farina. 2006) The medicinal mushroom, Agaricus blazei Murrill, common to the tropical rain forests near Sao Paulo, Brazil, has traditionally been used to stimulate the immune system, to treat digestive and circulatory disorders, and to lower cholesterol. But its lipid fraction, ergosterol, which is converted to vitamin D2 when exposed to UV radiation, was found to reduce tumor growth significantly in sarcoma-bearing mice at doses of 400+ mg/kg without side effects, suggesting that either ergosterol or its metabolites inhibits tumor-induced neovascularization. (Takaku. 2001) This is the first report of ergosterol’s antiangiogenic character. Later study of this mushroom found additional antiangiogenic constituents. (Kimura. 2004)

Another popular medicinal mushroom is Ganoderma lucidum, used largely in East Asia. Its attributes include the induction of programmed cell death in tumors (apoptosis), accompanied by the inhibition of cell proliferation and suppression of cell migration, especially in prostate cancer, where VEGF was down-regulated. (Stanley. 2005) It is desirable to keep cancer growth stagnant for as long a time as possible. Black raspberry extract was able to do that, as identified in research at Louisiana State University, where investigators saw potent inhibition of angiogenesis and concomitant vessel growth. Gallic acid was pinpointed as a major agent, which worked best in conjugation with less potent fractions, the synergy of which has yet to be elucidated. (Zhijun. 2005)

By disrupting the growth of new vessels from pre-existing capillaries, the green tea catechin, epigallocatechin gallate (EGCG) interrupts cell tube formation in the angiogenesis process by stopping VEGF signals from reaching their receptors. (Rodriguez. 2006) Likewise, blueberries are antiangiogenic. But these little beauties also have the distinction of being able to regenerate rhodopsin, the ocular molecule responsible for turning light energy onto nerve signals. Chinese researchers also found that blueberries can help to forestall a few age-related chronic diseases, such as diabetes, hyperlipidemia, hypertension, neurodegeneration, and even obesity through its apoptosis, antioxidant and anti-inflammation effects. (Chen. 2010)

If there is a favorite among anti-cancer alternative treatments, curcumin might hog the spotlight. Chemoprevention—the use of chemicals to prevent the development of cancer—is a promising anti-cancer approach with limited side effects compared to traditional chemotherapy. Curcumin, isolated from the kitchen spice turmeric, demonstrates the capability of suppressing, retarding, and even inverting carcinogenesis. It is able to induce apoptosis in cancer cells without cytotoxic effects on healthy cells while inhibiting the formation of tumors. It is well tolerated and is selective for cancer cells. (Lopez-Lazaro. 2008) No definitive dose has been identified, but trials using up to 8,000 mg a day have found no adverse effects. Its particular effectiveness appears to lie in colon cancer lines (Johnson. 2007), but its antiproliferative effects may extend to others (Hanif. 1997) (Lopez-Lazaro. 2008) The military can win a war by cutting off the enemy’s supplies. Could the war on cancer do the same?

References

Bennewith KL, Dedhar S.
Targeting hypoxic tumour cells to overcome metastasis.
BMC Cancer. 2011 Nov 30;11(1):504.

Bamias A, Dimopoulos MA.
Angiogenesis in human cancer: implications in cancer therapy.
Eur J Intern Med. 2003 Dec;14(8):459-469.

Kaan E Biron, Dara L. Dickstein, Rayshad Gopaul, Wilfred A. Jefferies
Amyloid Triggers Extensive Cerebral Angiogenesis Causing Blood Brain Barrier Permeability and Hypervascularity in Alzheimer’s Disease
PLoS ONE. 6(8); 31 Aug 2011: e 23789

Bisht M, Dhasmana DC, Bist SS.
Angiogenesis: Future of pharmacological modulation.
Indian J Pharmacol. 2010 Feb;42(1):2-8.

Chen CF, Li YD, Xu Z.
Chemical principles and bioactivities of blueberry
Yao Xue Xue Bao. 2010 Apr;45(4):422-9.

Annelyse Duvoix, Romain Blasius, Sylvie Delhalle, Michael Schnekenburger, et al
Chemopreventive and therapeutic effects of curcumin
Cancer Letters. 2005. 223: 181-190

Farina HG, Pomies M, Alonso DF, Gomez DE.
Antitumor and antiangiogenic activity of soy isoflavone genistein in mouse models of melanoma and breast cancer.
Oncol Rep. 2006 Oct;16(4):885-91.

Folkman J.
Role of angiogenesis in tumor growth and metastasis.
Semin Oncol. 2002 Dec;29(6 Suppl 16):15-8.

Folkman J.
Antiangiogenesis in cancer therapy–endostatin and its mechanisms of action.
Exp Cell Res. 2006 Mar 10;312(5):594-607.

Hanif R, Qiao L, Shiff SJ, Rigas B.
Curcumin, a natural plant phenolic food additive, inhibits cell proliferation and induces cell cycle changes in colon adenocarcinoma cell lines by a prostaglandin-independent pathway.
J Lab Clin Med. 1997 Dec;130(6):576-84.

Hansel TT, Kropshofer H, Singer T, Mitchell JA, George AJ.
The safety and side effects of monoclonal antibodies.
Nat Rev Drug Discov. 2010 Apr;9(4):325-38.

Huang Z, Bao SD.
Roles of main pro- and anti-angiogenic factors in tumor angiogenesis.
World J Gastroenterol. 2004; 10(4): 463-70

Johnson JJ, Mukhtar H.
Curcumin for chemoprevention of colon cancer.
Cancer Lett. 2007 Oct 8;255(2):170-81.

Joshi J, Ghaisas S, Vaidya A, Vaidya R, Kamat DV, Bhagwat AN, Bhide S.
Early human safety study of turmeric oil (Curcuma longa oil) administered orally in healthy volunteers.
J Assoc Physicians India. 2003 Nov;51:1055-60.

Kajdaniuk D, Marek B, Fołtyn W, Kos-Kudła B.
Vascular endothelial growth factor (VEGF) in endocrinology and oncology.
Endokrynol Pol. 2011;62(Supl. III):14-22.

Kimura Y, Kido T, Takaku T, Sumiyoshi M, Baba K.
Isolation of an anti-angiogenic substance from Agaricus blazei Murill: its antitumor and antimetastatic actions.
Cancer Sci. 2004 Sep;95(9):758-64.

Li WW, Li VW, Hutnik M, Chiou AS.
Tumor angiogenesis as a target for dietary cancer prevention.
J Oncol. 2012;2012:879623.

Polverini PJ.
The pathophysiology of angiogenesis.
Crit Rev Oral Biol Med. 1995;6(3):230-47.

López-Lázaro, Miguel
Anticancer and carcinogenic properties of curcumin: Considerations for its clinical development as a cancer chemopreventive and chemotherapeutic agent
Molecular Nutrition & Food Research. Supplement: Natural Products and Dietary Prevention of Cancer. Vol 52, Iss S1, pages S103–S127, June 2008

Rodriguez, S.K., Guo, W., Liu, L., Band, M.A., Paulson, E.K., Meydani, M.
Green Tea Catechin, Epigallocatechin-3-Gallate (Egcg) Inhibits Vascular Endothelial Growth Factor Angiogenic Signaling by Disrupting the Formation of a Receptor Complex
International Journal of Cancer. April 1, 2006; 118(7):1635-44.

Rupnick MA, Panigrahy D, Zhang CY, Dallabrida SM, Lowell BB, Langer R, Folkman MJ.
Adipose tissue mass can be regulated through the vasculature.
Proc Natl Acad Sci U S A. 2002 Aug 6;99(16):10730-5.

Sagar SM, Yance D, Wong RK.
Natural health products that inhibit angiogenesis: a potential source for investigational new agents to treat cancer-Part 1.
Curr Oncol. 2006 Feb;13(1):14-26.

Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, Eddlemon P, Munshi N, Anaissie E, Wilson C, Dhodapkar M, Zeddis J, Barlogie B.
Antitumor activity of thalidomide in refractory multiple myeloma.
N Engl J Med. 1999 Nov 18;341(21):1565-71.

Stanley G, Harvey K, Slivova V, Jiang J, Sliva D.
Ganoderma lucidum suppresses angiogenesis through the inhibition of secretion of VEGF and TGF-beta1 from prostate cancer cells.
Biochem Biophys Res Commun. 2005 Apr 29;330(1):46-52.

Takaku T, Kimura Y, Okuda H.
Isolation of an antitumor compound from Agaricus blazei Murill and its mechanism of action.
J Nutr. 2001 May;131(5):1409-13.

Zhijun Liu, Joshua Schwimer, Dong Liu, Frank L. Greenway, Catherine T. Anthony, and Eugene A. Woltering
Black Raspberry Extract and Fractions Contain Angiogenesis Inhibitors
J. Agric. Food Chem., 2005, 53 (10), pp 3909–3915

*These statements have not been evaluated by the FDA.
These products are not intended to treat, diagnose, cure, or prevent any disease.

What Gets YOU Inflamed?

knee-inflammationAre you an adult? Would you prefer the pound(s) of cure to the ounce of prevention? One of the sad commentaries about adulthood is that we don’t take care of ourselves until something hurts, the detection of which relies on the nervous system. The nervous system is plastic, meaning that it exhibits a wide range of responses according to different conditions. The perception of pain depends on more than one factor, the environment included. With inflammation, however, there exists a hypersensitivity state that makes us aware of what’s going on. This realization is called nociception, involving a network that identifies a noxious condition that evokes responses ranging from mild to severe. Once the pain message is recognized by the nervous system it registers as an “ouch.” The greater the intensity of the stimulus, the greater is the perception of pain. In some cases, no external trigger is needed, such as one would experience with arthritis pain.

Inflammation is the body’s attempt at self-protection, the intention of which is to remove the harmful stimuli, including damaged cells, irritants or pathogens. If the stimulus comes from outside, it can be removed, although pain may linger. If it comes from inside, the body is left to its own devices. In either instance, tissue repair is the ultimate goal. To our dismay, inflammation may beget further inflammation in a self-perpetuating cascade. This occurs because of cellular alterations that cause mediator chemicals to be released and certain white cells, called macrophages, to become activated. The job of the macrophage is to swallow (-phage) the debris that comes from, or causes, tissue damage. Without inflammation, infections and wounds would never heal. In fact, too much anti-inflammatory medication, such as cortisone, slows wound healing (Goforth, 1980). The innate immunity with which we were born is always at the ready to start the inflammatory cascade and to bring healing.

Signs of overt inflammation include pain, redness, immobility (as in loss of function), swelling, and heat (more blood to the area makes it feel warm). Covert inflammation, occurring with internal organs, does not necessarily present with all these signs. Pain arises when swelling pushes on nerves, but sometimes the brain gets used to it and ignores the stimulus. The risk for inflammatory conditions rises with weight gain, as determined by an increase in white blood cells. Regardless of body mass index, C-reactive protein and homocysteine are markers for the presence of inflammatory state, which is at the center of many disorders, from arthritis, through Crohn’s disease, to various allergies and vitamin deficiencies.

Treatment for inflammation abounds in the world of allopathic medicine. Most of us know about NSAIDS, non-steroidal anti-inflammatory drugs, among which Tylenol is not, but aspirin, naproxen and ibuprofen are. Then, there are the corticosteroids—or just plain steroids—that are naturally made by the body in the adrenal glands. But these guys, given as drugs, prevent phospholipid release, and that undermines the activity of eosinophils, which are designed to fight back against allergy, for example, by releasing histamine.

Of the alternative modalities to address inflammation, ginger has accrued quite a following. For hundreds of years it’s been used to treat gastric distress, including dyspepsia and constipation. Recent research points to ginger’s role as an anti-inflammatory agent in the prevention of colon cancer, where inflammation has been identified as a precursor to the disease (Zick, 2011), the markers of which are pro-inflammatory prostaglandins—primarily PGE2—produced by cyclooxygenase (COX) as an early event in the course of the condition (Jiang, 2012).

In a British examination of pain studies, those suffering from osteoarthritis, dysmenorrhea, and acute muscle pain had been administered ginger as the sole treatment. Though additional rigorous trials are anticipated, these subjects reported a reduction in pain, as cited on subjective assessment tools (Terry, 2011). Even before interest in alternative medicine was accelerated to its present status, scientists scrutinized ginger’s reputation in the Ayurvedic community among people treated with the herb for rheumatic concerns, finding efficacy that paralleled traditional interventions (Srivastava, 1989). Applying oral powdered ginger to generalized musculoskeletal discomfort, Danish physicians realized that the safety factor of ginger far exceeded that of any known drugs, while presenting significant efficacy in the relief of pain and swelling via the inhibition of pro-inflammatory prostaglandins (Srivastava, 1992).

By sequestering these incendiary prostaglandins (PG’s), ginger proves itself to be on a par with NSAIDS, minus the concerns of adverse side effects. Similar to prostaglandins in promoting physical aberrations are leukotrienes, products of an enzyme called lipoxygenase (LOX), like COX an offspring of arachidonic acid metabolism. Leukotrienes generally work within the immune system, while PG’s almost always play a role in pure inflammation and pain. (There are beneficent PG’s, by the way.)  Leukotrienes are signaling molecules that call immune cells to the site of infiltration, as from airborne allergens. Bluntly, ginger suppresses the synthesis of leukotrienes (Grzanna, 2005), a property that separates it from NSAIDS. Other of ginger’s attributes point to an anti-oxidant character in the interruption of free radical generation (Ali, 2008), which is helpful in the fight against allergens and pain.

Nitric Oxide (NO) is one of the few signaling gases in the body. The smooth muscle that lines blood vessels is told by NO to relax, thus dilating the vessels and lowering blood pressure. In excessive concentrations, though, NO becomes a pro-oxidant as a naturally unstable free radical, especially when made by white cells (monocytes and macrophages)  during their battle against an infective agent. One logistician that maintains regulation of NO is ginger, where it was shown to control white cell activation as part of its job as an anti-inflammatory vehicle (Shimoda, 2010). Modulating inflammation is what ginger does, and not so gingerly, at that.

References

Ali BH, Blunden G, Tanira MO, Nemmar A.
Some phytochemical, pharmacological and toxicological properties of ginger (Zingiber officinale Roscoe): a review of recent research.
Food Chem Toxicol. 2008 Feb;46(2):409-20. Epub 2007 Sep 18.

ltman RD, Marcussen KC.
Effects of a ginger extract on knee pain in patients with osteoarthritis.
A Arthritis Rheum. 2001 Nov;44(11):2531-8.

Drozdov VN, Kim VA, Tkachenko EV, Varvanina GG.
Influence of a specific ginger combination on gastropathy conditions in patients with osteoarthritis of the knee or hip.
J Altern Complement Med. 2012 Jun;18(6):583-8. doi: 10.1089/acm.2011.0202.

Frondoza CG, Sohrabi A, Polotsky A, Phan PV, Hungerford DS, Lindmark L.
An in vitro screening assay for inhibitors of proinflammatory mediators in herbal extracts using human synoviocyte cultures.
In Vitro Cell Dev Biol Anim. 2004 Mar-Apr;40(3-4):95-101.

Goforth P, Gudas CJ.
Effects of steroids on wound healing: a review of the literature.
J Foot Surg. 1980 Spring;19(1):22-8.

Grzanna R, Lindmark L, Frondoza CG
Ginger–an herbal medicinal product with broad anti-inflammatory actions.
J Med Food. 2005 Summer;8(2):125-32.

Jiang Y, Turgeon DK, Wright BD, Sidahmed E, Ruffin MT, Brenner DE, Sen A, Zick SM.
Effect of ginger root on cyclooxygenase-1 and 15-hydroxyprostaglandin dehydrogenase expression in colonic mucosa of humans at normal and increased risk for colorectal cancer.
Eur J Cancer Prev. 2012 Dec 6.

Levy AS, Simon O, Shelly J, Gardener M.
6-Shogaol reduced chronic inflammatory response in the knees of rats treated with complete Freund’s adjuvant.
BMC Pharmacol. 2006 Oct 1;6:12.

Lu H, Huang D, Saederup N, Charo IF, Ransohoff RM, Zhou L.
Macrophages recruited via CCR2 produce insulin-like growth factor-1 to repair acute skeletal muscle injury.
FASEB J. 2011 Jan;25(1):358-69.

Ramji, Divya; ho, chi; Huang, Qingron; Rafi, Mohamed; Huang, Mou
Isolation of gingerols and shogaols from ginger and evaluation of their chemopreventive activity on prostate cancer cells and anti-inflammatory effect on 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced mouse ear inflammation
RUcore – Rutgers University Community Repository. 2007
http://mss3.libraries.rutgers.edu/dlr/showfed.php?pid=rutgers-lib:21328

Shen CL, Hong KJ, Kim SW.
Effects of ginger (Zingiber officinale Rosc.) on decreasing the production of inflammatory mediators in sow osteoarthrotic cartilage explants.
J Med Food. 2003 Winter;6(4):323-8.

Sehwan Shima, Sokho Kima, Dea-Seung Choia, Young-Bae Kwonb, Jungkee Kwona
Anti-inflammatory effects of [6]-shogaol: Potential roles of HDAC inhibition and HSP70 induction
Food and Chemical Toxicology. Volume 49, Issue 11, November 2011, Pages 2734–2740

Shimoda H, Shan SJ, Tanaka J, Seki A, Seo JW, Kasajima N, Tamura S, Ke Y, Murakami N.
Anti-inflammatory properties of red ginger (Zingiber officinale var. Rubra) extract and suppression of nitric oxide production by its constituents.
J Med Food. 2010 Feb;13(1):156-62.

Srivastava KC, Mustafa T.
Ginger (Zingiber officinale) and rheumatic disorders.
Med Hypotheses. 1989 May;29(1):25-8.

Srivastava KC, Mustafa T.
Ginger (Zingiber officinale) in rheumatism and musculoskeletal disorders.
Med Hypotheses. 1992 Dec;39(4):342-8.

Terry R, Posadzki P, Watson LK, Ernst E.
The use of ginger (Zingiber officinale) for the treatment of pain: a systematic review of clinical trials.
Pain Med. 2011 Dec;12(12):1808-18.

Tripathi S, Maier KG, Bruch D, Kittur DS.
Effect of 6-gingerol on pro-inflammatory cytokine production and costimulatory molecule expression in murine peritoneal macrophages.
J Surg Res. 2007 Apr;138(2):209-13. Epub 2007 Feb 8.

Tripathi S, Bruch D, Kittur DS.
Ginger extract inhibits LPS induced macrophage activation and function.
BMC Complement Altern Med. 2008 Jan 3;8:1. doi: 10.1186/1472-6882-8-1.

Zick SM, Turgeon DK, Vareed SK, Ruffin MT, Litzinger AJ, Wright BD, Alrawi S, Normolle DP, Djuric Z, Brenner DE.
Phase II study of the effects of ginger root extract on eicosanoids in colon mucosa in people at normal risk for colorectal cancer.
Cancer Prev Res (Phila). 2011 Nov;4(11):1929-37.

*These statements have not been evaluated by the FDA.
These products are not intended to treat, diagnose, cure, or prevent any disease.