Written by an award-winning medical journalist, this is the first book to discuss the complementary therapies used by German doctors for the treatment of cancer. In clinics all across Germany, doctors have achieved a fully documented 88% remission rate in their cancer patients using natural, nontoxic treatments.

This inspiring and informative book relates the stories of many patients who have seen real, remarkable results from innovative treatments such as Polyerga(R) and Carnivora(R) therapy, as well as from galavanotherapy, hyperthermia, noni juice, mushrooms, and induced remission therapy.

And ... unlike here in the United States, in Europe these therapies are not considered alternative medicine, but rather mainstream approaches to fighting cancer.

In German Cancer Therapies, Dr. Morton Walker discusses seven cutting-edge treatment programs, with careful and medically responsible consideration given to the pros and cons of each. He also includes the following resources:

Biography

Dr. Walker attended New York University, 1947 to 1949. He graduated with the degree of Doctor of Podiatric Medicine (D.P.M.) from the Illinois College of Podiatric Medicine, attending 1949 to 1953. Previously licensed in three states, he practiced podiatry for over 16 years and was awarded 18 medals by the American Podiatry Association for podiatric research and medical writing during this time. Then he discontinued his foot care practice and became a medical journalist fulltime, freelance for the next 42 years.

During this period he had 91 health consumer books published plus more than 5,000 clinical journal articles and magazine articles printed. His work includes the writing of 4,000-word monthly columns on natural and nontoxic methods of healing for 32 years for the Townsend Letter, The Examiner of Alternative Medicine.

His books are published in 14 languages among 28 countries. Some of his titles have sold millions of copies. He has been designated "The Guru of Chelation Therapy" in as much as he had had ten titles published about this subject alone including the techniques of intravenous, oral, and anal chelation administration. For thirty-three consecutive years he lectured before the American Cancer Control Society.

Designated as "The World's Leading Medical Journalist on Holistic Medicine," he was presented with Humanitarian Awards by The American College for the Advancement in Medicine, The American Cancer Control Society, and The Institute of Orthomolecular Medicine.

He came out of retirement in order to enlighten the public worldwide about "Cancer's Cause Cancer's Cure" as discovered by Mirko Beljanski, Ph.D.

Reviews:

A German doctor achieved remission for 98 percent of patients who came to him with early malignancies before they underwent radiation
therapy or chemotherapy. Rare Carolina Plant ‘‘Eats’’ Cancer Cells Carnivora®

A German doctor achieved remission for 98 percent of patients who came to him with early malignancies before they underwent radiation
therapy or chemotherapy. Rare Carolina Plant ‘‘Eats’’ Cancer Cells Carnivora®

Dr. C. Joe Schneller M.D., N.D., D.Sc., D.Ac., D.C. and Inventor of World's First Hybrid Darkfield Microscope performs preliminary study preceding double blind clinical study demonstrating how three Capsules of Carnivora wake up important white blood cells & NK cells of the immune system creating "Powerful Immune Defense."

* Ronald Reagan: In 1985, former president Ronald Reagan sent for Carnivora herbal drops. He ingested a once-diluted version of the drops, drinking from a glass several times a day.

Note: this information first appeared in the July 2003 nationally released text "German Cancer Therapies," page 101. "...Having therapies from around the world at his disposal... U.S. president Ronald Reagan had sent to... Germany for Carnivora herbal extract to take as a preventive... Thereafter, he drank thirty drops of the extract in a glass of purified water or herb tea four times a day. According to records kept by the extract's manufacturer, the U.S. president continued to buy and swallow these drops...

* Dr. Robert C. Atkins, MD, medical director of the Atkins Center in New York City, employed Carnivora as part of his generalized model for... immune modulation. He was impressed mightily by the results achieved when the remedy was used. "The reason these results are impressive is that they show that (Carnivora) 'works' and is suitable to act as an effective partner to other nontoxic (remedies) that also work," Dr. Atkins stated. Excerpt from "German Cancer Therapies" page 62.

"Make no mistake: It's your Immune System that heals you!" 

In the 1970s, German physician Helmut Keller was looking for alternatives to the toxic chemicals produced by the drug companies. He also marveled at Venus’s-flytrap and its ability to digest protein (insects) without harming itself and without a digestive system.

Dr. Keller believes the key compounds are droserone (D), plumbagin (P), and hydroplumbagin, also found in other carnivorous plants. These remarkable and hard-to- make compounds are powerful oxidation catalysts, not dissimilar to the famous Koch catalysts.

In the 1930s, Dr. William F. Koch was using catalysts to speed oxidation in cells. He cured many dreaded diseases. His successes created political problems forcing him to emigrate to Brazil to continue his work. D and P modulate the immune system.

That is, they lift a weakened immune system, or stimulate a proper balance of activation and suppression. Too little of the former can lead to cancer and infection. Too little of the latter can lead to “autoimmune” disease. 

At the Wellness Directory of Minnesota, we hate to give false hope to anyone, however, we must tell you that, according to Morton Walker, DPM, in an article entitled, "The Carnivora Cure for Cancer, AIDS and Other Pathologies" published in Immune Perspectives, Summer 1994: "[The Carnivora extract] is highly effective for the total elimination of the HIV virus in vivo from human blood and may be considered a cure for the autoimmune deficiency syndrome AIDS."

In 1988, the active component of Carnivora, plumbagin, was isolated.

 It has proven itself to be, in vivo and in vitro (in live subjects and in the laboratory), a powerful immuno-stimulant. Since 1981, over 2000 patients have been treated with Carnivora, including President Reagan. (Follow physicians and the rich when they get cancer; they usually avoid, at all costs, chemotherapy.) 

Studies have shown it to reduce tumor weight with no side effects, and in some cases there have been complete remission. Carnivora is non-toxic and non-mutagenic (does not cause cellular mutations).

One patient who used Carnivora extract was Ronald Asti, a person with AIDS who was suffering from ARC (AIDS-related complex). He traveled to Germany for treatment, and returned four months later, completely free of AIDS, his blood showing no signs of the HIV-1 antigen after multiple tests.

A commercial Carnivora product is manufactured by the Carnivora Research Company and, thus far, can be still be purchased for shipment to the US. However, Dr Helmut Keller of Bad Steben, Germany, states that he would prefer to induce treatment himself, and then discharge the patient back to her/his physician with an optimal schedule for treatment.

Here are some addresses for further information: 

Carnivora Research, Inc.
Tel: 866-836-8735 (from inside US)
001-1-203-532-0957 (from outside the US) 
www.carnivora.com 

Dr Helmut Keller
Chronic Disease Control and Treatment Center Institute of Integrative Medicine At Stella Maris Clinic
David Alfaro Siqueiros #25 int. 201-b, Zona Rio Tijuana B.C. Mexico
Tel: 011 52 6 634 6259 (from US) 
doc_h_keller@yahoo.com

"President Ronald Reagan used Carnivora successfully in 1985 when he had it sent directly to the White House."

 In Germany, a pharmaceutical extract of Venus’ Flytrap called Carnivora is used in the treatment of chronic diseases, including most forms of cancer, ulcerative colitis, multiple sclerosis, all types of herpes infections, chronic arthritis, and almost any immune deficiency state, including AIDS. Carnivora is dispensed orally, by inhalation, or by injection. However, individuals cannot legally import Carnivora to the U.S. without first proving that they suffer from a life-threatening disease.  Fortunately, fresh Venus’ Flytrap extract can be both purchased and used legally in the United States, though few people are aware of its uses.

In cases of cancer, Venus’ Flytrap is reported to work therapeutically to shrink solid tumors, and in fact works for any type of cancer except for blood abnormalities, such as leukemia.  It is also noted to work best if the patient has not previously undergone chemotherapy or radiation therapy.

The discoverer of this herb’s usefulness is researcher and oncologist, Helmut Keller, M.D. Keller began studying Venus’ Flytrap at Boston University in 1980, but moved to Germany a year later to find more freedom for his research.

One of his patients interviewed in 1991 was 65-year-old Betty Williams of Ames, Iowa. Diagnosed with inflammatory breast disease, the most lethal form of breast cancer, she went to Dr. Keller for treatment. Her case study revealed that the skin of her right breast was at first swollen, warm, hardened, and painful, and finally turned black. Diagnosis by biopsy revealed that it was inflammatory carcinoma. Doctors gave her no chance for survival, and predicted death within a few weeks.  The oncologists said that they would try chemotherapy, then radiation, and finally surgery to buy her a little more time.  When she learned of Dr. Keller, she decided to try his Carnivora treatment.  She received one three-hour intravenous injection a day.  She experienced no side effects, and eventually recovered completely. 

According to Morton Walker of The Herb Quarterly, one of Venus’ Flytrap’s faithful users is President Ronald Reagan.  Walker reported that following the removal of malignant polyps from his colon, President Reagan sent to Nordhalben, Germany for an herbal extract of the Venus’ Flytrap to take as a preventative against the spread of cancer. Thereafter, he drank thirty drops of the extract in a glass of water or tea four times a day.  As of 1995, the former president was still taking the Venus’ Flytrap extract.

In addition to its success with cancer, Venus’ Flytrap extract has had a dramatic effect on patients infected with the HIV virus.  Dr. Keller learned that various strengths of the Carnivora formulations work for all diseases in which immune stimulation and modulation are required. Carnivora increases the number and activity of the sick person’s T-helper cells and other immune system components. Laboratory test readings recorded by Dr. Keller on HIV- positive patients show the patients T-helper cell counts rose from as low as 11 per cubic millimeter of blood to well beyond 700, while the T-suppressor cells decreased sharply.  This makes the individual’s important helper/ suppressor ratio almost normal.

The most surprising result has been Venus’ Flytrap’s direct effect in reducing the viability of HIV.  An identified biochemical ingredient in Venus’ Flytrap actually kills the AIDS virus. The Beta-2 Microglobulin test, which measures the amounts of plasma proteins produced by HIV, also decreases. This test for Beta-2 levels indicates that the patient is not advancing to full-blown AIDS.

Given the research conducted on these remarkable plants, the conclusion can be drawn that Venus’ Flytrap and Cat’s Claw both have tremendous potential as a preventative and as a treatment for many of today’s serious health concerns. Taken together, they enhance each other for ultimate benefit.

Since Venus’ Flytrap has not yet gained popularity in the United States, it can be hard to find if you don’t know where to look.  The only known company manufacturing the extract in the U.S. is Native Essence Herb Company.  This company offers each herb individually as a potent extract, or also as a combination of the two. The concentrated liquid herbal solution of Venus’ Flytrap and Cat’s Claw mixed together called Venus’ Flytrap/Cat’s Claw 50/50.  Native Essence’s Herbal Solutions™ products are uniquely prepared in the traditional Native American manner, using only the finest freshly-grown herbs, which are always organically grown or ecologically wildcrafted.

Although people are generally less familiar with taking liquid herbal supplements than capsules, liquid supplements are almost universally recognized to be superior. Liquid herbal extracts and tinctures offer better absorption by the body over capsules and tablets. With any capsule or tablet, the body has to break it down to some degree before it can be assimilated, whereas liquid supplements are quickly absorbed and used by the body.  Liquid formulas can be easily added to any beverage.

Molecular Recognition. International Symposium Sopron, Hungary, 1988

*B. Kreher-1, A. Neszmelyi-2, K. Polos-3, H. Wagner-1.

1 - Institute of Pharmaceutical Biology, University of Munich, Karlstrasse 29, D-8000 Munchen 2 FRG 
2 - Central Research Institute for Chemistry, Hungarian Academy of Sciences, 59 Pusztaszeri ut, H-1025 Budapest, Hungary
3 - Pharmat. Res. Inst., H-1368 Budapest, Hungary

* Facilitates Immuno-Modulatory Action / Homeostasis of T-helper & T-suppressor cells of the Immune System

* Responds to abnormal cells only 

* Arginine - Supports NK (natural killer cell) function. Improves immune responses to foreign entities, crucial for tissue repair)

* Asparagine - Explusion of harmful ammonia, increased resistance to fatigue and increase of endurance

* Drosera aliciae - potent free radical scavenger
* Droserae Herba, Drosera rotundifolia. Drosera spatulata, Drosera tokaiensis

* Gallic Acid  - Antioxidant, Immune stimulative

* Formic Acid  - Natural bactericidal / fungicidal

* Hydroplumbagin / Plumbagin  - Immune Modulation / Stimulation
* Plumbagin (5-hydroxy-2-methyl-1, 4-naphthoquinone)
* Ramentaceone (naphthoquinone), 4-naphthoquinone derivatives

* Myricetin - Bioflavonoid. Identical properties as Quercetin

* Quercetin - Anti-oxidant, free radical scavenger, bioflavonoid, protectant, anti-inflammatory

* Threonine - Aids in function of intestinal / digestive tracts. Assists in metabolism and assimilation of nutrients; Prevention of fat build-up in the liver

Int Immunopharmacol. 2009 Jul;9(7-8):949-58. Epub 2009 Apr 15.

Radiation Biology & Health Sciences Division, Bhabha Atomic Research Centre, Mumbai-400085, India.

http://www.ncbi.nlm.nih.gov/pubmed/19374955

Abstract: Plumbagin (5-hydroxy-2-methyl-1, 4-naphthoquinone), a quinone isolated from the roots of Plumbago zeylanica was recently reported to suppress the activation of NF-kappaB in tumor cells. NF-kappaB, a ubiquitous transcription factor, plays a central role in regulating diverse processes in leukocytes like cellular proliferation, expression of immunoregulatory genes and apoptosis during innate and adaptive immune responses.

* Plumbagin completely inhibited Con A induced IkappaB-alpha degradation and NF-kappaB activation.

* Further, plumbagin prevented Graft Versus Host Disease-induced mortality in mice.

* To our knowledge this is first report showing immunomodulatory effects of plumbagin in lymphocytes via modulation of NF-kappaB activation.

Biochem Pharmacol. 2006 Nov 30;72(11):1605-21. Epub 2006 Aug 4.

Aggarwal BB, Shishodia S, Sandur SK, Pandey MK, Sethi G.

Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. aggarwal@mdanderson.org

http://www.ncbi.nlm.nih.gov/pubmed/16889756

Abstract: Although inflammation has long been known as a localized protective reaction of tissue to irritation, injury, or infection, characterized by pain, redness, swelling, and sometimes loss of function, there has been a new realization about its role in a wide variety of diseases, including cancer. While acute inflammation is a part of the defense response, chronic inflammation can lead to cancer, diabetes, cardiovascular, pulmonary, and neurological diseases.

Several pro-inflammatory gene products have been identified that mediate a critical role in suppression of apoptosis, proliferation, angiogenesis, invasion, and metastasis. Among these gene products are TNF and members of its superfamily, IL-1alpha, IL-1beta, IL-6, IL-8, IL-18, chemokines, MMP-9, VEGF, COX-2, and 5-LOX. The expression of all these genes are mainly regulated by the transcription factor NF-kappaB, which is constitutively active in most tumors and is induced by carcinogens (such as cigarette smoke), tumor promoters, carcinogenic viral proteins (HIV-tat, HIV-nef, HIV-vpr, KHSV, EBV-LMP1, HTLV1-tax, HPV, HCV, and HBV), chemotherapeutic agents, and gamma-irradiation.

*These observations imply that anti-inflammatory agents that suppress NF-kappaB or NF-kappaB-regulated products should have a potential in both the prevention and treatment of cancer. The current review describes in detail the critical link between inflammation and cancer.

Biotechnol Appl Biochem. 2008 Sep 9. [Epub ahead of print]

Krolicka A, Szpitter A, Maciag M, Biskup E, Gilgenast E, Romanik G, Kaminski M, Wegrzyn G, Lojkowska E.

http://www.ncbi.nlm.nih.gov/pubmed/18782083

Abstract: The objective of this research was to evaluate antioxidant as well as antibacterial properties of secondary metabolites obtained from Drosera aliciae plants grown in vitro and examine the mechanism of their antimicrobial action. Bactericidal activity of extracts from D. aliciae as well as pure ramentaceone (naphthoquinone) present in this plant were examined against human pathogenic strains both resistant and susceptible to antibiotics.

Chloroform extract proved to be more effective than methanol preparation against all of the tested strains except for Pseudomonas aeruginosa isolates with the lowest minimal bactericidal concentration (MBC) values in the case of Staphylococcus aureus (25-50 mg fresh weight ml-1). The influence of D. aliciae extracts and ramentaceone on the synthesis of DNA, RNA or proteins in cultures of Enterococcus faecalis was estimated by measurement of incorporation of radioactive precursors: [3H] thymidine, [3H] uridine or [3H] leucine, respectively.

* Methanol extract from D. aliciae, except for a moderate effect on DNA synthesis, had no influence on RNA and protein synthesis.

* Chloroform preparation caused about a 75% decrease in [3H] uridine incorporation in comparison to control after 60 min and a significant reduction in DNA and protein synthesis (44% and 30% respectively).

* Ramentaceone also reduced DNA and RNA synthesis but less efficiently than chloroform extract and caused no changes in [3H] leucine incorporation.

* Methanol extract from D. aliciae proved to be an effective antioxidant in both the DPPH and FRAP assay with the activities exceeding those of well known antioxidants - flavonoids.

* Chloroform extract and ramentaceone showed no antioxidative properties.

Toxicol Appl Pharmacol. 2007 Sep 15;223(3):267-76. Epub 2007 Jun 7.

Kawiak A, Piosik J, Stasilojc G, Gwizdek-Wisniewska A, Marczak L, Stobiecki M, Bigda J, Lojkowska E.

Department of Biotechnology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Kladki 24, 80-822 Gdansk, Poland.

http://www.ncbi.nlm.nih.gov/pubmed/17618663

Abstract:

* Reactive oxygen species (ROS) have been recognized as key molecules, which can selectively modify proteins and therefore regulate cellular signalling including apoptosis.

* Plumbagin (found in many plants, including carnivora / venus flytrap), a naphthoquinone exhibiting anti-tumor activity, is known to generate ROS and has been found to inhibit the activity of topoisomerase II (Topo II) through the stabilization of the Topo II-DNA cleavable complex.

The objective of this research was to clarify the role of ROS and Topo II inhibition in the induction of apoptosis mediated by plumbagin. As determined by the comet assay, plumbagin induced DNA cleavage in HL-60 cells, whereas in a cell line with reduced Topo II activity-HL-60/MX2, the level of DNA damage was significantly decreased. The onset of DNA strand break formation in HL-60 cells was delayed in comparison with the generation of intracellular ROS.

In HL-60/MX2 cells, ROS were generated at a similar rate, whereas a significant reduction in the level of DNA damage was detected. The pretreatment of cells with N-acetylcysteine (NAC) attenuated plumbagin-induced DNA damage, pointing out to the involvement of ROS generation in cleavable complex formation.

* These results suggest that plumbagin-induced ROS does not directly damage DNA but requires the involvement of Topo II.

* Furthermore, experiments carried out using light spectroscopy indicated no direct interactions between plumbagin and DNA.

* The induction of apoptosis was significantly delayed in HL-60/MX2 cells indicating the involvement of Topo II inhibition in plumbagin-mediated apoptosis.

* Thus, these findings strongly suggest ROS-mediated inhibition of Topo II as an important mechanism contributing to the apoptosis-inducing properties of plumbagin.

Pharm Res. 2008 Sep;25(9):2171-80. Epub 2008 Jan 23.

Powolny AA, Singh SV.

Department of Pharmacology and Urology, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

http://www.ncbi.nlm.nih.gov/pubmed/18213451

Abstract

PURPOSE: To investigate the mechanism of human prostate cancer cell growth inhibition by plumbagin, a constituent of the widely used medicinal herb Plumbago zeylanica L.

MATERIALS AND METHODS: Cell viability was determined by trypan blue dye exclusion assay. Apoptosis induction was assessed by analysis of cytoplasmic histone-associated DNA fragmentation. Cell cycle distribution and generation of reactive oxygen species (ROS) were determined by flow cytometry. The effect of plumbagin treatment on cellular redox status was determined by analysis of intracellular glutathione (GSH) levels and expression of genes involved in ROS metabolism.

RESULTS: Plumbagin treatment decreased viability of human prostate cancer cells (PC-3, LNCaP, and C4-2) irrespective of their androgen responsiveness or p53 status. Plumbagin-mediated decrease in cell viability correlated with apoptosis induction, which was accompanied by ROS generation and depletion of intracellular GSH levels. Pretreatment of cells with the antioxidant N-acetylcysteine inhibited plumbagin-mediated ROS generation and apoptosis. Plumbagin treatment also resulted in altered expression of genes responsible for ROS metabolism, including superoxide dismutase 2 (Mn-SOD).

CONCLUSION: The present study points towards an important role of ROS in plumbagin-induced apoptosis in human prostate cancer cells.

Nat Prod Commun. 2009 Aug;4(8):1063-8.

Grevenstuk T, Gonçalves S, Almeida S, Coelho N, Quintas C, Gaspar MN, Romano A.

Faculty of Sciences and Technology, University of Algarve, Faro, Portugal.

http://www.ncbi.nlm.nih.gov/pubmed/19768984

Abstract:

Evaluation of the antioxidant activity of the methanol, water and n-hexane extracts of Drosera intermedia, determined by the Folin-Ciocalteau (F-C), trolox equivalent antioxidant capacity (TEAC) and oxygen radical antioxidant capacity (ORAC) assays showed that the methanol extract had the highest antioxidant activity (F-C: 378.6 +/- 31.5 micromol(GAE)/mg(extract); TEAC: 332.2 +/- 29.1 micromol(TE)/mg(extract); ORAC: 64.7 +/- 7.8 micromol(TE)/mg(extract). Antimicrobial activity was tested against seven bacterial and eight yeast strains using the agar diffusion assay, followed by the determination of minimum inhibitory concentrations (MIC).

* All tested Drosera intermedia extracts demonstrated strong antimicrobial properties with a broad spectrum of activity.

* However, the n-hexane extract exhibited much greater activity than water and methanol extracts.

* The most susceptible microorganisms to the n-hexane extract were Staphylococcus epidermidis ATCC 12228 and Candida albicans YP0175, for which a MIC value of 13.0 microg/mL was scored.

J Ethnopharmacol. 2009 Aug 17;125(1):90-6. Epub 2009 Jun 18.

Fukushima K, Nagai K, Hoshi Y, Masumoto S, Mikami I, Takahashi Y, Oike H, Kobori M.

School of Agriculture, Tokai University, Kawayou, Minamiaso-mura, Kumamoto 869-1404, Japan.

http://www.ncbi.nlm.nih.gov/pubmed/19540325

Abstract:

ETHNOPHARMACOLOGICAL RELEVANCE:

Several Northern Hemisphere Drosera species have been used in the therapy of respiratory tract infections as the traditional medicine Droserae Herba.

AIM OF THE STUDY:

To determine the anti-inflammatory effects of Drosera species and to investigate a substitute material for Droserae Herba, we examined the effect of extracts of Drosera rotundifolia, Drosera tokaiensis and Drosera spatulata on activated T cell membrane (aTc-m)-induced inflammatory gene expression in HMC-1 human mast cells.

MATERIALS AND METHODS:

Drosera rotundifolia, Drosera spatulata and Drosera tokaiensis were collected in Japan. Herbs were extracted with 80% EtOH, and subsequently applied to OASIS HLB column. HMC-1 cells were treated with each Drosera column-adsorbed fraction for 15min, and subsequently added to aTc-m and incubated for 16h. Inflammatory gene and protein expressions were determined by DNA microarray, RT-PCR and Western blotting.

RESULTS:

Drosera rotundifolia and Drosera tokaiensis fractions, but not the Drosera spatulata fraction, suppressed inflammatory gene expression induced by aTc-m in HMC-1 cells.

CONCLUSIONS:

* Drosera rotundifolia and Drosera tokaiensis suppressed activation of HMC-1 cells induced by aTc-m.

* Since the Drosera tokaiensis fraction was more effective than the traditionally used Drosera rotundifolia, Drosera tokaiensis is a likely substitute as a source of Droserae Herba.

Biotechnol Appl Biochem. 2008 Sep 9. [Epub ahead of print]

Krolicka A, Szpitter A, Maciag M, Biskup E, Gilgenast E, Romanik G, Kaminski M, Wegrzyn G, Lojkowska E.

http://www.ncbi.nlm.nih.gov/pubmed/18782083

Abstract:

The objective of this research was to evaluate antioxidant as well as antibacterial properties of secondary metabolites obtained from Drosera aliciae plants grown in vitro and examine the mechanism of their antimicrobial action. Bactericidal activity of extracts from D. aliciae as well as pure ramentaceone (naphthoquinone) present in this plant were examined against human pathogenic strains both resistant and susceptible to antibiotics.

Chloroform extract proved to be more effective than methanol preparation against all of the tested strains except for Pseudomonas aeruginosa isolates with the lowest minimal bactericidal concentration (MBC) values in the case of Staphylococcus aureus (25-50 mg fresh weight ml-1). The influence of D. aliciae extracts and ramentaceone on the synthesis of DNA, RNA or proteins in cultures of Enterococcus faecalis was estimated by measurement of incorporation of radioactive precursors: [3H] thymidine, [3H] uridine or [3H] leucine, respectively.

* Methanol extract from D. aliciae, except for a moderate effect on DNA synthesis, had no influence on RNA and protein synthesis.

* Chloroform preparation caused about a 75% decrease in [3H]uridine incorporation in comparison to control after 60 min and a significant reduction in DNA and protein synthesis (44% and 30% respectively).

* Ramentaceone also reduced DNA and RNA synthesis but less efficiently than chloroform extract and caused no changes in [3H] leucine incorporation.

* Methanol extract from D. aliciae proved to be an effective antioxidant in both the DPPH and FRAP assay with the activities exceeding those of well known antioxidants - flavonoids.

* Chloroform extract and ramentaceone showed no antioxidative properties.

Carnivora - Induced Production of Antifungal Naphthoquinones in the Pitchers of Carnivorous Plant Nepenthes Khasiana

J Exp Bot. 2010 Mar;61(3):911-22. Epub 2009 Dec 16.

Eilenberg H, Pnini-Cohen S, Rahamim Y, Sionov E, Segal E, Carmeli S, Zilberstein A.

Department of Plant Sciences, The George S Wise Faculty of Life Sciences, Tel Aviv University, Ramat Aviv 69978, Israel.

http://www.ncbi.nlm.nih.gov/pubmed/20018905

Abstract:

Nepenthes spp. are carnivorous plants that have developed insect capturing traps, evolved by specific modification of the leaf tips, and are able to utilize insect degradation products as nutritional precursors. A chitin-induced antifungal ability, based on the production and secretion to the trap liquid of droserone and 5-O-methyldroserone, is described here. Such specific secretion uniquely occurred when chitin injection was used as the eliciting agent and probably reflects a certain kind of defence mechanism that has been evolved for protecting the carnivory-based provision of nutritional precursors.

* The pitcher liquid containing droserone and 5-O-methyldroserone at 3:1 or 4:1 molar ratio, as well as the purified naphthoquinones, exerted an antifungal effect on a wide range of plant and human fungal pathogens.

* When tested against Candida and Aspergillus spp., the concentrations required for achieving inhibitory and fungicidal effects were significantly lower than those causing cytotoxicity in cells of the human embryonic kidney cell line, 293T.

* These naturally secreted 1,4-naphthoquinone derivatives, that are assumed to act via semiquinone enhancement of free radical production, may offer a new lead to develop alternative antifungal drugs with reduced selectable pressure for potentially evolved resistance.

Carnivora - Anti-Inflammatory Effects of Plumbagin are Mediated by Inhibition of NF-kappaB Activation in Lymphocytes

Rahul Checker, Deepak Sharma, Santosh Kumar Sandur, Shazia Khanam, T B Poduval

Radiation Biology & Health Sciences Division, Bhabha Atomic Research Centre, Mumbai-400085, India.

http://lib.bioinfo.pl/pmid:19374955

Abstract:

Plumbagin (5-hydroxy-2-methyl-1, 4-naphthoquinone), a quinone isolated from the roots of Plumbago zeylanica was recently reported to suppress the activation of NF-kappaB in tumor cells. NF-kappaB, a ubiquitous transcription factor, plays a central role in regulating diverse processes in leukocytes like cellular proliferation, expression of immunoregulatory genes and apoptosis during innate and adaptive immune responses.

Consequently, plumbagin might affect the biological functions of leukocytes participating in various immune responses. The present report describes novel immunomodulatory effects of plumbagin. Plumbagin inhibited T cell proliferation in response to polyclonal mitogen Concanavalin A (Con A) by blocking cell cycle progression. It also suppressed expression of early and late activation markers CD69 and CD25 respectively, in activated T cells. At these immunosuppressive doses (up to 5 microM), plumbagin did not reduce the viability of lymphocytes.

* Further, the inhibition of T cell proliferation by plumbagin was accompanied by a decrease in the levels of Con A induced IL-2, IL-4, IL-6 and IFN-gamma cytokines.

* Similar immunosuppressive effects of plumbagin on cytokine levels were seen in vivo. To characterize the mechanism of inhibitory action of plumbagin, the mitogen induced IkappaB-alpha degradation and nuclear translocation of NF-kappaB was studied in lymphocytes.

* Plumbagin completely inhibited Con A induced IkappaB-alpha degradation and NF-kappaB activation.

* Further, plumbagin prevented Graft Versus Host Disease-induced mortality in mice.

* To our knowledge this is the first report showing the immunomodulatory effects of plumbagin in lymphocytes via modulation of NF-kappaB activation.

Keywords: plumbagin; nf-kappab; nf-kappab activation; lymphocyte; con; activation; ikappab-alpha; ikappab-alpha degradation; cell; anti-inflammatory effect; zeylanica; anti-inflammatory; inhibition; proliferation; immunomodulatory effect; 

Groups: All@BHABHA ATOMIC RESEARCH CENTRE;

Carnivora - Anti-Cancer Mechanism of Plumbagin, a Natural Compound, on Non-Small Cell Lung Cancer Cells

ROHINI GOMATHINAYAGAM, SRINIVASAN SOWMYALAKSHMI, FIRDAUS MARDHATILLAH, RAJ KUMAR, MOHAMMAD A. AKBARSHA and  CHENDIL DAMODARAN

Department of Clinical Sciences, College of Health Sciences, University of Kentucky, Lexington, KY, U.S.A.

Department of Animal Science, School of Life Sciences, Bharathidasan University, Tiruchirappalli 620 024, India

Correspondence to: Chendil Damodaran, Department of Clinical Sciences, College of Health Sciences, University of Kentucky, Room 124E, 900 South Limestone Street, Lexington, KY-40536-0200, U.S.A. Tel: +1 859 323 1100 ext. 80851/80879, Fax: +1 859 323 8957, e-mail: dchen2@uky.edu

http://ar.iiarjournals.org/content/28/2A/785.abstract

Abstract:

Background:

Lung cancer is the leading cause of cancer-related deaths in the United States. Prevailing treatment options have limited therapeutic success in lung cancer, particularly non-small cell lung cancer (NSCLC), as it becomes resistant to therapy. Hence, better therapeutic options are immediately required for lung cancer. Plumbagin, a natural compound has been recently examined for its anticancer effect on different cancers.

Materials and Methods:

To determine the anticancer effect of plumbagin on NSCLC cell lines H460 and A549, cell viability, apoptotic, Western blot and reporter assays were performed.

Results:

* Plumbagin significantly inhibited the growth of H460 cells compared to A549 cells, and down-regulated the expression of EGFR/Neu and its downstream signaling (Akt, NF-κB, Bcl-2 and survivin) in H460 cells.

* In addition, plumbagin up-regulated the expression of p53 and p21CIP1/WAF1 causing cell cycle arrest in the G2/M-phase by down-regulating G2/M regulatory proteins (cyclinB1 and Cdc25B) in H460 cells.

* Furthermore, it activated the JNK/p38 signaling, leading to caspase-3 activation resulting in the induction of apoptosis.

Conclusion:

*Plumbagin exerted anticancer activity on NSCLC cells by modulating the pro-survival and pro-apoptotic signaling that causes induction of apoptosis.

J Biol Chem. 2006 Jun 23;281(25):17023-33. Epub 2006 Apr 19.

Sandur SK, Ichikawa H, Sethi G, Ahn KS, Aggarwal BB.

Cytokine Research Laboratory, Department of Experimental Therapeutics, Unit 143, the University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.

http://www.ncbi.nlm.nih.gov/pubmed/16624823

Abstract:

Plumbagin, derived from the medicinal plant Plumbago zeylanica, modulates cellular proliferation, carcinogenesis, and radioresistance, all known to be regulated by the activation of the transcription factor NF-kappaB, suggesting plumbagin might affect the NF-kappaB activation pathway.

* We found that plumbagin inhibited NF-kappaB activation induced by TNF, and other carcinogens and inflammatory stimuli (e.g. phorbol 12-myristate 13-acetate, H2O2, cigarette smoke condensate, interleukin-1beta, lipopolysaccharide, and okadaic acid).

* Plumbagin also suppressed the constitutive NF-kappaB activation in certain tumor cells.

* The suppression of NF-kappaB activation correlated with sequential inhibition of the tumor necrosis factor (TNF)-induced activation of IkappaBalpha kinase, IkappaBalpha phosphorylation, IkappaBalpha degradation, p65 phosphorylation, p65 nuclear translocation, and the NF-kappaB-dependent reporter gene expression activated by TNF, TNFR1, TRAF2, NIK, IKK-beta, and the p65 subunit of NF-kappaB.

* Plumbagin also suppressed the direct binding of nuclear p65 and recombinant p65 to the DNA, and this binding was reversed by dithiothreitol both in vitro and in vivo.

* However, plumbagin did not inhibit p65 binding to DNA when cells were transfected with the p65 plasmid containing cysteine 38 mutated to serine.

* Plumbagin down-regulated the expression of NF-kappaB-regulated anti-apoptotic (IAP1, IAP2, Bcl-2, Bcl-xL, cFLIP, Bfl-1/A1, and survivin), proliferative (cyclin D1 and COX-2), and angiogenic (matrix metalloproteinase-9 and vascular endothelial growth factor) gene products. This led to potentiation of apoptosis induced by TNF and paclitaxel and inhibited cell invasion.

* Overall, our results indicate that plumbagin is a potent inhibitor of the NF-kappaB activation pathway that leads to suppression of NF-kappaB-regulated gene products. This may explain its cell growth modulatory, anticarcinogenic, and radiosensitizing effects previously described.

Carnivora - Inhibition of Nox-4 Activity by Plumbagin, a Plant-Derives BioActive Naphthpqionone

Yaxian Ding, Zi-Jiang Chen,  Shiguo Liu, Danian Che, Michael Vetter, Chung-Ho Chang

Article first published online: 18 FEB 2010

DOI: 10.1211/0022357055119

2005 Royal Pharmaceutical Society of Great Britain

http://onlinelibrary.wiley.com/doi/10.1211/0022357055119/abstract

Abstract:

NAD(P)H oxidase contributes to the pathogenesis of cancer and cardiovascular diseases such as hypertension, atherosclerosis, restenosis, cardiac hypertrophy and heart failure. Plumbagin, a plant-derived naphthoquinone, has been shown to exert anticarcinogenic and anti-atherosclerosis effects in animals.

However, the molecular mechanisms underlying these effects remain unknown. It is possible that the beneficial effect of plumbagin is due to the inhibition of NAD(P)H oxidase. Human embryonic kidney 293 (HEK293) and brain tumour LN229 cells express mainly Nox-4, a renal NAD(P)H oxidase. We have examined the effect of plumbagin on Nox-4 activity in HEK293 and LN229 cells using lucigenin-dependent chemiluminescence assay.

* Plumbagin inhibited the activity of Nox-4 in a time- and dose-dependent manner in HEK293 and LN229 cells. Production of superoxide in HEK293 cells was inhibited by diphenyleneiodonium (DPI), a NAD(P)H oxidase inhibitor.

* The superoxide production in HEK293 cells was NADPH- and NADH-dependent indicating that the superoxide was generated by a NAD(P)H oxidase in HEK293 cells, but not by the redox-cycling of lucigenin.

* Furthermore, plumbagin inhibited the superoxide production in Nox-4 transfected COS-7 cells.

* These results indicated that plumbagin directly interacted with Nox-4 and inhibited its activity.

Immunobiology. 2011 Mar;216(3):367-73. Epub 2010 Aug 19.

Bhaskar S, Shalini V, Helen A.

Department of Biochemistry, University of Kerala, Thiruvananthapuram, Kerala, India.

http://www.ncbi.nlm.nih.gov/pubmed/20828867

Abstract:

Toll-like receptors (TLRs) have been shown to play a pivotal role in both innate and adaptive immune responses. TLR family is the essential recognition and signaling component of mammalian host defense. Both genetic and biochemical data support a common signaling pathway that finally leads to the activation of NF-κB and induction of the cytokines and co-stimulatory molecules required for the activation of the adaptive immune response. The present study was designed to examine the involvement of TLR2 and TLR4 in the oxidized LDL induced inflammation in human PBMCs and the effect of flavonoid quercetin on TLR-NF-κB signaling mechanism. LDL was isolated from human plasma and oxidation of LDL was done by incubating with 10 μM CuSO₄ overnight at 37°C. The isolated human PBMCs in culture were used as the model system.

* 50 μg/ml ox-LDL treatment significantly up regulated TLR2 and TLR4 expression in isol human PBMCs after 24 h of culture and this was down regulated by quercetin at 25 μM concentration.

* ox-LDL caused a significant activation of NF-κB as evidenced by the detection of enhanced p65 subunit in nuclear extracts.

* Supplementation of quercetin significantly modulates the NF-κB p65 nuclear translocation.

* The cytokine IL-6 production was significantly increased in ox-LDL treated group and was decreased by quercetin treatment.

* Quercetin mediated reduction of TLR2 and TLR4 expression and the inhibition of nuclear translocation of NF-κB p65 in turn decreased the inflammatory enzymes like 5-LOX and COX and also decreased the mRNA expression of inducible enzymes like COX-2 and iNOS.

* Quercetin inhibited the ox-LDL induced TLR2 and TLR4 expression at mRNA level and modulated the TLR-NF-κB signaling pathway thereby inhibited the cytokine production and down regulated the activity of inflammatory enzymes thus have protective effect against the ox-LDL induced inflammation in PBMCs.

Carnivora - The Natural Flavanoid Quercetin Ameliorates Cerulein-Induced Acute Pancreatitis in Mice

Biol Pharm Bull. 2010;33(9):1534-9.

Carvalho KM, Morais TC, de Melo TS, de Castro Brito GA, de Andrade GM, Rao VS, Santos FA.

Post-Graduate Programme in Medical Sciences, Faculty of Medicine, Federal University of Ceará, Brazil.

http://www.ncbi.nlm.nih.gov/pubmed/20823570

Abstract:

Many plant-derived flavonoids including quercetin exhibit antioxidant and antiinflammatory properties. Proinflammatory cytokines and oxidative stress play an important role in acute pancreatitis. This study aimed to evaluate the effect of quercetin on cerulein-induced acute pancreatitis in mice. Animal groups were pretreated with quercetin (25, 50, 100 mg/kg, per os (p.o.)), thalidomide (200 mg/kg, p.o.) or vehicle (2% dimethyl sulfoxide (DMSO)) 1 h before hourly (x5) intraperitoneal injections of cerulein. A saline (0.9%, NaCl)-treated control group was included for comparison.

*Cerulein significantly enhanced the serum levels of amylase and lipase, and pancreatic myeloperoxidase activities, malondialdehyde and the proinflammatory cytokines tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and IL-6, as well as the pancreatic wet weight/body weight ratio.

*Cerulein significantly reduced the serum levels of IL-10. Histological assessment of the pancreas showed tissue edema, neutrophil infiltration, acinar vacuolization, and cell necrosis and a marked increase in the immunoreactivity staining for TNF-alpha.

* Pretreatment with quercetin or thalidomide significantly attenuated the severity of cerulein-induced acute pancreatitis as evidenced by effective reductions in the pancreatic wet weight/body weight ratio, biochemical indices, proinflammatory cytokines, myeloperoxidase activity, malondialdehyde formation, and an increase in antiinflammatory cytokine IL-10.

* Quercetin treatment also markedly suppressed the histological changes such as pancreatic edema, inflammatory cell infiltration, acinar cell necrosis, and the expression of TNF-alpha.

* Taken together, these results indicate that quercetin ameliorates the severity of cerulein-induced acute pancreatitis by acting as an antiinflammatory and antioxidant agent.

Carnivora - Quercetin Increases Brain and Muscle Mitochondrial Biogenesis and Exercise Tolerance

Am J Physiol Regul Integr Comp Physiol. 2009 Apr;296(4):R1071-7. Epub 2009 Feb 11.

Davis JM, Murphy EA, Carmichael MD, Davis B.

University of South Carolina, Department of Exercise Science, Columbia, SC 29208, USA. markd@mailbox.sc.edu

http://www.ncbi.nlm.nih.gov/pubmed/19211721

Abstract:

Quercetin is one of a broad group of natural polyphenolic flavonoid substances that are being investigated for their widespread health benefits. These benefits have generally been ascribed to its combination of antioxidant and anti-inflammatory activity, but recent in vitro evidence suggests that improved mitochondrial biogenesis could play an important role. In addition, the in vivo effects of quercetin on mitochondrial biogenesis exercise tolerance are unknown. We examined the effects of 7 days of quercetin feedings in mice on markers of mitochondrial biogenesis in skeletal muscle and brain, and on endurance exercise tolerance.

Mice were randomly assigned to one of the following three treatment groups: placebo, 12.5 mg/kg quercetin, or 25 mg/kg quercetin. Following 7 days of treatment, mice were killed, and soleus muscle and brain were analyzed for mRNA expression of peroxisome proliferator-activated receptor-gamma coactivator (PGC-1alpha) and sirtuin 1 (SIRT1), and mitochondrial DNA (mtDNA) and cytochrome c. Additional mice underwent a treadmill performance run to fatigue or were placed in voluntary activity wheel cages, and their voluntary activity (distance, time, and peak speed) was recorded.

* Quercetin increased mRNA expression of PGC-1alpha and SIRT1 (P < 0.05), mtDNA (P < 0.05) and cytochrome c concentration (P < 0.05).

* These changes in markers of mitochondrial biogenesis were associated with an increase in both maximal endurance capacity (P < 0.05) and voluntary wheel-running activity (P < 0.05).

* These benefits of querectin on fitness without exercise training may have important implications for enhancement of athletic and military performance and may also extend to prevention and/or treatment of chronic diseases.

Carnivora - Formic Acid Induces Yca1p-Independent Apoptosis-like Cell Death in the Yeast Saccharomyces Cerevisiae

FEMS Yeast Res. 2008 Jun;8(4):531-9. Epub 2008 Apr 29.

Du L, Su Y, Sun D, Zhu W, Wang J, Zhuang X, Zhou S, Lu Y.

Department of Biochemistry, School of Life Sciences, Sun Yat-sen University, Guangzhou, Republic of China.

http://www.ncbi.nlm.nih.gov/pubmed/18452540

Abstract

Formic acid disrupts mitochondrial electron transport and sequentially causes cell death in mammalian ocular cells by an unidentified molecular mechanism. Here, we show that a low concentration of formic acid induces apoptosis-like cell death in the budding yeast Saccharomyces cerevisiae, with several morphological and biochemical changes that are typical of apoptosis, including chromatin condensation, DNA fragmentation, externalization of phosphatidylserine, reactive oxygen species (ROS) production, loss of mitochondrial membrane potential and mitochondrion destruction. This process may not be dependent on the activation of Yca1p, the yeast caspase counterpart.

* In addition, the cell death induced by formic acid is associated with ROS burst,while intracellular ROS accumulate more rapidly and to a higher level in the YCA1 disruptant than in the wild-type strain during the progression of cell death.

* Our data indicate that formic acid induces yeast apoptosis via an Yca1p-independent pathway and it could be used as an extrinsic inducer for identifying the regulators downstream of ROS production in yeast.

J Pharm Pharmacol. 2010 Jul;62(7):908-14.

Choi DH, Li C, Choi JS.

College of Medicine, Chosun University, Gwangju, Republic of Korea.

http://www.ncbi.nlm.nih.gov/pubmed/20636879

Abstract

OBJECTIVES:

The effects of myricetin, a natural flavonoid, on the pharmacokinetics of losartan and its active metabolite, EXP-3174, were investigated in rats. Losartan and myricetin interact with cytochrome P450 (CYP) enzymes and P-glycoprotein, and the increase in the use of health supplements may result in myricetin being taken concomitantly with losartan as a combination therapy to treat or prevent cardiovascular diseases.

METHODS:

The pharmacokinetic parameters of losartan and EXP-3174 were determined after oral administration of losartan (9 mg/kg) to rats in the presence or absence of myricetin (0.4, 2 and 8 mg/kg). The effects of myricetin on P-glycoprotein as well as CYP3A4 and CYP2C9 activity were also evaluated.

KEY FINDINGS:

* Myricetin inhibited CYP3A4 and CYP2C9 enzyme activity with a 50% inhibition concentration of 7.8 and 13.5 microm, respectively.

* In addition, myricetin significantly enhanced the cellular accumulation of rhodamine 123 in MCF-7/ADR cells overexpressing P-glycoprotein in a concentration-dependent manner.

* The pharmacokinetic parameters of losartan were significantly altered by myricetin compared with the control.

* The presence of myricetin (2 or 8 mg/kg) increased the area under the plasma concentration-time curve of losartan by 31.4-61.1% and peak plasma concentration of losartan by 31.8-50.2%.

* Consequently, the absolute bioavailability of losartan in the presence of myricetin increased significantly (P < 0.05, 2 mg/kg; P < 0.01, 8 mg/kg) compared with the control.

* There was no significant change in the time to reach the peak plasma concentration, apparent volume of distribution at steady state or terminal half-life of losartan in the presence of myricetin.

* Furthermore, concurrent use of myricetin (8 mg/kg) significantly decreased the metabolite-parent area under the plasma concentration-time curve ratio by 20%, implying that myricetin may inhibit the CYP-mediated metabolism of losartan to its active metabolite, EXP-3174.

CONCLUSIONS:

The enhanced bioavailability of losartan may be mainly due to inhibition of the CYP3A4- and CYP2C9-mediated metabolism of losartan in the small intestine or in the liver, and the P-glycoprotein efflux pump in the small intestine by myricetin.

Int J Oncol. 2010 Aug;37(2):377-85.

Lo C, Lai TY, Yang JH, Yang JS, Ma YS, Weng SW, Chen YY, Lin JG, Chung JG.

School of Chinese Medicine, China Medical University, Taichung 404, Taiwan, ROC.

http://www.ncbi.nlm.nih.gov/pubmed/20596665

Abstract:

The natural antioxidant gallic acid (GA) has demonstrated a significant inhibition of cell proliferation and induction of apoptosis in a series of cancer cell lines. However, there is no available information to show whether gallic acid induces apoptosis in human skin cancer cells. In the present study, we report GA-induced apoptosis in A375.S2 human melanoma cells.

* Gallic acid affected morphological changes, decreased the percentage of viable cells and induced apoptosis in A375.S2 cells in a dose- and time-dependent manner.

* Observation of the molecular mechanism of apoptosis in A375.S2 cells showed that gallic acid up-regulated the proapoptotic proteins such as Bax, and induced caspase cascade activity, but down-regulated antiapoptotic proteins such as Bcl-2.

* Gallic acidinduced reactive oxygen species (ROS) and intracellular Ca2+ productions and decreased the level of mitochondrial membrane potential (DeltaPsim) in A375.S2 cells in a time-dependent manner.

* Gallic acid triggered cytosolic release of apoptotic molecules, cytochrome c, promoted activation of caspase-9 and caspase-3, and ultimately apoptotic cell death.

* In addition, gallic acid also promoted cytosolic release of apoptosis-inducing factor (AIF) and endonuclease G (Endo G).

* Therefore, gallic acid may also induce apoptosis through a caspase-independent pathway.

* Our results suggest that gallic acid might be a potential anticancer compound; however, in depth in vivo studies are needed to elucidate the exact mechanism.

Nutr Cancer. 2010;62(5):601-10.

Reddivari L, Vanamala J, Safe SH, Miller JC Jr.

Colorado State University, Fort Collins, Colorado, USA.

http://www.ncbi.nlm.nih.gov/pubmed/20574921

Abstract:

We recently reported that colored potato extracts and an anthocyanin rich fraction suppressed lymph-node carcinoma of the prostate (LNCaP) and prostate cancer-3 (PC-3) prostate cancer cell proliferation and induced apoptosis via caspase-dependent and caspase-independent pathways.

* Chlorogenic acid, caffeic acid, gallic acid, catechin, malvidin, and glycoalkaloids (alpha-chaconine and solanine) have now been identified as the major bioactive components of potato, and their effects on LNCaP and PC-3 cell proliferation and apoptosis have been investigated. alpha-chaconine (5 microg/ml) and gallic acid (15 microg/ml) exhibited potent antiproliferative properties and increased cyclin-dependent kinase inhibitor p27 levels in both cell lines.

* Both alpha-chaconine and gallic acid induced poly [adenosine diphosphate (ADP)] ribose polymerase cleavage and caspase-dependent apoptosis in LNCaP cells; however, caspase-independent apoptosis through nuclear translocation of endonuclease G was observed in both LNCaP and PC-3 cells. alpha-chaconine and gallic acid activated c-Jun N-terminal protein kinase (JNK), and this response played a major role in induction of caspase-dependent apoptosis in LNCaP cells; whereas modulation of JNK and mitogen-activated protein kinase did not affect alpha-chaconine- and gallic acid-induced caspase-independent apoptosis.

* These results suggest that apoptosis induced by whole potato extracts in prostate cancer cell lines may be in part due to alpha-chaconine and gallic acid.

Carnivora - L-Arginine Reverses Radiation-Induced Immune Dysfunction: The Need for Optimum Treatment Window

Radiat Res. 2009 Feb;171(2):180-7.

Shukla J, Chatterjee S, Thakur VS, Premachandran S, Checker R, Poduval TB.

Immunology and Hyperthermia Section, Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Trombay, Mumbai - 400 085, India.

http://www.ncbi.nlm.nih.gov/pubmed/19267543

Abstract:

The aim of the present study was to investigate the protective efficacy of l-arginine in mitigating the injury induced by 2 Gy of total-body gamma radiation (TBI). Mice exposed to radiation (TBI group) had significantly decreased spleen weight, splenocyte numbers and bone marrow cellularity.

*Administration of l-arginine 2 h after TBI (TBI + l-arginine group) was effective in reducing the radiation-induced depletion of spleen and bone marrow cellularity but was not effective when administered before TBI (l-arginine + TBI group).

* The radiation-induced decrease in Con A-induced spleen cell proliferation, specific antibody response of spleen B cells to sheep red blood cells, and spleen RNA content was reversed in mice in the TBI + l-arginine group.

* The radiation-induced increase in serum TNF-alpha levels, serum nitrate/nitrite (NOx) levels, spleen DNA fragmentation, spleen nitric oxide synthase (NOS) activity, spleen inducible NOS (iNOS) activity, and hepatic iNOS activity was reversed in mice in the TBI + l-arginine group.

* l-Arginine administered before TBI could not reverse these changes.

* Mice in the TBI + l-arginine group had significantly increased spleen arginase activity compared to mice from either the TBI or l-arginine + TBI group.

* The results suggest the importance of the time of administration of l-arginine and the l-arginine pathway in mitigating the radiation-induced host immune dysfunction.

J Surg Res. 2007 Jun 1;140(1):99-108. Epub 2007 Feb 8.

Chatterjee S, Premachandran S, Shukla J, Poduval TB.

Immunology and Hyperthermia Section, Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Trombay, Mumbai, India.

http://www.ncbi.nlm.nih.gov/pubmed/17292408

Abstract

BACKGROUND:

Dexamethasone (DEX) is demonstrated to have anti-inflammatory properties and known to induce hemodynamic improvement in sepsis and septic shock. L-arginine (L-arg), a semi-essential amino acid, depending on its metabolic pathway, becomes very essential in stress situations such as heatstroke, burns, sepsis, trauma, and wound healing.

The aim of this study was to evaluate the synergistic therapeutic effect of Dexamethasone and L-arginine in rescuing the mice from experimental septic shock induced by bacterial lipopolysaccharide (LPS). The experiments were designed to delineate the molecular mechanisms responsible for the increased therapeutic benefit of the combination therapy (CT) in LPS-induced septic shock.

METHODS:

Acute endotoxemia was induced in Swiss male mice by i.p. injection of LPS (18 mg kg(-1)) at 0 h. lipopolysaccharide-treated mice were divided into four groups.

The first group (Dexamethasone group) received Dexamethasone (2 mg kg(-1)) i.p. at +2 h of lipopolysaccharide.

The second group (L-arg group) received L-arginine i.p. at a dose of 120 mg/kg at +6 h of lipopolysaccharide injection.

The third group (combination therapy group) received Dexamethasone (2 mg kg(-1)) at +2 h lipopolysaccharide followed by L-arginine at +6 h of lipopolysaccharide injection.

The fourth group received saline in place of L-arginine or Dexamethasone ( lipopolysaccharide group).

A sham group was also included, where normal mice received saline in place of lipopolysaccharide or L-arginine or Dexamethasone. At +6 h, mice from sham group, lipopolysaccharide group, and Dexamethasone group were sacrificed at +24 h. Mice from sham group, Dexamethasone group, L-arginine group, and combination therapy group were sacrificed to examine various parameters associated with lipopolysaccharide endotoxemia.

RESULTS:

* The CT with Dexamethasone followed by L-arginine significantly increased the survival of mice injected with a lethal dose of lipopolysaccharide.

* Monotherapy with either Dexamethasone or L-arginine given at the same dose and time did not increase the survival of the mice injected with lipopolysaccharide.

* Dexamethasone administration could significantly reduce the levels of serum TNF-alpha, IL-1beta, IFN-gamma, aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), and nitrite.

* Dexamethasone also down-regulated the expression of liver-inducible nitric oxide synthase (iNOS), and up-regulated the levels of serum anti-inflammatory cytokines like TGF-beta1 and IL-4, hepatic and splenic arginase, in LPS-injected mice.

* The enhanced therapeutic effect of combination therapy correlated with reduced pathological symptoms, decreased Th1 cytokines, increased TGF-beta1 and arginase levels compared to the mice administered with either of the monotherapies.

* The combination therapy group had significantly increased expression of hepatic Hsp 70 and reduced septic shock associated histopathology, in lung and liver, compared to the mice treated with either Dexamethasone or L-arginine.

CONCLUSIONS:

The therapeutic combination therapy with Dexamethasone and L-arginine, at the appropriate dose, time, and sequence of administration, changed the cytokine profile, in favor of reducing the inflammatory response. The significantly enhanced survival observed in the combination therapy group was accompanied by an increased hepatic Hsp 70, hepatic arginase, splenic arginase, and decreased organ injury. This novel concept of combined therapy could form the basis of an effective therapeutic approach in the treatment of sepsis and septic shock.

Nitric Oxide. 2006 Dec;15(4):408-16. Epub 2006 Apr 26.

Chatterjee S, Premachandran S, Bagewadikar RS, Bhattacharya S, Chattopadhyay S, Poduval TB.

Immunology and Hyperthermia Section, Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400 085, India.

http://www.ncbi.nlm.nih.gov/pubmed/16765619

Abstract:

We have demonstrated that therapeutic administration of L-arginine (L-arg) (120 mg/kg) at +2 h of whole body hyperthermia (WBH) could rescue the mice from heatstroke-induced death. Studies were undertaken to elucidate the role of L-arginine in the immunomodulation of the heat-stressed mice.

* Administration of L-arginine (L-arg), (120 mg/kg, i.p.), at +2 h of WBH, rescued the mice from heat-induced death and reduced the hypothermia.

* At +4 and +24 h of WBH, levels of IL-1beta, IFN-gamma, nitrite, TNF-alpha, IL-4, TGF-beta1, inducible form of nitric oxide synthase (iNOS), and corticosterone significantly increased compared to the sham group.

* The elevated levels of Th(1) cytokines, namely TNF-alpha, IL-1beta, IFN-gamma, nitrite, and iNOS, decreased significantly both at +4 and +24 h of WBH, following L-arginine administration.

* However, L-arginine administration did not reduce the increased levels of Th(2) cytokines, namely IL-4 and TGF-beta1, in WBH mice at +4 h of WBH.

* L-arginine administration significantly increased the levels of Th(2) cytokines at +24 h of WBH, compared to the saline-treated WBH mice.

* L-arginine administration significantly increased both the splenic and hepatic arginase activity at +4 and +24 h of WBH compared to the saline-treated WBH mice.

* L-NAME treatment at +2 h of WBH and anti-TGF-beta antibody treatment at 0 h of WBH significantly increased the mortality compared to the saline-treated WBH mice.

* Altered liver histopathology was attenuated following the administration of L-arginine at +2 h of WBH.

* These results suggest that therapeutic administration of L-arginine at appropriate concentration and time attenuates the acute inflammatory response, leading to the rescue of mice from heatstroke.

* L-arginine is a chemical building block called “an amino acid.” It is obtained from the diet and is necessary for the body to make proteins. L-arginine is found in red meat, poultry, fish, and dairy products. It can also be made in a laboratory and used as medicine.

* L-arginine is used for heart and blood vessel conditions including congestive heart failure (CHF), chest pain, high blood pressure, and coronary artery disease. L-arginine is also used for recurrent pain in the legs due to blocked arteries (intermittent claudication), decreased mental capacity in the elderly (senile dementia), erectile dysfunction (ED), and male infertility.

* Some people use L-arginine for preventing the common cold, improving kidney function after a kidney transplant, high blood pressure during pregnancy (pre-eclampsia), improving athletic performance, boosting the immune system, and preventing inflammation of the digestive tract in premature infants.

* L-arginine is used in combination with a number of over-the-counter and prescription medications for various conditions. For example, L-arginine is used along with ibuprofen for migraine headaches; with conventional chemotherapy drugs for treating breast cancer; with other amino acids for treating weight loss in people with AIDS; and with fish oil and other supplements for reducing infections, improving wound healing, and shortening recovery time after surgery.

* Some people apply L-arginine to the skin to speed wound healing and for increasing blood flow to cold hands and feet, especially in people with diabetes. It is also used as a cream for sexual problems in both men and women.

* L-arginine is converted in the body into a chemical called nitric oxide. Nitric oxide causes blood vessels to open wider for improved blood flow.

* L-arginine also stimulates the release of growth hormone, insulin, and other substances in the body.

* L-arginine increases blood flow and seems to decrease blood pressure.

* Sildenafil (Viagra) can lower blood pressure. L-arginine can also lower blood pressure. Taking sildenafil (Viagra) and L-arginine together might cause the blood pressure to go too low. Blood pressure that is too low can cause dizziness and other side effects.

Other Names:

2-Amino-5-guanidinopentanoic Acid, (2S)-2-Amino-5-{[amino (imino) methyl]amino}pentanoic Acid, Acide 2-Amino-5-guanidinopentanoïque, Arg, Arginine, Arginine Ethyl Ester, Arginine Ethyl Ester Dihydrochloride, Arginine Ethyl Ester HCl, Arginine HCl, Arginine Hydrochloride, Di-Arginine Malate, Di-Arginine Orotate, Di-L-Arginine-L-Malate, Dl-Arginine, L-Arginina, L-Arginine Ethyl Ester Dichloride, L-Arginine HCl, L-Arginine Hexanoate, L-Arginine Hydrochloride, L-Arginine Ketoisocaproic Acid, L-Arginine L-Pyroglutamate, L-Arginine Pyroglutamate, L-Arginine Taurinate, Malate de Di-Arginine, Orotate de Di-Arginine, R-Gene 10.

Asparagine, the beta-amido derivative of aspartic acid, is one of the 20 building blocks of protein.

* Asparagine is nonessential to the diet since the body can synthesize it. Only the l-stereoisomer participates in the biosynthesis of mammalian proteins. Its structure is identical to that of the amino acid aspartic acid, except that the latter compound's acidic side-chain carboxyl group has been coupled with ammonia, yielding an amide.

* Asparagine has carboxamide as the side chain's functional group.

* Asparagine is the ß-amide of aspartic acid synthesized from aspartic acid and ATP (adenosine triphosphate).

* The first amino acid to be isolated from its natural source, asparagine was purified from asparagus juice in 1806; proof of the occurrence of this amino acid in proteins was finally obtained in 1932.

* Asparagine plays an important role in the biosynthesis of glycoproteins and is also essential to the synthesis of a large number of other proteins.

* Asparagine is normally available as a white crystalline solid which dissolves in water.

* Asparagine can be produced within a cell through an enzyme called asparagine synthetase or it can absorbed into the cell from the outside.

* Asparagine is one of the principal and frequently the most abundant amino acids involved in the transport of nitrogen.

* Asparagine is an amino acid required by cells for the production of protein.

* Asparagine is an essential component of those proteins that are concerned with signalling, neuronal development and transmission across nerve endings.

* Asparagine is essential to all living cells for the production of many proteins.

* Cells can either internally produce asparagine or they can absorb asparagine from outside the cell, as it is obtained from a person's diet and made available through the bloodstream to all cells in the body.

* L-asparagine is an amino acid involved in the metabolic control of cell functions in nerve and brain tissue.

* Asparagine is very active in converting one amino acid into another (amination and transamination) when the need arises.

* Asparagine serves as an amino donor in liver transamination processes. In the liver, a function of asparagine involves converting one amino acid to another.

* Asparagine helps maintain an equilibrium of the central nervous system and has therapeutic properties, but is toxic when used in excess. It also participates in metabolic control of the brain and nervous system having some therapeutic uses in these areas.

* In the central nervous system, asparagine is needed to maintain a balance, preventing over nervousness or being overly calm. Like glutamine, asparagine is important in the metabolism of toxic ammonia in the body.

* The relatively unreactive, neutral amide group in the side chain of asparagine confers no special properties upon this amino acid once it is included within a protein by two peptide bonds.

* Both asparagine and glutamine are made with high-energy ATP and can return this energy when they metabolize back to aspartic acid and glutamic acid respectively. Both require vitamin B6 and enzymes for their formation.

* In plants, asparagine is a reversible combination of ammonia and aspartic acid. This is important in plant metabolism in order to preserve ammonia.

Asparagine Deficiency:

Asparagine deficiency is rare. However, an asparagine deficiency could be a contributing cause of fatigue and immune system stress including autoimmune disorders, infections and severe allergies.

Asparagine:

Asparagine, created from another amino acid, aspartic acid, is needed to maintain balance in the central nervous system; it prevents you from being either overly nervous or overly calm. As it is converted back into aspartic acid, asparagine releases energy that brain and nervous system cells use for metabolism. It promotes the process by which one amino acid is transformed into another in the liver.



Aspartic Acid:

* Because aspartic acid increases stamina, it is good for fatigue and depression, and plays a vital role in metabolism.

*  Chronic fatigue may result from low levels of aspartic acid, because this leads to lowered cellular energy.

* In proper balance, aspartic acid is beneficial for neural and brain disorders; it has been found in increased levels in persons with epilepsy and in decreased levels in people with some types of depression.

* It is good for athletes and helps to protect the liver by aiding in the removal of excess ammonia.

* Aspartic acid combines with other amino acids to form molecules that absorb toxins and remove them from the bloodstream.

* It also helps to move certain minerals across the intestinal lining and into the blood and cells, aids cell function, and aids the function of RNA and DNA, which are the carriers of genetic information.

* It enhances the production of immune globulins and antibodies (immune system proteins).

* Plant protein, especially that found in sprouting seeds, contains an abundance of aspartic acid.