CAT'S CLAWS AND SHARK CARTILAGE, CANCER AND INFLAMMATIONS / UÑA DE GATO Y CARTILAGO DE TIBURON, CANCER E INFLAMACION.

  

Cat's Claws and Shark Cartilage, Antitumor and anti-inflammatory effects !

 

  Uña de Gato y Cartilago de Tiburon, efectos antitumorales y antiinlamatorios !

 

 

 

 

EDITORIAL ENGLISH
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Hello friends of the Net, DERMAGIC again with you. Today a quite interesting NON DERMATOLOGIC topic. THE CAT'S CLAW AND THE SHARK CARTILAGE:

THE CAT'S CLAW is not in fact the "fingernail of a cat", it is a plant from PERU called UNCARIA TOMENTOSA, to which have been discovered some beneficent actions for the organism, being able to be used in:  

1.) arthritis, osteoarthritis.
 

2.) rheumatism.
 

3.) bursitis.
 

4.) gout.
 

5.) immunologic deficiencies.
 

6.) intestinal permeability.
 

7.) intoxications.
 

8.) inhibits the platelet aggregation.
 

9.) anti-inflammatory.
 

10.) Anti-cancer activity (breas cancer, lung cancer, thyroid cancer).
 

11.) aids.
 

12.) Diabetes and others.

Which demonstrate from this plant native from the Peruvian Amazon its usefulness today as anti-inflammatory and anti-tumor effects.

THE SHARK CARTILAGE is not left behind, as many studies have shown that its components have been used in conditions such as:  

1,) ANTI-TUMOR-CANCER (tumor growth).
 

2.) ANTI ANGIOGENESIS (atherosclerosis, suppression of atherogenesis, TROMBOSIS).
 

3.) PSORIASIS.
 

4.) anti-inflammatory.
 

5.) analgesic.
 

6.) hemodialysis.
 

7.) fibrosis.
 

8.) viral and protozoan infections.
 

9.) hyperglycemia and others. 

In these 70 references you will know the chemical components of UNCARIA TOMENTOSA (CAT'S CLAW) and SHARK CARTILAGE and their beneficial effects on different diseases...So

The really TRUTH is that these products today in day they are a truthful sample that that these ALTERNATIVE medicines are occupying an important place in our SCIENTIFIC WORLD.

Greetings to all !

Dr. Jose Lapenta 

EDITORIAL ESPAÑOL 

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Hola amigos de la Red, DERMAGIC nuevamente con ustedes. Hoy en día un tema NO DERMATOLOGICO  muy interesante: LA UÑA GATO Y EL CARTILAGO DEL TIBURÓN.

LA UÑA DE GATO no es de hecho la "uña de un gato", es una planta del PERÚ llamada UNCARIA TOMENTOSA, a la que se han descubierto algunas acciones benéficas para el organismo, pudiendo utilizarse en:

1.) artritis, osteoartritis.

2.) reumatismo. 

3.) bursitis.

4.) gota.

5.) deficiencias inmunológicas.

6.) permeabilidad intestinal.

7.) intoxicaciones.

8.) inhibe la agregación plaquetaria.

9.) Antiinflamatorio.

10. Actividad anticancerígena (cáncer de senos, cáncer de pulmón, cáncer de tiroides).

11.) SIDA.

12.) Diabetes y otros.

Que demuestran que esta planta proveniente de la Amazonía peruana es de gran utilidad hoy en día debido a sus demostrados efectos antiinflamatorios y antitumorales.

EL CARTILAGO DEL TIBURÓN no se queda atrás, ya que muchos estudios han demostrado que sus componentes han sido utilizados en condiciones tales como:

1,) ANTI-TUMOR-CANCER (crecimiento tumoral).

2.) ANTI-ANGIOGENESIS (aterosclerosis, supresión de la aterogénesis, TROMBOSIS).

3.) PSORIASIS.

4) antiinflamatorio.

5. analgésico.

6.) hemodiálisis.

7.) fibrosis.

8.) infecciones virales y protozoarias.

9.) hiperglucemia y otros.


En estas 70 referencias conocerás los componentes químicos de la  UNCARIA TOMENTOSA (UÑA DE GATO) y CARTILAGO DE TIBURON y sus efectos beneficiosos sobre diferentes enfermedades ...De modo que:

La VERDAD realmente es que estos productos hoy en día son una muestra verídica que estos medicamentos ALTERNATIVOS están ocupando un lugar importante en nuestro MUNDO CIENTÍFICO.

Saludos a todos. !

Dr. Jose Lapenta.

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BIBLIOGRAPHICAL REFERENCES / REFERENCIAS BIBLIOGRAFICAS
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UNCARIA TOMENTOSA- CAT'S CLAW- UÑA DE GATO
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1.) Enhanced DNA repair, immune function and reduced toxicity of C-MED-100, a novel aqueous extract from Uncaria tomentosa. 
2.) Uncaria tomentosa (Willd.) D.C.: cat's claw, una de gato, or saventaro. 
3.) Stimulation of interleukin-1 and -6 production in alveolar macrophages by the neotropical liana, Uncaria tomentosa (una de gato). 
4.) Uncaria tomentosa (Willd.) DC.--ethnomedicinal use and new pharmacological, toxicological and botanical results. 
5.) Induction of apoptosis and inhibition of proliferation in human tumor cells treated with extracts of Uncaria tomentosa. 
6.) Evaluation of the toxicity of Uncaria tomentosa by bioassays in vitro. 
7.) Pentacyclic oxindole alkaloids from Uncaria tomentosa induce human endothelial cells to release a lymphocyte-proliferation-regulating factor. 
8.) Depletion of specific binding sites for estrogen receptor by Uncaria tomentosa. 
9.) Antiinflammatory actions of cat's claw: the role of NF-kappaB. 
10.) Mutagenic and antimutagenic activities of Uncaria tomentosa and its extracts.
11.) Plant metabolites. New compounds and anti-inflammatory activity of Uncaria tomentosa.
12.) New polyhydroxylated triterpenes from Uncaria tomentosa.
13.) Plant metabolites. Structure and in vitro antiviral activity of quinovic acid glycosides from Uncaria tomentosa and Guettarda platypoda.
14.) [Phytochemical and biological study of Uncaria tomentosa].
15.) The alkaloids of Uncaria tomentosa and their phagocytosis-stimulating action].
16.) CAT'S CLAW (Una de Gato) #K725 INGREDIENTS: 
17.) The antiproliferative effects of Uncaria tomentosa extracts and fractions on the growth of breast cancer cell line.
18.) Uncaria tomentosa-Adjuvant Treatment for Breast Cancer: Clinical Trial.
19.) Anticancer activity of the Uncaria tomentosa (Willd.) DC. preparations with different oxindole alkaloid composition.
20.) Cat's claw: an Amazonian vine decreases inflammation in osteoarthritis.
21.) Uncaria tomentosa acts as a potent TNF-alpha inhibitor through NF-kappaB.
22.) The Immunomodulatory Potential of Selected Bioactive Plant-Based Compounds in Breast Cancer: A Review.
23.) Uncaria tomentosa (cat's claw) improves quality of life in patients with advanced solid tumors.
24.) Quinovic acid glycosides purified fraction from Uncaria tomentosa induces cell death by apoptosis in the T24 human bladder cancer cell line.
25.) Antiproliferative and pro-apoptotic effects of Uncaria tomentosa in human medullary thyroid carcinoma cells.
26.) An active ingredient of Cat's Claw water extracts identification and efficacy of quinic acid.
27.) [Cat's Claw: an herb from the Peruvian Amazon].
28.) Prevention of experimental diabetes by Uncaria tomentosa extract: Th2 polarization, regulatory
T cell preservation or both?
29.) Herbal medications commonly used in the practice of rheumatology: mechanisms of action, efficacy, and side effects.
30.) Mitraphylline inhibits lipopolysaccharide-mediated activation of primary 31.) Anti-inflammatory activity of Mitraphylline isolated from Uncaria tomentosa bark.
32.) Synthesis and biological evaluation of quinic acid derivatives as anti-inflammatory agents.
 

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 CARTILAGO DE TIBURON / SHARK CARTILAGE

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1.) How useful are unconventional cancer treatments?
2.) A monoclonal antibody which recognizes a glycosaminoglycan epitope in both dermatan sulfate and chondroitin sulfate proteoglycans of human skin.
3.) [The national cancer fund (Koningin Wilhelmina Fonds) and the Houtsmuller-therapy for cancer].
4.) Effect of U-995, a potent shark cartilage-derived angiogenesis inhibitor, on anti-angiogenesis and anti-tumor activities.
5.) Shark cartilage-containing preparation: protection against reactive oxygen species.
6.) The effect of shark cartilage extracts on the growth and metastatic spread of the SCCVII carcinoma.
7.) Phase I/II trial of the safety and efficacy of shark cartilage in the treatment of advanced cancer.
8.) Occurrence of a novel collagen with three distinct chains in the cranial cartilage of the squid Sepia officinalis: comparison with shark cartilage collagen.
9.) Antiangiogenic properties of a novel shark cartilage extract: potential role in the treatment of psoriasis.
10.) Dietary supplement use by women at risk for breast cancer recurrence. The Women's Healthy Eating and Living Study Group.
11.) The analgesic and anti-inflammatory effects of shark cartilage are due to a peptide molecule and are nitric oxide (NO) system dependent.
12.) Shark cartilage-induced hepatitis.
13.) Anti-inflammatory and analgesic activity of a water-soluble fraction from shark cartilage.
14.) Shark-cartilage containing preparation protects cells against hydrogen peroxide induced damage and mutagenesis.
15.) McGuire TR, Kazakoff PW, Hoie EB, Fienhold MA
Department of Pharmacy Practice, University of Nebraska, 
16.) Demonstration of immunogenic keratan sulphate in commercial chondroitin 6-sulphate from shark cartilage. Implications for ELISA assays.
17.) Production and characterization of monoclonal antibodies to shark cartilage proteoglycan.
18.) Differential effects of glycosaminoglycans on neurite outgrowth from hippocampal and thalamic neurones.
19.) Structural studies on sulfated oligosaccharides derived from the carbohydrate-protein linkage region of chondroitin 6-sulfate proteoglycans of shark cartilage. II. Seven compounds containing 2 or 3 sulfate residues.
20.) Structural studies on sulfated oligosaccharides derived from the carbohydrate-protein linkage region of chondroitin 6-sulfate proteoglycans of shark cartilage. I. Six compounds containing 0 or 1 sulfate and/or phosphate residues.
21.) In vitro control of neuronal polarity by glycosaminoglycans.
22.) A novel angiogenic inhibitor derived from Japanese shark cartilage (I). Extraction and estimation of inhibitory activities toward tumor and embryonic angiogenesis.
23.) Determination of the distribution of constituent disaccharide units within the chain near the linkage region of shark-cartilage chondroitin sulfate C.
24.) Suppression of atherogenesis in hypercholesterolemic rabbits by chondroitin-6-sulfate.
25.) High-field n.m.r. studies of keratan sulphates. 1H and 13C assignments of keratan sulphate from shark cartilage.
26.) Ultrastructural cytochemistry of proteoglycans associated with calcification of shark cartilage.
27.) Distribution of different molecular species of collagen in the vertebral cartilage of shark (Carcharius acutus).
28.) Shark cartilage contains inhibitors of tumor angiogenesis.
29.) Galactose 6-sulfate sulfatase activity in Morquio syndrome.
30.) Comparative studies of water sorption of hyaline cartilage.
31.) Structure of chondroitin sulfates. Analyses of the products formed from chondroitin sulfates A and C by the action of the chondroitinases C and AC from Flavobacterium heparinum.
32.) Fish Immunoglobulins.
33.) Camelid and shark single domain antibodies: structural features and therapeutic potential.
34.) Antiangiogenic and anticancer molecules in cartilage.
35.) Antiangiogenic and antimetastatic properties of Neovastat (AE-941), an orally active extract derived from cartilage tissue.
36.) Neovastat--a novel antiangiogenic drug for cancer therapy.
37.) Pro-inflammatory properties of shark cartilage supplement.
38.) Medical Gains of Chondroitin Sulfate Upon Fucosylation.
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 CAT'S CLAW- / UÑA DE GATO- UNCARIA TOMENTOSA
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1.) Enhanced DNA repair, immune function and reduced toxicity of C-MED-100, a novel aqueous extract from Uncaria tomentosa. 
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J Ethnopharmacol 2000 Feb;69(2):115-126   (ISSN: 0378-8741)
Sheng Y [Find other articles with this Author]
Department of Cell and Molecular Biology, University of Lund, Sweden. yezhou.sheng@wblab.lu.se.
Female W/Fu rats were gavaged daily with a water-soluble extract (C-MED-100) of Uncaria tomentosa supplied commercially by CampaMed at the doses of 0, 5, 10, 20, 40 and 80 mg/kg for 8 consecutive weeks. Phytohemagglutinin (PHA) stimulated lymphocyte proliferation was significantly increased in splenocytes of rats treated at the doses of 40 and 80 mg/kg. White blood cells (WBC) from the C-MED-100 treatment groups of 40 and 80 mg/kg for 8 weeks or 160 mg/kg for 4 weeks were significantly elevated compared with controls (P < 0.05). In a human volunteer study, C-MED-100 was given daily at 5 mg/kg for 6 consecutive weeks to four healthy adult males. No toxicity was observed and again, WBC were significantly elevated (P < 0.05) after supplement. Repair of DNA single strand breaks (SSB) and double strand breaks (DSB) 3 h after 12 Gy whole body irradiation of rats were also significantly improved in C-MED-100 treated animals (P < 0.05). The LD50 and MTD of a single oral dose of C-MED-100 in the rat were observed to be greater than 8 g/kg. Although the rats were treated daily with U. tomentosa extracts at the doses of 10-80 mg/kg for 8 weeks or 160 mg/kg for 4 weeks, no acute or chronic toxicity signs were observed symptomatically. In addition, no body weight, food consumption, organ weight and kidney, liver, spleen, and heart pathological changes were found to be associated with C-MED-100 treatment.
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2.) Uncaria tomentosa (Willd.) D.C.: cat's claw, una de gato, or saventaro. 
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J Altern Complement Med 1999 Apr;5(2):143-51   (ISSN: 1075-5535)
Reinhard KH [Find other articles with this Author]
Apotheke am Oswaldgarten, Giessen, Germany.
Recently, Uncaria tomentosa (Willd.) D.C. has become known as a healing plant with an ethnomedicinal background. There have been several reports on its constituents, in particular, oxindole alkaloids. It was found that 2 chemotypes of Uncaria tomentosa with different alkaloid patterns occur in nature. The roots of one type contain pentacyclic oxindoles and the other contains tetracyclic oxindoles. This difference should be considered when the plant is to be used for medicinal applications. Tetracyclic oxindole alkaloids act on the central nervous system, whereas pentacyclic oxindole alkaloids affect the cellular immune system. Recent studies have shown that the tetracyclic alkaloids exert antagonistic effects on the action of the pentacyclic alkaloids. Mixtures of these 2 types of drugs are therefore unsuitable for medicinal uses. 
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3.) Stimulation of interleukin-1 and -6 production in alveolar macrophages by the neotropical liana, Uncaria tomentosa (una de gato). 
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J Ethnopharmacol 1999 Feb;64(2):109-15   (ISSN: 0378-8741)
Lemaire I; Assinewe V; Cano P; Awang DV; Arnason JT [Find other articles with these Authors]
Department of Cellular and Molecular Medicine, University of Ottawa, Ont., Canada.
Two extracts of different collections of the traditional medicine una de gato (Uncaria tomentosa) from Peru were characterized by High Pressure Liquid Chromatography as containing approximately 6 mg/g total oxindole content prior to studies with alveolar macrophages. The plant preparations greatly stimulated IL-1 and IL-6 production by rat macrophages in a dose dependent manner in the range of 0.025-0.1 mg/ml. They were also able to enhance IL-1 and -6 in lipopolysaccharide-stimulated macrophages. The results suggest a strong immunostimulant action of this plant. 
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4.) Uncaria tomentosa (Willd.) DC.--ethnomedicinal use and new pharmacological, toxicological and botanical results. 
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J Ethnopharmacol 1999 Jan;64(1):23-34   (ISSN: 0378-8741)
Keplinger K; Laus G; Wurm M; Dierich MP; Teppner H [Find other articles with these Authors]
Immodal Pharmaka GmbH, Volders, Austria.
The medicinal system of the Ashaninka Indians in Peru is portrayed. Three categories of medical disorders and healers are recognized. A human is viewed to consist of a physical and a spiritual being who communicate with each other by means of a regulating element. The significance of Uncaria tomentosa (Willd.) DC. (Rubiaceae), locally known as una de gato, in traditional medicine is emphasized by its exclusive use by priests to influence this regulation. Pharmacological and toxicological results obtained with extracts or isolated compounds are summarized. Pentacyclic oxindole alkaloids stimulate endothelial cells in vitro to produce a lymphocyte-proliferation-regulating factor. Tetracyclic oxindole alkaloids act as antagonists. A significant normalization of lymphocyte percentage was observed in vivo although total leucocyte numbers did not change. 
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5.) Induction of apoptosis and inhibition of proliferation in human tumor cells treated with extracts of Uncaria tomentosa. 
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Anticancer Res 1998 Sep-Oct;18(5A):3363-8   (ISSN: 0250-7005)
Sheng Y; Pero RW; Amiri A; Bryngelsson C [Find other articles with these Authors]
Department of Cell and Molecular Biology, University of Lund, Sweden. Yezhou.Sheng@wblab.lu.se.
Growth inhibitory activities of novel water extracts of Uncaria tomentosa (C-Med-100) were examined in vitro using two human leukemic cell lines (K562 and HL60) and one human EBV-transformed B lymphoma cell line (Raji). The proliferative capacities of HL60 and Raji cells were strongly suppressed in the presence of the C-Med-100 while K562 was more resistant to the inhibition. Furthermore, the antiproliferative effect was confirmed using the clonogenic assay, which showed a very close correlation between C-Med-100 concentration and the surviving fraction. The suppressive effect of Uncaria tomentosa extracts on tumor cell growth appears to be mediated through induction of apoptosis which was demonstrated by characteristic morphological changes, internucleosomal DNA fragmentation after agarose gel electrophoresis and DNA fragmentation quantification. C-Med-100 induced a delayed type of apoptosis becoming most dose-dependently prominent after 48 hours of exposure. Both DNA single and double strand breaks were increased 24 hours after C-Med-100 treatment, which suggested a well-established linkage between the DNA damage and apoptosis. The induction of DNA strand breaks coupled to apoptosis may explain the growth inhibition of the tumor cells by Uncaria tomentosa extracts. These results provide the first direct evidence for the antitumor properties of Uncaria tomentosa extracts to be via a mechanism of selective induction of apoptosis. 
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6.) Evaluation of the toxicity of Uncaria tomentosa by bioassays in vitro. 
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J Ethnopharmacol 1997 Aug;57(3):183-7   (ISSN: 0378-8741)
Santa Maria A; Lopez A; Diaz MM; Alban J; Galan de Mera A; Vicente Orellana JA; Pozuelo JM [Find other articles with these Authors]
Departamento de Toxicologia, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain.
Aqueous extracts of Uncaria tomentosa (Willdenow ex Roemer and Schultes) DC. (Rubiaceae) ('Una de gato'), were analyzed for the presence of toxic compounds in Chinese hamster ovary cells (CHO) and bacterial cells (Photobacterium phosphoreum). Toxicity was evaluated by four systems: Neutral red assay (NR), total protein content (KB), tetrazolium assay (MTT) and Microtox test. The extracts of U. tomentosa did not show toxicity in vitro at the concentrations tested. Testing in vitro could be a valuable tool for evaluating toxicity of medicinal plants. 
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7.) Pentacyclic oxindole alkaloids from Uncaria tomentosa induce human endothelial cells to release a lymphocyte-proliferation-regulating factor. 
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Planta Med 1998 Dec;64(8):701-4   (ISSN: 0032-0943)
Wurm M; Kacani L; Laus G; Keplinger K; Dierich MP [Find other articles with these Authors]
Institut fur Hygiene, Leopold-Franzens-Universitat Innsbruck, Austria.
In the present study we show that pentacyclic but not tetracyclic oxindole alkaloids from Uncoria tomentosa (Willd.) DC. (Rubiaceae) induced EA.hy926 endothelial cells to release some yet to be determined factor(s) into the supernatant; this factor was shown to significantly enhance proliferation of normal human resting or weakly activated B and T lymphocytes. In contrast, proliferation of normal human lymphoblasts and of both the human lymphoblastoid B cell line Raji and the human lymphoblastoid T cell line Jurkat was inhibited significantly while cell viability was not affected. Tetracyclic oxindole alkaloids dose-dependently reduce the activity of pentacyclic oxindole alkaloids on human endothelial cells. 
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8.) Depletion of specific binding sites for estrogen receptor by Uncaria tomentosa. 
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Proc West Pharmacol Soc 1998;41:123-4   (ISSN: 0083-8969)
Salazar EL; Jayme V [Find other articles with these Authors]
Unidad de Investigacion Medica en Biologia de la Reproduccion, Hospital de Gineco Obstetricia Luis Castelazo Ayala IMSS, Mexico, D.F. 
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9.) Antiinflammatory actions of cat's claw: the role of NF-kappaB. 
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Aliment Pharmacol Ther 1998 Dec;12(12):1279-89   (ISSN: 0269-2813)
Sandoval-Chacon M; Thompson JH; Zhang XJ; Liu X; Mannick EE; Sadowska-Krowicka H; Charbonnet RM; Clark DA; Miller MJ [Find other articles with these Authors]
LSU Medical Center, Department of Paediatrics and Stanley S. Scott Cancer Center, New Orleans, LA 70112, USA.
BACKGROUND: Uncaria tomentosa is a vine commonly known as cat's claw or 'una de gato' (UG) and is used in traditional Peruvian medicine for the treatment of a wide range of health problems, particularly digestive complaints and arthritis. PURPOSE: The aim of this study was to determine the proposed anti-inflammatory properties of cat's claw. Specifically: (i) does a bark extract of cat's claw protect against oxidant-induced stress in vitro, and (ii) to determine if UG modifies transcriptionally regulated events. METHODS: Cell death was determined in two cell lines, RAW 264.7 and HT29 in response to peroxynitrite (PN, 300 microM). Gene expression of inducible nitric oxide synthase (iNOS) in HT29 cells, direct effects on nitric oxide and peroxynitrite levels, and activation of NF-kappaB in RAW 264.7 cells as influenced by UG were assessed. Chronic intestinal inflammation was induced in rats with indomethacin (7.5 mg/kg), with UG administered orally in the drinking water (5 mg/mL). RESULTS: The administration of UG (100 microg/mL) attenuated (P < 0.05) peroxynitrite-induced apoptosis in HT29 (epithelial) and RAW 264.7 cells (macrophage). Cat's claw inhibited lipopolysaccharide-induced iNOS gene expression, nitrite formation, cell death and inhibited the activation of NF-kappaB. Cat's claw markedly attenuated indomethacin-enteritis as evident by reduced myeloperoxidase activity, morphometric damage and liver metallothionein expression. CONCLUSIONS: Cat's claw protects cells against oxidative stress and negated the activation of NF-kappaB. These studies provide a mechanistic evidence for the widely held belief that cat's claw is an effective anti-inflammatory agent. 
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10.) Mutagenic and antimutagenic activities of Uncaria tomentosa and its extracts.
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J Ethnopharmacol 1993 Jan;38(1):63-77 
Rizzi R, Re F, Bianchi A, De Feo V, de Simone F, Bianchi L, Stivala LA
Departmento di Farmacologia, Chemioterapia e Tossicologia Medica, Universita degli Studi di Milano, Italy. 
Mutagenic and antimutagenic activities of extracts and chromatographic fractions of Uncaria tomentosa bark are reported. The plant extracts and fractions show no mutagenic effect in different strains of Salmonella typhimurium with and without metabolic activation. However, the plant extracts and fractions show a protective antimutagenic effect in vitro against photomutagenesis induced by 8-methoxy-psoralen (8-MOP) plus UVA in S. typhimurium TA 102. A decoction of U. tomentosa ingested daily for 15 days by a smoker decreased the mutagenicity induced in S. typhimurium TA98 and TA100 by the subject's urine. 
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11.) Plant metabolites. New compounds and anti-inflammatory activity of Uncaria tomentosa.
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J Nat Prod 1991 Mar-Apr;54(2):453-9 
Aquino R, De Feo V, De Simone F, Pizza C, Cirino G
Dipartimento di Chimica delle Sostanze Naturali, Universita degli Studi di Napoli Federico II, Italy. 
Bioassay-directed fractionation of the anti-inflammatory extracts of Uncaria tomentosa, using the carrageenan-induced edema in rat paw, has led to the isolation of a new quinovic acid glycoside 7 as one of the active principles. Furthermore, a new triterpene 8 was isolated as its methyl ester. The structures were elucidated by spectral and chemical studies. 
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12.) New polyhydroxylated triterpenes from Uncaria tomentosa.
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J Nat Prod 1990 May-Jun;53(3):559-64 
Aquino R, De Simone F, Vincieri FF, Pizza C, Gacs-Baitz E
Dipartimento di Chimica delle Sostanze Naturali, Universita degli Studi di Napoli, Italy. 
Three novel polyhydroxylated triterpenes have been isolated from Uncaria tomentosa. Their structures were established as 1, 2, and 3 by detailed spectral studies including 1H-13C correlations via long range couplings using the INAPT pulse sequence, nOeds, and 2D 1H-13C direct chemical shift correlation (HETCOR) nmr techniques. 
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13.) Plant metabolites. Structure and in vitro antiviral activity of quinovic acid glycosides from Uncaria tomentosa and Guettarda platypoda.
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J Nat Prod 1989 Jul-Aug;52(4):679-85 
Aquino R, De Simone F, Pizza C, Conti C, Stein ML
Dipartimento di Chimica delle Sostanze Naturali, Universita di Napoli, Italy. 
A reinvestigation of the bark of Uncaria tomentosa afforded, in addition to the major quinovic acid glycosides 1-3, three further glycosides 4-6. The structures were elucidated by spectral and chemical studies. Furthermore, a series of antiviral tests were performed on all these glycosides and on the related glycosides 7-9, previously isolated from Guettarda platypoda. 
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14.) [Phytochemical and biological study of Uncaria tomentosa].
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Boll Soc Ital Biol Sper 1989 Jun;65(6):517-20 
Senatore A, Cataldo A, Iaccarino FP, Elberti MG
The investigation on steroidic fraction of Uncaria tomentosa, commonly called Una de gato, showed the presence of beta-sitosterol (60%), stigmasterol, and campesterol. The percentage of sterols have been carried out by GLC. The spectroscopic data 1H-NMR and MS of the three compounds are also reported, with the beta-sitosterol as the main sterol. Preliminary pharmacological investigations prove a moderate antiinflammatory activity. 
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15.) The alkaloids of Uncaria tomentosa and their phagocytosis-stimulating action].
Planta Med 1985 Oct;(5):419-23 
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16.) CAT'S CLAW (Una de Gato) #K725 INGREDIENTS: 
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Each VEGICAP®: Capsule Contains: 500 Mg. of Cat's Claw (Una de Gato), (Uncaria Tomentosa Standardized 4:1 Extract) 
This concentrated herbal extract contains no sugar, yeast, corn, wheat, rice, soy, artificial color, flavor or preservatives. Contains NO animal products. VEGICAPS®: is a registered trademark of GS Technologies. 
 PHYSIOLOGY: 
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After using cat's claw in working with approximatly 150 patients between 1988 and 1992, Dr. Brent Davis reports that Uncaria Tomentosa has the ability to break through severe intestinal derangements that no other available products can touch. He refers to the herb as "the opener of the way" because of its remarkable ability to cleanse the entire intestinal tract and help patients suffering from many different stomach and bowel disorders. A wealth of beneficial phytochemicals have been found in cat's claw including quinovic acid glycosides, several oxindol alkaloids, proanthocyanidins, polyphenols, triterpines and the plant sterols beta-siosterol, stigmasterol and campesterol. Rynchophylline a fifth alkaloid found in cat's claw displays an ability to inhibit platelet aggregation and thrombosis. This suggests that cat's claw be be useful in preventing strokes and reducing the risk of heart attack by lowering blood pressure, increasing circulation, inhibiting formation of plaque on arterial walls and formation of blood clots in the brain, heart and arteries. 
 INDICATIONS: 
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May be useful as an anti-inflammatory, arthritis, rheumatism, bursitis and gout, immune deficiencies, intestinal permeability and toxic overload. 
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17.) The antiproliferative effects of Uncaria tomentosa extracts and fractions on the growth of breast cancer cell line.
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Anticancer Res. 2001 Jul-Aug;21(4A):2457-61.
Riva L1, Coradini D, Di Fronzo G, De Feo V, De Tommasi N, De Simone F, Pizza C.
Author information
1Oncologia Sperimentale C, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milano, Italy.
Abstract
Uncaria tomentosa, also known as "Uña de gato", is a Rubiaceae species widely used in South-American folk medicine for the treatment of cancer, arthritis, gastritis and epidemic diseases. Extracts of the plant have been shown to possess cytostatic and anti-inflammatory activity as well as mutagenic and antimutagenic properties. However, to date no studies have been carried out to verify the direct antitumor activity of the extracts. The present study investigates the effects of some extracts and their chromatographic fractions from the bark of U. tomentosa on the growth of a human breast cancer cell line (MCF7). Our data indicated that, in addition to the antimutagenic activity, U. tomentosa extracts and fractions exert a direct antiproliferative activity on MCF7. The bioassay-directed fractionation from barks and leaves resulted in the isolation of two active fractions, which displayed an IC50 of 10 mg/ml and 20 mg/ml, respectively and an antiproliferative effect, with about 90% of inhibition at a concentration of 100 mg/ml.
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18.) Uncaria tomentosa-Adjuvant Treatment for Breast Cancer: Clinical Trial.
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Evid Based Complement Alternat Med. 2012;2012:676984. doi: 10.1155/2012/676984. Epub 2012 Jun 28.
Santos Araújo Mdo C1, Farias IL, Gutierres J, Dalmora SL, Flores N, Farias J, de Cruz I, Chiesa J, Morsch VM, Chitolina Schetinger MR.
Author information
1Department of Chemistry, Federal University of Santa Maria, Avenida Roraima, Predio18, 97105-900 Santa Maria, Rs, Brazil.
Abstract
Breast cancer is the most frequent neoplasm affecting women worldwide. Some of the recommended treatments involve chemotherapy whose toxic effects include leukopenia and neutropenia. This study assessed the effectiveness of Uncaria tomentosa (Ut) in reducing the adverse effects of chemotherapy through a randomized clinical trial. Patients with Invasive Ductal Carcinoma-Stage II, who underwent a treatment regimen known as FAC (Fluorouracil, Doxorubicin, Cyclophosphamide), were divided into two groups: the UtCa received chemotherapy plus 300 mg dry Ut extract per day and the Ca group that only received chemotherapy and served as the control experiment. Blood samples were collected before each one of the six chemotherapy cycles and blood counts, immunological parameters, antioxidant enzymes, and oxidative stress were analyzed. Uncaria tomentosa reduced the neutropenia caused by chemotherapy and was also able to restore cellular DNA damage. We concluded that Ut is an effective adjuvant treatment for breast cancer.
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19.) Anticancer activity of the Uncaria tomentosa (Willd.) DC. preparations with different oxindole alkaloid composition.
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Phytomedicine. 2010 Dec 1;17(14):1133-9. doi: 10.1016/j.phymed.2010.04.013. Epub 2010 Jun 25.
Pilarski R1, Filip B, Wietrzyk J, Kuraś M, Gulewicz K.
Author information
1Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14 str., 61-704 Poznań, Poland.
Abstract
The activity of Uncaria tomentosa preparations on cancer cells was studied using in vitro and in vivo models. IC (50) values were calculated for preparations with different quantitative and qualitative oxindole alkaloid composition: B/W(37) --bark extracted in water at 37 °C, B/W(b)--bark extracted in boiling water, B/50E(37) --bark extracted in 50% ethanol at 37 °C, B/E(b)--bark extracted in boiling 96% ethanol, B/96E(37) --bark extracted in 96% ethanol at 37 °C and B/SRT--bark extracted in water and dichloromethane. Generally, the results obtained showed a high correlation between the total oxindole alkaloid content (from 0.43% to 50.40% d.m.) and the antiproliferative activity of the preparations (IC(50) from >1000 μg/ml to 23.57 μg/ml). B/96E(37) and B/SRT were the most cytotoxic preparations, whereas the lowest toxicity was observed for B/W(37). B/96E(37) were shown to be active against Lewis lung carcinoma (LL/2) [IC(50) =25.06 μg/ml], cervical carcinoma (KB) [IC(50) =35.69 μg/ml] and colon adenocarcinoma (SW707) [IC(50) =49.06 μg/ml]. B/SRT was especially effective in inhibiting proliferation of cervical carcinoma (KB) [IC(50) =23.57 μg/ml], breast carcinoma (MCF-7) [IC(50) =29.86 μg/ml] and lung carcinoma (A-549) [IC(50) =40.03 μg/ml]. Further animal studies on mice bearing Lewis lung carcinoma showed significant inhibition of tumor growth by B/W(37) administered for 21 days at daily doses of 5 and 0.5 mg (p=0.0009). There were no significant changes in the cell cycles of tumor cells with the exception of cell decrease at the G₂/M phase after the administration of B/96E(37) at a daily dose of 0.5 mg and the G(1)/G(0) cells cycle arrest demonstrated after the B/SRT therapy at a daily-dose of 0.05 mg. All tested preparations were
non-toxic and well tolerated.
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20.) Cat's claw: an Amazonian vine decreases inflammation in osteoarthritis.
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Complement Ther Clin Pract. 2007 Feb;13(1):25-8. Epub 2006 Dec 13.
Hardin SR1.
Author information
1University of North Carolina at Charlotte, School of Nursing, 9201 University Blvd, Charlotte, NC 28223, USA. srhardin@email.uncc.edu
Abstract
Cat's claw (Uncaria tomentosa and Uncaria guianesis) is a medicinal plant from the Amazon commonly used to treat disorders such as arthritis, gastritis and osteoarthritis. The mechanism of cat's claw appears to be as an inhibitor of TNFalpha and antioxidant. Understanding the processes in osteoarthritis may facilitate and clarify the potential role of cat's claw as a complementary therapy to assist in the reduction of pro-inflammatory mediators and effectors. The clinical relevance of this therapy as a viable modality of intervention will be discussed.
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21.) Uncaria tomentosa acts as a potent TNF-alpha inhibitor through NF-kappaB.
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J Ethnopharmacol. 2010 Feb 17;127(3):685-93. doi: 10.1016/j.jep.2009.12.004. Epub 2009 Dec 6.
Allen-Hall L1, Arnason JT, Cano P, Lafrenie RM.
Author information
1Laurentian University, Biomolecular Science, Sudbury Regional Hospital, Sudbury, Ontario, Canada.
Abstract
AIM OF THE STUDY:
Uncaria tomentosa, commonly known as Cat's Claw or Uña de gato, is a medicinal plant that has been shown to have effective anti-inflammatory activities. We have previously shown that treatment of monocyte-like THP-1 cells with Uncaria tomentosa inhibits the production of the pro-inflammatory cytokine TNF-alpha while augmenting the production of IL-1beta. Since TNF-alpha and IL-1beta are usually regulated similarly and share a number of common promoter elements, including NF-kappaB and AP-1, the ability of Uncaria tomentosa to differentially regulate these inflammatory cytokines is of particular interest.
MATERIALS AND METHODS:
To determine the mechanism of action of Uncaria tomentosa, we investigated the effects of specific inhibitors of NF-kappaB on cellular responses including transcription factor activation using TransAM assays, the expression of cytokines as measured by ELISA, and cell survival as measured by changes in cell number following treatment.
RESULTS:
Treatment with Uncaria tomentosa inhibited the LPS-dependent activation of specific NF-kappaB and AP-1 components. In addition, treatment with Uncaria tomentosa enhanced cell death when NF-kappaB was inhibited. The ability of Uncaria tomentosa to inhibit TNF-alpha production was diminished when NF-kappaB activation was prevented by drugs that mask NF-kappaB subunit nuclear localization signals, while IL-1beta expression was unchanged.
CONCLUSIONS:
These results demonstrate that Uncaria tomentosa is able to elicit a response via an NF-kappaB-dependent mechanism. Further studies to characterize the mechanism by which Uncaria tomentosa can affect this pathway could provide a means to develop anti-TNF-alpha therapies.
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22.) The Immunomodulatory Potential of Selected Bioactive Plant-Based Compounds in Breast Cancer: A Review.
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Anticancer Agents Med Chem. 2016 Aug 17. [Epub ahead of print]
Baraya YU, Wong KK, Yaacob NS1.
Author information
1Department of Chemical Pathology, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, 16150 Kubang Kerian, Kelantan, Malaysia. niksoriani@usm.my.
Abstract
Breast cancer has continued to cause high cancer death rates among women worldwide. The use of plants' natural products in breast cancer treatment has received more attention in recent years due to their potentially wider safety margin and the potential to complement conventional chemotherapeutic drugs. Plant-based products have demonstrated anticancer potential through different biological pathways including modulation of the immune system. Immunomodulatory properties of medicinal plants have been shown to mitigate breast cancer cell growth. Different immune cell types participate in this process especially cytotoxic T cells and natural killer cells, and cytokines including chemokines and tumor necrosis factor-α. Medicinal plants such as Glycyrrhiza glabra, Uncaria tomentosa, Camellia sinensis, Panax ginseng, Prunus armenaica (apricot), Allium sativum, Arctium lappa and Curcuma longa were reported to hold strong potential in breast cancer treatment in various parts of the world. Interestingly, research findings have shown that these plants possess bioactive immunomodulators as their main constituents producing the anticancer effects. These immunomodulatory compounds include ajoene, arctigenin, β-carotene, curcumin, epigallocatechin-3-gallate, ginsan, glabridin and quinic acid. In this review, we discussed the ability of these eight immunomodulators in regulating the immune system potentially applicable in breast cancer treatment via anti-inflammatory (curcumin, arctigenin, glabridin and ajoene) and lymphocytes activation (β-carotene, epigallocatechin-3-gallate, quinic acid and ginsan) properties, as well as future research direction in their use for breast cancer treatment.
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23.) Uncaria tomentosa (cat's claw) improves quality of life in patients with advanced solid tumors.
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J Altern Complement Med. 2015 Jan;21(1):22-30. doi: 10.1089/acm.2014.0127. Epub 2014 Dec 11.
de Paula LC1, Fonseca F, Perazzo F, Cruz FM, Cubero D, Trufelli DC, Martins SP, Santi PX, da Silva EA, Del Giglio A.
Author information
11 Department of Hematology and Oncology, School of Medicine, ABC Foundation, Brazilian Institute for Cancer Control , São Paulo, Brazil .
Abstract
OBJECTIVE:
Cat's claw (Uncaria tomentosa) is a native Amazon plant that exhibits anti-inflammatory and antitumor properties. We wanted to assess its activity for symptom management of terminal cancer patients.
METHODS:
This prospective phase II study assessed the effects of a 100-mg dose of a dry extract of U. tomentosa three times per day in patients with advanced solid tumors who had no further therapeutic options and a life expectancy of at least 2 months. The European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ C30) and Functional Assessment of Chronic Illness Therapy - Fatigue questionnaires were used to assess the participants' quality of life, the Hospital Anxiety and Depression Scale questionnaire was used to assess anxiety and depression, and the Pittsburgh Sleep Quality Index was used to assess sleep quality. In addition, several biochemical and inflammatory parameters were analyzed.
RESULTS:
Fifty-one volunteers were recruited. Their median age was 64 (range, 33-85) years, and 47% of patients were female. More than 65% of patients had scores on the Karnofsky Performance Scale of 80% or less. Treatment improved the patients' overall quality of life (p=0.0411) and social functioning (p=0.0341), as assessed by the EORTC QLQ C-30, and reduced fatigue (p=0.0496) according to the Chalder Fatigue Questionnaire. None of the biochemical or inflammatory parameters assessed (interleukin-1 and -6, C-reactive protein, tumor necrosis factor-α, erythrocyte sedimentation rate, and α-1-acid glycoprotein) changed significantly. No tumor response was detected according to the Response Evaluation Criteria In Solid Tumors; however, the disease stabilized for more than 8 months in four participants. The medication was well tolerated by most patients.
CONCLUSION:
Use of cat's claw might be beneficial in patients with advanced cancer by improving their quality of life and reducing fatigue. The mechanism of action does not seem to be related to the anti-inflammatory properties of this plant.
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24.) Quinovic acid glycosides purified fraction from Uncaria tomentosa induces cell death by apoptosis in the T24 human bladder cancer cell line.
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Food Chem Toxicol. 2014 May;67:222-9. doi: 10.1016/j.fct.2014.02.037. Epub 2014 Mar 6.
Dietrich F1, Kaiser S2, Rockenbach L1, Figueiró F1, Bergamin LS1, da Cunha FM3, Morrone FB4, Ortega GG2, Battastini AM5.
Author information
1Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul (UFRGS), Rua Ramiro Barcelos, 2600 - anexo - Santana, CEP 90035-003, Porto Alegre, RS, Brazil.
2Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul (UFRGS), Avenida Ipiranga 2752 - Santa Cecília, CEP 90610-000, Porto Alegre, RS, Brazil.
3Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul (UFRGS), Rua Ramiro Barcelos, 2600 - anexo - Santana, CEP 90035-003, Porto Alegre, RS, Brazil.
4Laboratório de Farmacologia Aplicada, Faculdade de Farmácia, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Avenida Ipiranga, 6681 - Partenon, CEP 90619-900, Porto Alegre, RS, Brazil.
5Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul (UFRGS), Rua Ramiro Barcelos, 2600 - anexo - Santana, CEP 90035-003, Porto Alegre, RS, Brazil; Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul (UFRGS), Rua Ramiro Barcelos, 2600 - anexo - Santana, CEP 90035-003, Porto Alegre, RS, Brazil. Electronic address: abattastini@gmail.com.
Abstract
Bladder cancer is the second most prevalent malignancy in the genitourinary tract and remains a therapeutic challenge. In the search for new treatments, researchers have attempted to find compounds with low toxicity. With this goal in mind, Uncaria tomentosa is noteworthy because the bark and root of this species are widely used in traditional medicine and in adjuvant therapy for the treatment of numerous diseases. The objective of this study was to investigate the antitumor effect of one purified bioactive fraction of U.tomentosa bark on cell proliferation in two human bladder cancer cell lines, T24 and RT4. Quinovic acid glycosides purified fraction (QAPF) of U.tomentosa decreased the growth and viability of both T24 and RT4 cell lines. In T24 cells, QAPF induced apoptosis by activating caspase-3 and NF-κB. Further study showed that this fraction does not induce cell cycle arrest and does not alter PTEN and ERK levels. In conclusion, we demonstrated that QAPF of U.tomentosa has a potent inhibitory effect on the growth of human bladder cancer cell lines by inducing apoptosis through modulation of NF-κB, and we suggest that QAPF may become a potential therapeutic agent for the prevention and/or treatment of this cancer.
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25.) Antiproliferative and pro-apoptotic effects of Uncaria tomentosa in human medullary thyroid carcinoma cells.
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Rinner B1, Li ZX, Haas H, Siegl V, Sturm S, Stuppner H, Pfragner R.
Author information
1Department of Pathophysiology and Immunology, Medical University of Graz, Heinrichstrasse 31, A-8010 Graz, Austria.
Abstract
Medullary thyroid carcinoma (MTC), a rare calcitonin-producing tumor, is derived from parafollicular C-cells of the thyroid and is characterized by constitutive Bcl-2 overexpression. The tumor is relatively insensitive to radiation therapy as well as conventional chemotherapy. To date, the only curative treatment is the early and complete surgical removal of all neoplastic tissue. In this study, the antiproliferative and pro-apoptotic effects of fractions obtained from Uncaria tomentosa (Willd.) DC, commonly known as uña de gato or cat's claw were investigated. Cell growth of MTC cells as well as enzymatic activity of mitochondrial dehydrogenase was markedly inhibited after treatment with different fractions of the plant. Furthermore, there was an increase in the expressions of caspase-3 and -7 and poly(ADP-ribose) polymerase (PARP) fraction, while bcl-2 overexpression remained constant. In particular, the alkaloids isopterpodine and pteropodine of U. tomentosa exhibited a significant pro-apoptotic effect on MTC cells, whereas the alkaloid-poor fraction inhibited cell proliferation but did not show any pro-apoptotic effects. These promising results indicate the growth-restraining and apoptotic potential of plant extracts against neuroendocrine tumors, which may add to existing therapies for cancer.
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26.) An active ingredient of Cat's Claw water extracts identification and efficacy of quinic acid.
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J Ethnopharmacol. 2005 Jan 15;96(3):577-84. Epub 2004 Dec 8.
Sheng Y1, Akesson C, Holmgren K, Bryngelsson C, Giamapa V, Pero RW.
Author information
1Section for Immunology, Department of Clinical Medicine (Neuroscience), Lund University, BMC I:13, SE-221 84 Lund, Sweden.
Abstract
Historic medicinal practice has defined Cat's Claw, also known as Una de Gato or Uncaria tomentosa, as an effective treatment for several health disorders including chronic inflammation, gastrointestinal dysfunction such as ulcers, tumors and infections. The efficacy of Cat's Claw was originally believed, as early as the 1960s, to be due to the presence of oxindole alkaloids. However, more recently water-soluble Cat's Claw extracts were shown not to contain significant amounts of alkaloids (<0.05%), and yet still were shown to be very efficacious. Here we characterize the active ingredients of a water-soluble Cat's Claw extract called C-Med-100 as inhibiting cell growth without cell death thus providing enhanced opportunities for DNA repair, and the consequences thereof, such as immune stimulation, anti-inflammation and cancer prevention. The active ingredients were chemically defined as quinic acid esters and could also be shown to be bioactive in vivo as quinic acid.
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27.) [Cat's Claw: an herb from the Peruvian Amazon].
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Sidahora. 1995 Apr-May:35-6.
[Article in Spanish]
Steinberg PN.
Abstract
AIDS:
Uncaria tomentosa, also known as cat's claw, an herb from the highlands of the Peruvian Amazon, has been used by natives for hundreds of years to treat immunologic and digestive disorders. Research began in the 1970s to discover the benefits of this plant in relieving symptoms of cancers, arthritis, and other ailments. It has the ability to cleanse the digestive tract, aiding victims of Crohn's, colitis, gastritis and more. In a 1989 study by Klaus Keplinger, several alkaloid oxidants found in the plant's roots showed an ability to stimulate the immune system. The principal alkaloids are isopteropodine and rynchophyiline. Extracts of cat's claw mixed with AZT in an experimental drug, called Krallendom, were effective in reducing symptoms in AIDS patients in Austria. The plant has been useful in reducing secondary effects of radiation and chemotherapy in cancer victims as well.
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28.) Prevention of experimental diabetes by Uncaria tomentosa extract: Th2 polarization, regulatory
T cell preservation or both?
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J Ethnopharmacol. 2011 Sep 1;137(1):635-42. doi: 10.1016/j.jep.2011.06.021. Epub 2011 Jun 28
Domingues A1, Sartori A, Golim MA, Valente LM, da Rosa LC, Ishikawa LL, Siani AC, Viero RM.
Author information
1Department of Pathology, Medical School, São Paulo State University (UNESP), Botucatu, São Paulo 18618-000, Brazil. domingues1@gmail.com
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE:
Uncaria tomentosa (Willd.) DC (Rubiaceae) is a species native to the Amazon rainforest and surrounding tropical areas that is endowed with immunomodulatory properties and widely used around the world. In this study we investigated the immunomodulatory potential of Uncaria tomentosa (UT) aqueous-ethanol extract on the progression of immune-mediated diabetes.
MATERIALS AND METHODS:
C57BL/6 male mice were injected with MLDS (40 mg/kg) and orally treated with UT at 10-400mg/kg during 21 days. Control groups received MLDS alone or the respective dilution vehicle. Pancreatic mononuclear infiltrate and β-cell insulin content were analyzed by HE and immunohistochemical staining, respectively, and measured by digital morphometry. Lymphocyte immunophenotyping and cytokine production were determined by flow cytometry analysis.
RESULTS:
Treating the animals with 50-400mg/kg of UT caused a significant reduction in the glycemic levels, as well as in the incidence of diabetes. The morphometric analysis of insulitis revealed a clear protective effect. Animals treated with UT at 400mg/kg presented a higher number of intact islets and a significant inhibition of destructive insulitis. Furthermore, a significant protection against the loss of insulin-secreting presented β-cells was achieved, as observed by a careful immunohistochemical evaluation. The phenotypic analysis indicated that the groups treated with higher doses (100-400mg/kg) presented CD4(+) and CD8(+) T-cell values similar to those observed in healthy animals. These same higher doses also increased the number of CD4(+)CD25(+)Foxp3(+) regulatory T-cells. Moreover, the extract modulated the production of Th1 and Th2, with increased levels of IL-4 and IL-5.
CONCLUSIONS:
The extract was effective to prevent the progression of immune-mediated diabetes by distinct pathways.
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29.) Herbal medications commonly used in the practice of rheumatology: mechanisms of action, efficacy, and side effects.
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Semin Arthritis Rheum. 2005 Jun;34(6):773-84.
Setty AR1, Sigal LH.
Author information
1Massachusetts General Hospital, Department of Rheumatology, Boston, USA.
Abstract
OBJECTIVE:
To review the literature on herbal preparations commonly utilized in the treatment of rheumatic indications.
METHODS:
Search of MEDLINE (PubMed) was performed using both the scientific and the common names of herbs. Relevant articles in English were collected from PubMed and reviewed.
RESULTS:
This review summarizes the efficacy and toxicities of herbal remedies used in complementary and alternative medical (CAM) therapies for rheumatologic conditions, by elucidating the immune pathways through which these preparations have antiinflammatory and/or immunomodulatory activity and providing a scientific basis for their efficacy. Gammalinolenic acid suppresses inflammation by acting as a competitive inhibitor of prostaglandin E2 and leukotrienes (LTs) and by reducing the auto-induction of interleukin1alpha (IL-1alpha)-induced pro-IL-1beta gene expression. It appears to be efficacious in rheumatoid arthritis (RA) but not for Sjogrens disease. The antiinflammatory actions of Harpagophytum procumbens is due to its action on eicosanoid biosynthesis and it may have a role in treating low back pain. While in vitro experiments with Tanacetum parthenium found inhibition of the expression of intercellular adhesion molecule-1, tumor necrosis factor alpha (TNF-alpha), interferon-gamma, IkappaB kinase, and a decrease in T-cell adhesion, to date human studies have not proven it useful in the treatment of RA. Current experience with Tripterygium wilfordii Hook F, Uncaria tomentosa, finds them to be efficacious in the treatment of RA, while Urtica diocia and willow bark extract are effective for osteoarthritis. T. wilfordii Hook F extract inhibits the production of cytokines and other mediators from mononuclear phagocytes by blocking the up-regulation of a number of proinflammatory genes, including TNF-alpha, cyclooxygenase 2 (COX-2), interferon-gamma, IL-2, prostaglandin, and iNOS. Uncaria tomentosa and Urtica diocia both decrease the production of TNF-alpha. At present there are no human studies on Ocimum spp. in rheumatic diseases. The fixed oil appears to have antihistaminic, antiserotonin, and antiprostaglandin activity. Zingiber officinale inhibits TNF-alpha, prostaglandin, and leukotriene synthesis and at present has limited efficacy in the treatment of osteoarthritis.
CONCLUSIONS:
Investigation of the mechanism and potential uses of CAM therapies is still in its infancy and many studies done to date are scientifically flawed. Further systematic and scientific inquiry into this topic is necessary to validate or refute the clinical claims made for CAM therapies. An understanding of the mechanism of action of CAM therapies allows physicians to counsel effectively on their proper and improper use, prevent adverse drug-drug interactions, and anticipate or appreciate toxicities.
RELEVANCE:
The use of CAM therapies is widespread among patients, including those with rheumatic diseases. Herbal medications are often utilized with little to no physician guidance or knowledge. An appreciation of this information will help physicians to counsel patients concerning the utility and toxicities of CAM therapies. An understanding and elucidation of the mechanisms by which CAM therapies may be efficacious can be instrumental in discovering new molecular targets in the treatment of diseases.
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30.) Mitraphylline inhibits lipopolysaccharide-mediated activation of primary human neutrophils.
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Montserrat-de la Paz S1, Fernandez-Arche A2, de la Puerta R2, Quilez AM2, Muriana FJ3, Garcia-Gimenez MD2, Bermudez B4.
Author information
1Department of Pharmacology, School of Pharmacy, University of Seville, 41012, Seville, Spain ; Laboratory of Cellular and Molecular Nutrition, Instituto de la Grasa, CSIC, Seville, Spain.
2Department of Pharmacology, School of Pharmacy, University of Seville, 41012, Seville, Spain.
3Laboratory of Cellular and Molecular Nutrition, Instituto de la Grasa, CSIC, Seville, Spain.
4Department of Pharmacology, School of Pharmacy, University of Seville, 41012, Seville, Spain . Electronic address: bbermudez@us.es.
Abstract
BACKGROUND:
Mitraphylline (MTP) is the major pentacyclic oxindolic alkaloid presented in Uncaria tomentosa. It has traditionally been used to treat disorders including arthritis, heart disease, cancer, and other inflammatory diseases. However, the specific role of MTP is still not clear, with more comprehensivestudies, our understanding of this ancient herbal medicine will continue growing.
HYPOTHESIS/PURPOSE:
Some studies provided its ability to inhibit proinflamatory cytokines, such as TNF-α, through NF-κB-dependent mechanism. TNF-α primes neutrophils and modulates phagocytic and oxidative burst activities in inflammatory processes. Since, neutrophils represent the most abundant pool of leukocytes in human blood and play a crucial role in inflammation, we aimed to determine the ability of MTP to modulate neutrophil activation and differentially regulate inflammatory-related cytokines.
METHODS:
To determine the mechanism of action of MTP, we investigated the effects on LPS-activated human primary neutrophils responses including activation surface markers by FACS and the expression of inflammatory cytokines, measured by real time PCR and ELISA.
RESULTS:
Treatment with MTP reduced the LPS-dependent activation effects. Activated neutrophils (CD16(+)CD62L(-)) diminished after MTP administration. Moreover, proinflamatory cytokines (TNF-α, IL-6 or IL-8) expression and secretion were concomitantly reduced, similar to basal control conditions.
CONCLUSION:
Taken together, our results demonstrate that MTP is able to elicit an anti-inflammatory response that modulates neutrophil activation contributing to the attenuation of inflammatory episodes. Further studies are need to characterize the mechanism by which MTP can affect this pathway that could provide a means to develop MTP as new candidate for inflammatory disease therapies.
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31.) Anti-inflammatory activity of Mitraphylline isolated from Uncaria tomentosa bark.
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J Ethnopharmacol. 2012 Oct 11;143(3):801-4. doi: 10.1016/j.jep.2012.07.015. Epub 2012 Jul 27.
Rojas-Duran R1, González-Aspajo G, Ruiz-Martel C, Bourdy G, Doroteo-Ortega VH, Alban-Castillo J, Robert G, Auberger P, Deharo E.
Author information
1Unidad de Investigación en Productos Naturales, Laboratorios de Investigación y Desarrollo, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia, Av. Honorio Delgado 430, SMP, Lima, Peru.
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE:
Uncaria tomentosa (Willd. ex Roem. & Schult.) DC. (Rubiaceae) is widely used by populations living in South America to treat many ailments associated with inflammatory disorders. Mitraphylline was shown to be the major pentacyclic oxindolic alkaloid present in the bark chloroformic extract of this plant. Its activity against cytokines involved in inflammation process was tested in a murine model in vivo.
MATERIALS AND METHODS:
Mice received mitraphylline once a day for 3 days at 30 mg/kg/day by oral route. Then, they were subjected to bacterial lipopolysaccharide (LPS) endotoxin (15 mg/kg) and the LPS-induced production of 16 different cytokines was determined by Elisa multiplex. Control group received dexamethasone orally at 2mg/kg/day. Toxicity on K565 cells and murine peritoneal macrophages, in vitro, at doses up to 100 μM was monitored by XTT-colorimetric assay.
RESULTS AND CONCLUSIONS:
For the first time mitraphylline was tested in vivo against a large range of cytokines that play a crucial role in inflammation. Mitraphylline inhibited around 50% of the release of interleukins 1α, 1β, 17, and TNF-α. This activity was similar to dexamethasone. It also reduced almost 40% of the production of interleukin 4 (IL-4) while the corticoid did not. Lastly it did not show any toxicity on K565 cells nor murine macrophages at doses up to 100 μM.
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32.) Synthesis and biological evaluation of quinic acid derivatives as anti-inflammatory agents.
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Bioorg Med Chem Lett. 2009 Sep 15;19(18):5458-60. doi: 10.1016/j.bmcl.2009.07.096. Epub 2009 Jul 23.
Zeng K1, Thompson KE, Yates CR, Miller DD.
Author information
1Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Abstract
Quinic acid (QA) esters found in hot water extracts of Uncaria tomentosa (a.k.a. cat's claw) exert anti-inflammatory activity through mechanisms involving inhibition of the pro-inflammatory transcription factor nuclear factor kappa B (NF-kappaB). Herein, we describe the synthesis and biological testing of novel QA derivatives. Inhibition of NF-kappaB was assessed using A549 (Type II alveolar epithelial-like) cells that stably express a secreted alkaline phosphatase (SEAP) reporter driven by an NF-kappaB response element. A549-NF-kappaB cells were stimulated with TNF-alpha (10 ng/mL) in the presence or absence of QA derivative for 18 hours followed by measurement of SEAP activity. Amide substitution at the carboxylic acid position yielded potent inhibitors of NF-kappaB. A variety of modifications to the amide substitution were tolerated with the N-propyl amide derivative being the most potent. Further examination of the SAR demonstrated that acetylation of the hydroxyl groups reduced NF-kappaB inhibitory activity. QA amide derivatives lacked anti-oxidant activity and were found to be neither anti-proliferative nor cytotoxic at concentrations up to 100 microM. In conclusion, we have discovered a novel series of non-toxic QA amides that potently inhibit NF-kappaB, despite their lack of anti-oxidant activity. Mechanistic studies and pre-clinical efficacy studies in various inflammatory animal models are on-going.
 

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 CARTILAGO DE TIBURON / SHARK CARTILAGE

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1.) How useful are unconventional cancer treatments?
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Eur J Cancer 1999 Oct;35(11):1608-13 
Ernst E, Cassileth BR
Department of Complementary Medicine, School of Postgraduate Medicine and Health Sciences, University of Exeter, U.K. e.ernst@exeter.ac.uk 
Unconventional cancer treatments are used frequently. Therefore, oncologists need to know about them. This article gives an overview of current knowledge on the most prevalent complementary or alternative cancer therapies. A distinction is made between alleged cures, preventive and adjunctive measures. Shark cartilage, mistletoe, thymus therapy, essiac, hydrazine sulphate, 714-X, dietary regimens, green tea and Panax ginseng are all covered specifically. None of these treatments offer reasonable hope for a cure. Some strategies are promising in terms of cancer prevention. The true potential of unconventional therapies might lie in adjunctive and palliative care. It is concluded that good evidence in this area is scarce. Vis-a-vis the high prevalence of unconventional cancer treatments, rigorous investigations are mandatory, not least for increasing the safety of future patients. 
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2.) A monoclonal antibody which recognizes a glycosaminoglycan epitope in both dermatan sulfate and chondroitin sulfate proteoglycans of human skin.
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Histochem J 1999 Aug;31(8):549-58 
Sorrell JM, Carrino DA, Baber MA, Asselineau D, Caplan AI
Department of Biology and Skeletal Research Center, Case Western Reserve University, Cleveland, OH 44106, USA. 
Studies have been initiated to identify various cell surface and matrix components of normal human skin through the production and characterization of murine monoclonal antibodies. One such antibody, termed PG-4, identifies both cell surface and matrix antigens in extracts of human foetal and adult skin as the dermatan sulfate proteoglycans, decorin and biglycan, and the chondroitin sulfate proteoglycan versican. Treatment of proteoglycans with chondroitinases completely abolishes immunoreactivity for all of these antigens which suggests that the epitope resides within their glycosaminoglycan chains. Further evidence for the carbohydrate nature of the epitope derives from competition studies where protein-free chondroitin sulfate chains from shark cartilage react strongly; however, chondroitin sulfate chains from bovine tracheal cartilage fail to exhibit a significant reactivity, an indication that the epitope, although present in some chondroitin sulfate chains, does not consist of random chondroitin 4- or 6-sulfate disaccharides. The presence of the epitope on dermatan sulfate chains and on decorin was also demonstrated using competition assays. Thus, PG-4 belongs to a class of antibodies that recognize native epitopes located within glycosaminoglycan chains. It differs from previously described antibodies in this class in that it identifies both chondroitin sulfate and dermatan sulfate proteoglycans. These characteristics make PG-4 a useful monoclonal antibody probe to identify the total population of proteoglycans in human skin. 
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3.) [The national cancer fund (Koningin Wilhelmina Fonds) and the Houtsmuller-therapy for cancer].
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Ned Tijdschr Geneeskd 1999 Jul 3;143(27):1431-3 
Renckens CN, van Dam FS
Nederlands Kanker Instituut/Antoni van Leeuwenhoek ziekenhuis, afd. Psychosociaal Onderzoek en Epidemiologie, Amsterdam. 
Dr. Houtsmuller, a retired internist, introduced an anticancer diet ten years ago. He claimed to have cured himself from metastatic melanoma by following a diet consisting of healthy nutrients, large amounts of vitamins, minerals, antioxidants and shark cartilage powder in combination with psychological support. The efficacy of the therapy was never described in a scientific article. Currently about 63% of all cancer patients in the Netherlands using a diet use the Houtsmuller diet. The national cancer fund (Koningin Wilhelmina Fonds) invited him to speak at their 50-year commemorative symposium. Shortly before he admitted that his medical history did not mention metastatic melanoma. Dr. Houtsmuller has seriously damaged the position of physicians in the Netherlands by addressing patients directly without first seeking support from his scientific medical peers. Cancer organizations such as Koningin Wilhelmina Fonds are urged to properly inform the public about the real value or lack of value of alternative treatments in general and of alternative diets in particular. 
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4.) Effect of U-995, a potent shark cartilage-derived angiogenesis inhibitor, on anti-angiogenesis and anti-tumor activities.
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Anticancer Res 1998 Nov-Dec;18(6A):4435-41 
Sheu JR, Fu CC, Tsai ML, Chung WJ
Cancer Research Center, Gwo-Chyang GMP Pharmaceutical Co., Ltd., Tainan, Taiwan. acesane@ms4.hinet.net 
BACKGROUND: A potent angiogenesis inhibitor, U-995, has been purified from the cartilage of the blue shark (Prionace glauca). U-995 is composed of two single peptides with molecular mass of 10 and 14 kDa, respectively. MATERIALS AND METHODS: U-995 was designed to study human umbilical vein endothelial cell (HUVEC) migration and proliferation in vitro and angiogenesis induced by TNF alpha in chicken chorioallantoic membrane (CAM). Furthermore, we determined the ability of U-995 to inhibiting tumor cell growth and metastasis. RESULTS: U-995 (15 and 30 micrograms/ml) markedly inhibited HUVEC migration and, at 15-50 micrograms/ml produced a dose-dependent decline in [3H]-thymidine incorporation. 30 and 50 micrograms/ml of U-995, when added to TNF alpha-induced angiogenesis caused discontinuous and disrupted blood vessels. Moreover, U-995 (30 micrograms/ml) markedly prevented collagenase-induced collagenolysis. In addition, when 200 micrograms U-995 was injected i.p. into mice it suppressed sarcoma-180 cell growth and B16-F10 mouse melanoma cell metastasis in vivo. CONCLUSIONS: These results suggest that the anti-angiogenic effects of U-995 may be be due to interference with the proliferation and migration of HUVECs as well as inhibition of collagenolysis, thereby leading to inhibition of both angiogenesis and tumor cell growth. 
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5.) Shark cartilage-containing preparation: protection against reactive oxygen species.
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Food Chem Toxicol 1998 Dec;36(12):1079-84 
Felzenszwalb I, Pelielo de Mattos JC, Bernardo-Filho M, Caldeira-de-Araujo A
Universidade do Estado do, Rio de Janeiro, Instituto de Biologia, Departamento de Biofisica e Biometria, Brazil. 
There is overwhelming evidence to indicate that free radicals cause oxidative damage to lipids, proteins and nucleic acids and are involved in the pathogenesis of several degenerative diseases. Therefore, antioxidants, which can neutralize free radicals, may be of central importance in the prevention of these disease states. The protection that fruits and vegetables provide against disease has been attributed to the various antioxidants contained in them. Recently, an anti-inflammatory and analgesic activity of a water-soluble fraction from shark cartilage has been described. Using electrophoretical assays, bacteria survival and transformation and the Salmonella/mammalian-microsome assay, we investigated the putative role of shark cartilage-containing preparation in protecting cells against reactive oxygen species induced DNA damage and mutagenesis. If antimutagens are to have any impact on human disease, it is essential that they are specifically directed against the most common mutagens in daily life. Our data suggest that shark cartilage-containing preparation can play a scavenger role for reactive oxygen species and protects cells against inactivation and mutagenesis. 
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6.) The effect of shark cartilage extracts on the growth and metastatic spread of the SCCVII carcinoma.
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Acta Oncol 1998;37(5):441-5 
Horsman MR, Alsner J, Overgaard J
Danish Cancer Society, Department of Experimental Clinical Oncology, Aarhus University Hospital. 
This study was designed to investigate the potential of shark cartilage extracts to inhibit the growth and metastatic spread of a murine solid tumour. The SCCVII carcinoma, implanted in the right rear foot of C3H mice, was used. Following tumour implantation, two different commercially available extracts of shark cartilage (Sharkilage and MIA Shark Powder) were dissolved in water and orally administered to the mice at doses that ranged from 5 to 100 mg per mouse. These injections were repeated on a daily basis for up to 25 days post-implantation of the primary tumour. Compared to non-drug-treated animals, daily administration of the shark cartilage extracts did not show any adverse toxicity (as measured by changes in body weight and lethality). More importantly, none of the shark cartilage doses tested had any retarding effect on the growth of the primary tumour, nor did they inhibit the development of metastases seen in the lungs of the tumour-bearing mice at autopsy. In conclusion, our results offer no support for the proposed use of shark cartilage extracts as an anti-cancer therapy. 
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7.) Phase I/II trial of the safety and efficacy of shark cartilage in the treatment of advanced cancer.
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J Clin Oncol 1998 Nov;16(11):3649-55 
Miller DR, Anderson GT, Stark JJ, Granick JL, Richardson D
Cancer Treatment Research Foundation, Cancer Treatment Centers of America, Arlington Heights, IL 60005, USA. gary.anderson@ctca-corp.com 
PURPOSE: Patients with cancer and chronic inflammatory disorders have used shark cartilage (SC) preparations for many years. Preclinical studies that support their beneficial effects are scanty, and reports of clinical trials have been anecdotal. The proposed mechanisms of antitumor action include direct or indirect inhibition of angiogenesis. Because of the emerging use of SC as an alternative to conventional cancer therapy, this trial was launched to evaluate the safety and efficacy of SC. PATIENTS AND METHODS: Sixty adult patients with advanced previously treated cancer (breast, 16 patients; colorectal, 16 patients; lung, 14 patients; prostate, eight patients; non-Hodgkin lymphoma, three patients; brain, one patient; and unknown primary tumor, two patients) were enrolled. Eligibility criteria included confirmation of diagnosis, resistance to conventional therapy, objective measurable disease, life expectancy of 12 weeks or greater, Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, no recent or concomitant anticancer therapy, no prior SC, and informed consent. Patients underwent evaluation of the extent of disease, quality-of-life score (Functional Assessment of Cancer Therapy-General [FACT-G] scale), and hematologic, biochemical, and selected immune function studies at baseline and after 6 and 12 weeks of SC therapy. The dose of SC was 1 g/kg daily orally in three divided doses. Standard criteria were used to evaluate adverse events and response. RESULTS: Ten of 60 patients were lost to follow-up(LTFU) or refused further treatment (RFT) before the 6-week evaluation and were not assessable for toxicity and response. Three patients with stable disease at 6 weeks were LTFU or RFT thereafter. Of the 47 fully assessable patients, five were taken off study because of gastrointestinal toxicity or intolerance to SC. Progressive disease (PD) at 6 or 12 weeks occurred in 22 and five patients, respectively. Five patients died of PD while undergoing SC therapy. No complete (CRs) or partial responses (PRs) were noted. Median time to tumor progression in the entire study population was 7+/-9.7 weeks (mean, 11.4 weeks; range, 3.7 to 45.7 weeks). Ten (20%) of 50 assessable patients, or 16.7% of the 60 intent-to-treat patients, had stable disease (SD) for 12 weeks or more. The median time to tumor progression was 27 weeks, the mean was 28.8+/-9.9 weeks, and the range was 18.6 to 45.7 weeks. In this subset, FACT-G scores improved in four patients, were unchanged in four patients, and declined in two patients. Twenty-one adverse events (grade 1, eight events; grade 2, seven events; and grade 3, six events) were recorded, 14 of which were gastroenterologic (nausea, vomiting, constipation). CONCLUSION: Under the specific conditions of this study, SC as a single agent was inactive in patients with advanced-stage cancer and had no salutary effect on quality of life. The 16.7% rate of SD was similar to results in patients with advanced cancer treated with supportive care alone. 
 
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8.) Occurrence of a novel collagen with three distinct chains in the cranial cartilage of the squid Sepia officinalis: comparison with shark cartilage collagen.
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Biochim Biophys Acta 1998 Jul 23;1381(2):161-9 
Sivakumar P, Chandrakasan G
Department of Biochemistry, Central Leather Research Institute, Adyar, Chennai 600 020, India. 
A unique collagen with three distinct chains, was purified from the cranial cartilage of the squid Sepia officinalis, by pepsinisation and salt precipitation and compared with shark cartilage collagen. These chains, which were different from the known cartilage collagen chains, were referred as C1, C2 and C3, had approximate molecular weights of 105 kDa, 115 kDa and 130 kDa, respectively, and were present in a ratio of 3:2:1, suggestive of two molecules of composition, [(C1)2C2] and [C1C2C3]. These collagens were purified by fractionation at acid and neutral pH, and by ammonium sulfate precipitation. Solubility data indicated that this collagen was more crosslinked than the type I collagen isolated from cartilage of shark, Carcharius acutus. In vitro fibrillogenesis revealed that the sepia collagen formed denser aggregates, as compared to shark collagen, and was stabilised by a higher degree of carbohydrate association. Polyclonal antisera raised against shark collagen was also reactive against the sepia collagens, while the converse was not true, indicating the high immunospecificity of the latter. These results demonstrate collagen polymorphism in an invertebrate cartilage and may hold significance in understanding tissue calcification and molecular evolution. Further, these collagens may represent ancestral forms of vertebrate minor collagens like typeV/XI. Copyright 1998 Elsevier Science B.V. All rights reserved. 
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9.) Antiangiogenic properties of a novel shark cartilage extract: potential role in the treatment of psoriasis.
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J Cutan Med Surg 1998 Jan;2(3):146-52 
Dupont E, Savard PE, Jourdain C, Juneau C, Thibodeau A, Ross N, Marenus K, Maes DH, Pelletier G, Sauder DN
Les Laboratoires Aeterna, Ste-Foy, PQ, Canada. 
BACKGROUND: A number of inflammatory and immune diseases are associated with vascular changes. Psoriasis, as an example, is a common inflammatory skin disease with dilation of capillaries as an early histological change. In more developed psoriatic lesions there is proliferation of blood vessels and neovascularization. The use of agents that target these vascular changes represents a novel therapeutic strategy in the treatment of inflammatory diseases. Since cartilage is an avascular tissue, it has been hypothesized that there may be factors found in cartilage that inhibit blood vessel formation. OBJECTIVE: The objectives of this study were 1) to determine whether extracts of cartilage could inhibit angiogenesis, and 2) since altered angiogenesis is associated with certain diseases, including psoriasis, to examine whether inhibition of angiogenesis could potentially contribute to the treatment of psoriasis. METHODS: Extracts of shark cartilage were prepared by homogenization and ultrafiltration to derive the active agent termed AE -941. This agent was tested for antiangiogenesis activity using the embryonic vascularization test, which is a modification of the ex vivo chick embryo culture (CAM). Since one of the first steps in angiogenesis is degradation by metalloproteinases of the basement membrane of capillaries, AE -941 was tested for collagenase activity using a fluorogenic peptide substrate. Anti-inflammatory properties were tested using a cutaneous irritation model in humans. RESULTS: A dose dependent inhibition in embryonic neovascularization as well as in collagenase activity by AE -941 was demonstrated. When test compounds were applied on the forearms of test subjects, AE -941 was shown to have anti-inflammatory properties. Anecdotal data suggested that topical AE -941 had a beneficial effect in psoriasis. CONCLUSION: Our results show that AE -941 has anti-angiogenic and anti-inflammatory properties. Antiangiogenesis agents such as AE -941 provide an entirely new class of agents to treat cutaneous and systemic diseases associated with altered vascularity. 
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10.) Dietary supplement use by women at risk for breast cancer recurrence. The Women's Healthy Eating and Living Study Group.
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J Am Diet Assoc 1998 Mar;98(3):285-92 
Newman V, Rock CL, Faerber S, Flatt SW, Wright FA, Pierce JP
Department of Family and Preventive Medicine, University of California-San Diego, La Jolla 92093-0901, USA. 
OBJECTIVE: To develop a method of collecting, organizing, and analyzing information on nutrient and nonnutrient dietary supplement use by women at risk for breast cancer recurrence as a component of nutrition assessment and monitoring, and to describe the characteristics associated with dietary supplement use in this population at enrollment in a clinical trial to prevent breast cancer recurrence. DESIGN: Cross-sectional descriptive study design. SUBJECTS: Women diagnosed with breast cancer within the previous 4 years (n=435). ANALYSIS: Dietary supplements reported in four 24-hour dietary recalls were categorized according to primary nutrient and nonnutrient contents. Prevalence of dietary supplement use is described. Associations between supplement use and demographic and participant characteristics were examined using chi(2) analysis and logistic regression. RESULTS: Dietary supplement use was reported by 80.9% of the women. Increased likelihood of supplement use was associated with demographic (eg, older age, higher level of education, white race vs other ethnic groups) and personal (eg, lower body mass index, moderate alcohol consumption) characteristics. Use of vitamin C and related compounds, other nutrients (eg, n-3 fatty acids, evening primrose oil), and herbal products was inversely associated with months since diagnosis; use of miscellaneous supplements (eg, shark cartilage) was directly associated with more advanced stage at diagnosis. APPLICATIONS: Monitoring dietary supplement use is an important aspect of nutrition assessment, especially in populations with chronic health conditions or medical diagnoses. Demographic and personal characteristics, time passed since diagnosis, and stage of cancer at diagnosis are predictive of dietary supplement use by women at risk for breast cancer recurrence. Associations in this population may be present in other groups that are the object of nutrition intervention efforts. 
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11.) The analgesic and anti-inflammatory effects of shark cartilage are due to a peptide molecule and are nitric oxide (NO) system dependent.
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Biol Pharm Bull 1997 Nov;20(11):1151-4 
Fontenele JB, Araujo GB, de Alencar JW, Viana GS
Department of Physiology and Pharmacology, Federal University of Ceara, Fortaleza, CE, Brazil. 
The present work shows an antinociceptive and dose-dependent effect of shark cartilage hydrosoluble fraction (HF) on writhing and formalin tests in mice. The effect was not altered by thalidomide, a known inhibitor of tumor necrosis factor-alfa (TNF-alfa) synthesis. Similarly, the antinociceptive effect did not change in the presence of naloxone, indicating that the opioid system is not involved. However, the effect observed was blocked by L-arginine, a NO synthesis substrate, and it was potentiated by L-NAME, suggesting a role of the NO system in the shark cartilage antinociceptive effect. Effects similar to those seen with the HF were detected with peak II from gel filtration chromatography. The increase in vascular permeability induced by serotonin in rats was significantly abolished by the HF at the dose of 2 mg/kg, p.o., and again it was not potentiated by thalidomide. The observed blockade in the vascular permeability increase induced by histamine was detected only with a higher dose (10 mg/kg, p.o.). 
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12.) Shark cartilage-induced hepatitis.
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Ann Intern Med 1996 Nov 1;125(9):780-1 
Ashar B, Vargo E
Publication Types:
Letter 
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13.) Anti-inflammatory and analgesic activity of a water-soluble fraction from shark cartilage.
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Braz J Med Biol Res 1996 May;29(5):643-6 
Fontenele JB, Viana GS, Xavier-Filho J, de-Alencar JW
Departamento de Fisiologia e Farmacologia, Universidade Federal do Ceara, Fortaleza, CE, Brasil. 
The anti-inflammatory and analgesic activities of a water-soluble fraction (WSF), extracted with 0.1 M ammonium bicarbonate, pH 8.0, from shark cartilage were studied in several experimental models. Orally administered WSF (10 mg/kg) caused 25.7 and 23.6% inhibition of the paw edema produced in female Wistar rats (200-250 g) by carrageenan and dextran, respectively, after 3 h, as compared to controls. WSF administered orally had no effect on acetic acid-induced writhings in male Swiss mice (25-30 g) at the dose of 0.01 mg/kg but caused 52.8 and 61.4% inhibition at the doses of 0.1 and 0.5 mg/kg, respectively, compared to controls (No. of writhings/20 min, means +/- SEM: treated groups = 18.6 +/- 2.5, N = 12 and 15.2 +/- 1.4, N = 12, respectively; controls = 39.3 +/- 1.3, N = 77). In the formalin test (male Swiss mice, 25-30 g), orally administered WSF (0.5 and 1 mg/kg) caused 12.0 and 46.6% inhibition of licking time, respectively, only in the 2nd phase (inflammatory) of the test (licking time, means +/- SEM: treated group = 18.3 +/- 4.4 sec, N = 7 and 11.1 +/- 3.4 sec, N = 13; controls = 20.8 +/- 2.4 sec, N = 44). The results suggest that a molecule of a protein nature in shark cartilage is probably responsible for the effects observed. 
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14.) Shark-cartilage containing preparation protects cells against hydrogen peroxide induced damage and mutagenesis.
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Mutat Res 1996 Apr 6;367(4):204-8 
Gomes EM, Souto PR, Felzenszwalb I
CETOX-Departamento de Biofisica e Biometria, Universidade do Estado do Rio de Janeiro, Brazil. 
Natural products from flora and fauna are frequently used as nutritional supplements and medicaments. Two short-term assays were carried out and negative results were obtained for shark-cartilage containing preparation. The tests employed were the Salmonella/mammalian microsome assay using tester strains TA97, TA98, TA100, TA102 and TA1535 with or without S9 mix and the SOS-Chromotest with Escherichia coli strain PQ37. Evidence for shark-cartilage containing preparation functioning as an antimutagen was detected. Using bacterial survival assays with Escherichia coli fpg (BH20) and xthA (BW9091), we investigated the putative role of shark-cartilage containing preparation in protecting cells against lesions induced by hydrogen peroxide in normal and low iron level conditions. Our data suggest that shark-cartilage containing preparation can play a scavenger role for reactive oxygen species and protect against DNA lesions in both conditions. 
Antiproliferative activity of shark cartilage with and without tumor necrosis factor-alpha in human umbilical vein endothelium.
Pharmacotherapy 1996 Mar-Apr;16(2):237-44 
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15.) McGuire TR, Kazakoff PW, Hoie EB, Fienhold MA
Department of Pharmacy Practice, University of Nebraska, =============================================================
Omaha 68198-6045, USA. 
We evaluated the antiangiogenic activity of shark cartilage, tumor necrosis factor-alpha (TNF-alpha), and a combination of the two using a human umbilical vein endothelial cell proliferation assay. Proliferation of endothelium is a hallmark of angiogenesis, and inhibition of endothelial cell proliferation indicates potential antiangiogenic activity. Shark cartilage produced a concentration-dependent decline in endothelial cell 3H-thymidine incorporation. This activity was heat stable and was found in molecular weight fractions of less than 10 kd. The antiproliferative effect of shark cartilage was specific for vascular endothelium and did not affect the proliferative rate of human astrocytoma cells or human skin fibroblasts. Shark cartilage at a concentration of 500 mu g/ml and TNF-alpha at a concentration of 10 ng/ml reduced endothelial cell proliferation by 32% and 29%, respectively. Treatment of endothelial cells with the combination of shark cartilage and TNF-alpha resulted in a 44% reduction in endothelial cell proliferation. The isolation and identification of the active components of shark cartilage is continuing. 
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16.) Demonstration of immunogenic keratan sulphate in commercial chondroitin 6-sulphate from shark cartilage. Implications for ELISA assays.
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Clin Chim Acta 1995 May 15;236(2):195-204 
Moller HJ, Moller-Pedersen T, Damsgaard TE, Poulsen JH
Department of Clinical Biochemistry, K.H. University Hospital, Aarhus, Denmark. 
The prototype monoclonal keratan sulphate (KS) antibody 5D4 that is widely used for detection of KS in tissues and biological fluids reacts strongly with commercial low grade shark cartilage chondroitin 6-sulphate. Characterization of the immunogenic material by chondroitinase ABC digestion, ELISA inhibition studies, immunoblotting and HPLC analyses confirmed the presence of substantial amounts of KS, probably as a large proteoglycan (> 120 kDa). Commercial and heterogenic glycosaminoglycan preparations therefore must be used with great caution in immunological analyses. On the other hand the shark cartilage chondroitin 6-sulphate is an easy accessible source of immunogenic KS that can be used as a reference standard and as coating antigen in KS-ELISAs. The concentration of immunogenic KS in synovial fluid measured with an ELISA based solely on reagents of shark cartilage chondroitin 6-sulphate correlated well (r = 0.90) with the concentrations obtained with a traditional KS-ELISA that uses purified aggrecan as standard and coating antigen, and KS in both serum and synovial fluid could be measured with sufficient linearity. 
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17.) Production and characterization of monoclonal antibodies to shark cartilage proteoglycan.
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Braz J Med Biol Res 1994 Sep;27(9):2103-8 
Alves ML, Straus AH, Takahashi HK, Michelacci YM
Departamento de Bioquimica, Escola Paulista de Medicina, Sao Paulo, Brasil. 
1. Two proteoglycans, PG1 and PG2, have been isolated from shark cartilage. Both are highly polydisperse and large (molecular mass: 1-10 x 10(6) Daltons) and contain chondroitin sulfate and keratan sulfate side chains, but PG2 is somewhat smaller than PG1 and contains less keratan sulfate. 2. Monoclonal antibodies were raised against PG1. Many antibodies were obtained and one of them, MST1, was subcloned and further characterized. This monoclonal antibody reacts with PG1 and PG2 from shark cartilage and also with aggrecan from bovine trachea cartilage. Chondroitinase AC-treated proteoglycans react with MST1, indicating that the antibody does not recognize chondroitin sulfate. MST1 also recognizes aggrecan from human cartilage and a proteoglycan from bovine brain (neurocan) but it does not recognize proteoglycans from rat Walker tumor, fetal calf muscle and decorin from human myoma. 3. Using MST1 we were able to demonstrate that both PG1 and PG2 aggregate with hyaluronic acid. 
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18.) Differential effects of glycosaminoglycans on neurite outgrowth from hippocampal and thalamic neurones.
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J Cell Sci 1994 Jun;107 ( Pt 6):1437-48 
Fernaud-Espinosa I, Nieto-Sampedro M, Bovolenta P
Instituto Cajal, Madrid, Spain. 
Chondroitin sulphate proteoglycans are expressed in a temporally restricted pattern from embryonic day 17 to postnatal day 0 in both the thalamus and the cortical subplate, to which thalamic neurones transiently project. To study whether chondroitin sulphate proteoglycans could be specifically involved in the modulation of thalamic axon outgrowth, we compared neurite outgrowth from cultured rat embryonic hippocampal and thalamic neurones, in the presence of chondroitin sulphate type C (isolated from shark cartilage) and chondroitin sulphate type B (dermatan sulphate; isolated from bovine mucosa). When added to the culture medium, both types of glycosaminoglycan lowered the adhesion to laminin and polylysine of both hippocampal and thalamic neurones. However, only chondroitin sulphate specifically modified the pattern of thalamic but not hippocampal neurone outgrowth, promoting axon growth. The morphological changes induced by chondroitin sulphate were concentration dependent and correlated with the selective binding of chondroitin sulphate to the neuronal plasma membrane and its subsequent internalisation. Chondroitin sulphate loosely bound to the surface of hippocampal neurones, but was not internalised. These results indicate that proteoglycans, and in particular the glycosaminoglycan component of these molecules, can differentially modulate neurite outgrowth, depending on their biochemical composition and on the type of neurones they bind to; this would be a possible mechanism of controlling axon guidance in vivo. 
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19.) Structural studies on sulfated oligosaccharides derived from the carbohydrate-protein linkage region of chondroitin 6-sulfate proteoglycans of shark cartilage. II. Seven compounds containing 2 or 3 sulfate residues.
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J Biol Chem 1992 Mar 25;267(9):6036-43 
de Waard P, Vliegenthart JF, Harada T, Sugahara K
Department of Bio-Organic Chemistry, Utrecht University, The Netherlands. 
Shark cartilage proteoglycans bear predominantly chondroitin 6-sulfate. After exhaustive protease digestion, reductive beta-elimination and subsequent chondroitinase ABC digestion, 13 hexasaccharide alditols were obtained from the carbohydrate-protein linkage region and six of them contain 0 or 1 sulfate and/or 1 phosphate residue (Sugahara, K., Ohi, Y., Harada, T., de Waard, P., and Vliegenthart, J. F. G. (1992) J. Biol. Chem. 267, 6027-6035). The other seven compounds, which represent approximately 60% of the isolated linkage hexasaccharides, were analyzed by chondroitinase ACII digestion in conjunction with high performance liquid chromatography and by 500-MHz one- and two dimensional 1H NMR spectroscopy. All seven compounds have the following conventional structure in common. [formula: see text] Two disulfated compounds have an O-sulfate on C-6 of the Gal-2 residue attached to xylitol in combination with an O-sulfate on C-4 or on C-6 of the GalNAc residue. The third disulfated compound has O-sulfate on C-6 of Gal-2, and also on C-6 of Gal-3. Two of the trisulfated compounds also have O-sulfate on C-6 of both Gal-2 and Gal-3 with in addition sulfate on C-6 or C-4 of GalNAc. The other two trisulfated compounds have O-sulfate on C-6 of Gal-2 and on C-4 of Gal-3 in conjunction with sulfate on C-6 or C-4 of GalNAc. 
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20.) Structural studies on sulfated oligosaccharides derived from the carbohydrate-protein linkage region of chondroitin 6-sulfate proteoglycans of shark cartilage. I. Six compounds containing 0 or 1 sulfate and/or phosphate residues.
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J Biol Chem 1992 Mar 25;267(9):6027-35 
Sugahara K, Ohi Y, Harada T, de Waard P, Vliegenthart JF
Department of Biological Chemistry, Faculty of Pharmaceutical Sciences, Kyoto University, Japan. 
Shark cartilage proteoglycans bear predominantly chondroitin 6-sulfate. After exhaustive protease digestion, reductive beta-elimination, and subsequent chondroitinase ABC digestion, 13 hexasaccharide alditols, which are nonsulfated, sulfated, and/or phosphorylated, were obtained from the carbohydrate-protein linkage region. Six compounds, containing 0 or 1 sulfate and/or phosphate residue, represent approximately 40% of the isolated linkage hexasaccharide alditols. They were analyzed by chondroitinase ACII or alkaline phosphatase digestion in conjunction with high performance liquid chromatography, and by 500 MHz one- and two-dimensional 1H NMR spectroscopy. All six compounds have the conventional structure in common. Delta 4,5-GlcA beta 1-3GalNAc beta 1-4GlcA beta 1-3Gal beta 1-3Gal beta 1-4Xyl-ol One compound has no sulfate nor phosphate. Two of the monosulfated compounds have a O-sulfate on C-6 or on C-4 of the GalNAc residue. The third monosulfated compound has a novel O-sulfate on C-6 of the Gal residue attached to xylitol. The two phosphorylated compounds have O-phosphate on C-2 of Xyl-ol, and one of them has in addition sulfate on C-6 of GalNAc. 
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21.) In vitro control of neuronal polarity by glycosaminoglycans.
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Development 1992 Jan;114(1):17-29 
Lafont F, Rouget M, Triller A, Prochiantz A, Rousselet A
CNRS URA 1414, Ecole Normale Superieure, Paris, France. 
We have studied the effects of proteoglycans (PGs) and glycosaminoglycans (GAGs) on the growth and morphology of neurons in culture. PGs from glial cells or Engelbreth-Holm-Swarm tumor cells (EHS), pure bovine kidney heparan sulfate (HS), shark cartilage type C chondroitin sulfate (CSc) and bovine mucosa dermatan sulfate (DS) added to embryonic rat neurons strongly enhanced total neurite growth after 48 h in vitro. No trophic effects were seen when PGs treated with a mixture of glycanases were used. PGs, CSc and HS not only enhanced neurite growth but induced the appearance of a majority of neurons with a single long axon whereas, in contrast, DS increased dendrite growth. GAGs bound to the cell surface and were rapidly internalized, a feature that correlated well with the absence of neurotrophicity of GAGs previously immobilized on the culture substratum. Although the mechanisms involved in GAGs neurotrophic effects and in the separate regulation of neuronal polarity by HS and DS were not elucidated, we found that, as opposed to HS, DS was able to enhance neuronal adhesion and spreading and to maintain a high level of expression of microtubule-associated protein 2 (MAP2), a specific dendritic marker. This finding confirms and extends our previous observations on the role of adhesion in the regulation of dendrite growth. 
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22.) A novel angiogenic inhibitor derived from Japanese shark cartilage (I). Extraction and estimation of inhibitory activities toward tumor and embryonic angiogenesis.
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Cancer Lett 1990 Jun 15;51(3):181-6 
Oikawa T, Ashino-Fuse H, Shimamura M, Koide U, Iwaguchi T
Department of Cancer Therapeutics, Tokyo Metropolitan Institute of Medical Science, Japan. 
Guanidine extraction and crude fractionation of Japanese shark cartilage by ultrafiltration on a molecular weight basis were conducted and the antiangiogenic activities were assayed as to the inhibitions of tumor and embryonic angiogenesis. Significant inhibition of angiogenesis was found, and there was a linear relationship between the results of the two assays. The inhibitory activities were concentrated in the fraction in the molecular weight range of 103 to 104, and were resistant to heat treatment. 
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23.) Determination of the distribution of constituent disaccharide units within the chain near the linkage region of shark-cartilage chondroitin sulfate C.
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Biochim Biophys Acta 1987 Dec 7;926(3):239-48 
Uchiyama H, Kikuchi K, Ogamo A, Nagasawa K
School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan. 
A method for analyzing the distribution of constituent disaccharide units within the chain near the linkage region of chondroitin sulfate has been developed. The method consists of (a) chemical modification of the reducing terminal residue in the polysaccharide by a 2-(2,4-dinitrophenylamino)ethylamino (DNP-AEA) group, (b) controlled fragmentation of the DNP-AEA-labeled polysaccharide with chondroitinase AC-I, followed by separation of the digestion products into the DNP-AEA-labeled fragments and unlabeled fragments on octyl-Sepharose CL-4B gel, (c) fractionation of the DNP-AEA-labeled fragments into fractions having different chain-lengths on Sephadex G-100 (superfine), and (d) determination of the disaccharide unit composition of the de-dinitropheylated products (AEA-labeled fragments) by the method combining chondroitinase AC-II treatment with HPLC analysis. A preparation of shark cartilage chondroitin sulfate C, which had been characterized well with regard to molecular species (Mr 48,000; average number of repeating disaccharide units (dpav) 93-94; consisting of chondroitin 6-sulfated 66.8%, 4-sulfated 22.5%, disulfated (D type) 10.3%, and nonsulfated units 0.4%), was analyzed by the above method. On the basis of the data obtained, distribution features of the disaccharide units within the chain near the linkage region of the polysaccharide (dpav 27) were estimated. It was, however, difficult to propose a final primary sequence of the polysaccharide chain, although there was a definite trend towards an enrichment of 4-sulfated and nonsulfated disaccharide residues in the area close to the linkage region (dpav 3-9 or 11). This was apparent together with an enrichment of 6-sulfated and disulfated disaccharide residues in the area distant from the linkage region (dpav 11 or 13-27). 
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24.) Suppression of atherogenesis in hypercholesterolemic rabbits by chondroitin-6-sulfate.
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Artery 1987;14(6):316-37 
Matsushima T, Nakashima Y, Sugano M, Tasaki H, Kuroiwa A, Koide O
2nd Department of Internal Medicine, University of Occupational and Environmental Health, School of Medicine, Kitakyushu, Japan. 
The effect of chondroitin-6-sulfate, obtained from shark cartilage, on atherogenesis in rabbits fed a high-cholesterol diet was studied. Male Japanese white rabbits were housed for 10 weeks in three groups, one group was fed ordinary pellets and was injected intraperitoneally with saline (standard-diet group), one was fed pellets containing 1% cholesterol and was injected intraperitoneally with saline (cholesterol-diet group), and the third group was fed pellets containing 1% cholesterol, and was injected intraperitoneally with 10 mg of chondroitin-6-sulfate (C-6-S group). Injections were done daily. The plasma total cholesterol, and cholesterol from very low-density lipoprotein in the C-6-S group after 5 weeks in the test period, and low-density lipoprotein cholesterol in the C-6-S group at the end of the test period were lower than those of the cholesterol-diet group. Significantly fewer atherosclerotic lesions of the aortic surface were found macroscopically in the C-6-S group than in the cholesterol-diet group. The cholesterol, esterified cholesterol and calcium concentrations of the aortic intima-media in the C-6-S group were significantly lower than in the cholesterol-diet group. Hydroxyproline levels in these three groups were not different. The uronic acid concentration of the intima-media in the cholesterol-diet group was significantly higher than in the C-6-S group (P less than 0.02). Though the percentage of heparan sulfate on total glycosaminoglycans (GAGs) of the C-6-S group was lower than in the cholesterol-diet group, there were no significant differences in the percentages of dermatan sulfate and chondroitin-4/6-sulfate in total GAGs between the cholesterol-diet and C-6-S groups. These results suggest that chondroitin-6-sulfate suppresses cholesterol deposition in the aorta of rabbits fed a 1% cholesterol diet, probably partly due to a decrease in the plasma low-density lipoprotein cholesterol, and partly due to a change in arterial metabolism. 
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25.) High-field n.m.r. studies of keratan sulphates. 1H and 13C assignments of keratan sulphate from shark cartilage.
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Biochem J 1986 Jun 15;236(3):921-4 
Cockin GH, Huckerby TN, Nieduszynski IA
Keratan sulphate was extracted from a shark/whale cartilage preparation and examined by 400 MHz 1H- and 100 MHz 13C-n.m.r. spectroscopy. Assignment of the majority of the resonances was facilitated by two-dimensional 13C-1H correlation by using a modified COLOC procedure and a COSY-45 experiment. The spectra are consistent with an N-acetyl-lactosamine repeating unit that is predominantly sulphated at C-6 of both galactose and N-acetylglucosamine. Gel chromatography of a keratanase digest of the shark keratan sulphate confirmed the high degree of galactose sulphation. 
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26.) Ultrastructural cytochemistry of proteoglycans associated with calcification of shark cartilage.
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Anat Rec 1984 Feb;208(2):149-58 
Takagi M, Parmley RT, Denys FR, Yagasaki H, Toda Y
Proteoglycans (PGs) as well as sulfated glycosaminoglycans (GAGs) are closely associated with cartilage calcification. An inner zone of endoskeletal tesserae of sharks is composed of a unique calcified hyaline cartilage. Initial calcification can be seen in the cartilage close to the inner zone. We have ultrastructurally examined shark, Triakis scyllia, noncalcifying, calcifying, and calcified cartilage using the tannic acid-ferric chloride (TA-Fe), the high iron diamine (HID), and the HID-thiocarbohydrazide-silver proteinate (HID-TCH-SP) methods for localization of sulfated complex carbohydrates. In noncalcifying cartilage, TA-Fe and HID strongly stained matrix granules which were round, ovoid, elongated, or irregularly shaped and presumably represented PG monomers. The size and staining intensity of the reactive matrix granules progressively decreased in calcifying cartilage toward the calcification front of the calcified cartilage. Similarly, a progressive decrease in the size of the HID-TCH-SP stain deposits in the matrix granules was observed in the calcifying cartilage close to the calcification front and was interpreted as a decrease in length of sulfate containing GAG chains. In the calcified cartilage, the highly calcified areas were often localized in the calcification front and contained few or no small HID-TCH-SP stain deposits, whereas the weakly calcified regions contained more stain deposits. These results indicate that partial and complete degradation of sulfated GAGs and/or PGs may be a requisite for calcification of shark cartilage. 
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27.) Distribution of different molecular species of collagen in the vertebral cartilage of shark (Carcharius acutus).
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Connect Tissue Res 1984;12(2):111-8 
Rama S, Chandrakasan G
It is known that cartilage collagen in higher vertebrates conforms to Type II collagen but very little is known of the nature of shark cartilage. This study was undertaken to determine the differences, if any, between shark cartilage collagen and that of higher vertebrates. Collagen was obtained from shark cartilage by pepsin solubilization and characterized by amino acid analysis and determination of chain composition by SDS-polyacrylamide gel electrophoresis and CM-cellulose chromatography. Results indicated the presence not only of Type II collagen but also of Type I collagen. Type I collagen accounted for about one third of the total collagen content of shark cartilage. 
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28.) Shark cartilage contains inhibitors of tumor angiogenesis.
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Science 1983 Sep 16;221(4616):1185-7 
Lee A, Langer R
Shark cartilage contains a substance that strongly inhibits the growth of new blood vessels toward solid tumors, thereby restricting tumor growth. The abundance of this factor in shark cartilage, in contrast to cartilage from mammalian sources, may make sharks an ideal source of the inhibitor and may help to explain the rarity of neoplasms in these animals. 
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29.) Galactose 6-sulfate sulfatase activity in Morquio syndrome.
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Clin Chim Acta 1982 Jul 1;122(2):169-80 
Yutaka T, Okada S, Kato T, Inui K, Yabuuhi H
We have prepared a new substrate (o-beta-D-sulfo-galactosyl-(1-4)-beta-D-6-sulfo-2-acetamido-2-deoxyglucosyl- (1-4)-D-[1-3H]galactitol), from shark cartilage keratan sulfate, for the assay of galactose 6-sulfate sulfatase activity. Using this substrate, we found there was a striking deficiency of galactose 6-sulfate sulfatase activity, in addition to the known deficiency of N-acetylgalactosamine 6-sulfate sulfatase, in the cultured skin fibroblasts of patients with Morquio syndrome. Our results could be explained by the hypothesis that accumulation of keratan sulfate and chondroitin 6-sulfate in Morquio syndrome is due to a deficiency of galactose 6-sulfate sulfatase and N-acetylgalactosamine 6-sulfate sulfatase activity, which are necessary for the degradation of these two mucopolysaccharides. 
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30.) Comparative studies of water sorption of hyaline cartilage.
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Biochim Biophys Acta 1977 Mar 29;497(1):151-9 
Mathews MB, Decker L
Vapor phase, water sorption isotherms were obtained for specimens of bovine, sturgeon and shark cartilage and for membranes composed of collagen and various proportions of cartilage proteoglycan. The data were interpreted in the light of an elementary model for swelling of gels which regards equilibrium swelling a resultant of a balance between contractile forces of an elastic matrix and expansive forces, principally osmotic in nature. Swelling ratios for bovine and sturgeon cartilage compared at the same water vapor pressure are nearly identical, whereas the swelling ratios for shark cartilage are elevated. These high values are due principally to a higher ratio of glycosaminoglycan to collagen but also reflect a higher salt and urea content and possibly also a different type of collagen fibril network. 
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31.) Structure of chondroitin sulfates. Analyses of the products formed from chondroitin sulfates A and C by the action of the chondroitinases C and AC from Flavobacterium heparinum.
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Biochim Biophys Acta 1976 Dec 21;451(2):436-43 
Michelacci YM, Dietrich CP
The structures of chondroitin sulfate A from whale cartilage and chondroitin sulfate C from shark cartilage have been examined with the aid of the chondroitinases AC and C from Flavobacterium heparinum. The analyses of the products formed from the chondroitin sulfates by the action of the chondroitinases have shown that three types of oligosaccharides compose the structure of chondroitin sulfate A, namely, a dodeca-, hexa- and a tetra-saccharide, containing five, two and one 4-sulfated disaccharides per 6-sulfated disaccharide residue, respectively. The polymer contains an average of 3 mol of each oligosaccharide per mol of chondroitin sulfate A. Each mol of chondroitin sulfate C contains an average of 5 mol of 4-sulfated disaccharide units. A tetra-saccharide containing one 4-sulfated disaccharide and one 6-sulfated disaccharide C indicating that the 4-sulfated disaccharides are not linked together in one specific region but spaced in the molecule.   
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32.) Fish Immunoglobulins.
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Biology (Basel). 2016 Nov 21;5(4). pii: E45.
Mashoof S1, Criscitiello MF2,3.
Author information
Abstract
The B cell receptor and secreted antibody are at the nexus of humoral adaptive immunity. In this review, we summarize what is known of the immunoglobulin genes of jawed cartilaginous and bony fishes. We focus on what has been learned from genomic or cDNA sequence data, but where appropriate draw upon protein, immunization, affinity and structural studies. Work from major aquatic model organisms and less studied comparative species are both included to define what is the rule for an immunoglobulin isotype or taxonomic group and what exemplifies an exception.
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33.) Camelid and shark single domain antibodies: structural features and therapeutic potential.
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Curr Opin Struct Biol. 2016 Nov 16;45:10-16. doi: 10.1016/j.sbi.2016.10.019. [Epub ahead of print]
Könning D1, Zielonka S1, Grzeschik J1, Empting M2, Valldorf B1, Krah S3, Schröter C3, Sellmann C3, Hock B4, Kolmar H5.
Author information
1Institute for Organic Chemistry and Biochemistry, Technische Universität Darmstadt, Alarich-Weiss-Strasse 4, D-64287 Darmstadt, Germany.
2Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Department Drug Design and Optimization, Saarland University, Campus C2.3, D-66123 Saarbrücken, Germany.
3Protein Engineering and Antibody Technologies, Merck KGaA, Frankfurter Strasse 250, D-64293 Darmstadt, Germany.
4Protein Engineering and Antibody Technologies, Merck KGaA, Frankfurter Strasse 250, D-64293 Darmstadt, Germany. Electronic address: Bjoern.Hock@merckgroup.com.
5Institute for Organic Chemistry and Biochemistry, Technische Universität Darmstadt, Alarich-Weiss-Strasse 4, D-64287 Darmstadt, Germany. Electronic address: Kolmar@Biochemie-TUD.de.
Abstract
In addition to canonical antibodies composed of heavy and light chains, the adaptive immune systems of camelids and cartilaginous fish comprise heavy-chain only isotypes (HcAb) devoid of light chains, where antigen-binding is mediated exclusively by one variable domain. Due to their inherent favorable attributes, such as high affinity and specificity for their cognate antigen, extraordinary stability, small size and, most importantly, the possibility to complement classical antibodies in terms of 'drugable' target-space, HcAb-derived entities evolved as promising candidates for biomedical applications of which many have already proven to be successful in early stage clinical trials.
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34.) Antiangiogenic and anticancer molecules in cartilage.
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Expert Rev Mol Med. 2012 Jan 19;14:e10. doi: 10.1017/erm.2012.3.
Patra D1, Sandell LJ.
Author information
1Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, MO, USA.
Abstract
Cartilage is one of the very few naturally occurring avascular tissues where lack of angiogenesis is the guiding principle for its structure and function. This has attracted investigators who have sought to understand the biochemical basis for its avascular nature, hypothesising that it could be used in designing therapies for treating cancer and related malignancies in humans through antiangiogenic applications. Cartilage encompasses primarily a specialised extracellular matrix synthesised by chondrocytes that is both complex and unique as a result of the myriad molecules of which it is composed. Of these components, a few such as thrombospondin-1, chondromodulin-1, the type XVIII-derived endostatin, SPARC (secreted protein acidic and rich in cysteine) and the type II collagen-derived N-terminal propeptide (PIIBNP) have demonstrated antiangiogenic or antitumour properties in vitro and in vivo preclinical trials that involve several complicated mechanisms that are not completely understood. Thrombospondin-1, endostatin and the shark-cartilage-derived Neovastat preparation have also been investigated in human clinical trials to treat several different kinds of cancers, where, despite the tremendous success seen in preclinical trials, these molecules are yet to show success as anticancer agents. This review summarises the current state-of-the-art antiangiogenic characterisation of these molecules, highlights their most promising aspects and evaluates the future of these molecules in antiangiogenic applications.
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35.) Antiangiogenic and antimetastatic properties of Neovastat (AE-941), an orally active extract derived from cartilage tissue.
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Clin Exp Metastasis. 2002;19(2):145-53.
Dupont E1, Falardeau P, Mousa SA, Dimitriadou V, Pepin MC, Wang T, Alaoui-Jamali MA.
Author information
1Les Laboratoires AEterna Inc, Québec, Canada.
Abstract
A novel naturally occurring antiangiogenic agent isolated from cartilage, referred to as Neovastat (AE-941), was examined for its efficacy against tumor neovascularization and progression. Exposure to Neovastat results in ex ovo antiangiogenic properties in the chorioallantoid membrane of chicken embryo (71% decrease in the angiogenic index as compared to the basic fibroblast growth factor (bFGF) treated control embryos, P < 0.0001). Oral administration of Neovastat inhibits bFGF-induced angiogenesis in the Matrigel mouse model (87.5% decrease in hemoglobin as compared to the bFGF-treated control implants, P < 0.0001). Neovastat also induces a dose response decrease of lung metastases in the Lewis lung carcinoma model (oral administration; 69.1% of inhibition obtained at the maximal dose of 0.5 ml/day, P < 0.0001). Combined with a sub-optimal dose of cisplatinum (2 mg/kg, i.p.), Neovastat (0.5 ml/day) improved the therapeutic index by increasing the antimetastatic efficacy and by exerting a protective activity against cisplatinum-induced body weight loss and myelosuppression. In summary, our experimental data provide evidence of antiangiogenic and antimetastatic properties of Neovastat, following oral administration.
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36.) Neovastat--a novel antiangiogenic drug for cancer therapy.
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Gingras D1, Boivin D, Deckers C, Gendron S, Barthomeuf C, Béliveau R.
Author information
1Laboratoire de médecine moléculaire Hôpital Ste-Justine-UQAM, Centre de cancérologie Charles-Bruneau, Centre de Recherche de l'Hôpital Ste-Justine, Montréal, Québec, Canada.
Abstract
Neovastat (AE-941) is an antiangiogenic drug isolated from marine cartilage. It interferes with several steps associated with the development of angiogenesis through its ability to induce endothelial cell apoptosis, and to inhibit matrix metalloproteinase activities and vascular endothelial growth factor-mediated signaling pathways, suggesting that Neovastat behaves as a multifunctional antiangiogenic drug. Neovastat is orally bioavailable, and shows significant antitumor and antimetastatic properties in animal models. An excellent safety profile with few side effects has been monitored in more than 800 patients who have been exposed to Neovastat, some of whom for more than 4 years. This indicates that Neovastat is suitable for long-term use, either alone or in combination with other anticancer therapies. Accordingly, Neovastat is currently under evaluation in three pivotal clinical studies with two phase III clinical trials in patients with lung and renal carcinoma, and a phase II clinical trial in patients with multiple myeloma is ongoing.
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37.) Pro-inflammatory properties of shark cartilage supplement.
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Immunopharmacol Immunotoxicol. 2015 Apr;37(2):140-7. doi: 10.3109/08923973.2014.999160. Epub 2015 Jan 20.
Merly L1, Smith SL.
Author information
1Department of Biological Sciences, Florida International University , Miami, FL , USA.
Abstract
The erosion and breakdown of cartilage is generally recognized to be an integral manifestation of arthritic disease, which is often accompanied by the development and progression of inflammation associated with it. Commercial shark cartilage (SC) is a popular dietary supplement taken for the prevention and/or control of chronic disease, including arthritis. The efficacy of SC in maintaining joint health remains questionable; there is a lack of sufficient reliable information on its effect on immunocompetent cells, and the potential health risks involved have not been adequately assessed. Our earlier in vitro studies showed that SC extracts induce a Th1-type inflammatory cytokine response in human leucocytes, and collagen type II alpha 1 protein was shown to be an active cytokine-inducing component in SC. In this study, we further define the cellular response to SC stimulation by classifying leucocytes into primary and secondary responders employing enriched leucocyte subpopulations. Inhibitors of specific signaling pathways were used to verify the functional effect of SC on specific pathway(s) utilized. Results indicate the monocyte/macrophage as the initially responding cell, followed by lymphocytes and the production of interferon-γ. Chemokines, MCP-1 and RANTES, were produced at significant levels in stimulated leucocyte cultures. Initial cellular activation is likely followed by activation of Jun Kinase and p38 mitogen-activated protein kinase signal transduction pathways. This study presents evidence of significant immunological reactivity of components of commercial SC supplement, which could pose a potential health risk for consumers, particularly those with underlying inflammatory disease such as irritable bowel syndrome and arthritis.
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38.) Medical Gains of Chondroitin Sulfate Upon Fucosylation.
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Curr Med Chem. 2015;22(36):4166-76.
Pomin VH1.
Author information
1R. Prof. Rodolpho Paulo Rocco, 255, HUCFF-4A01, Ilha do Fundão, Rio de Janeiro, RJ, 21941-913, Brazil. pominvh@bioqmed.ufrj.br.
Abstract
Chondroitin sulfate (CS) is a glycosaminoglycan (GAG) composed of alternating N-acetyl galactosamine and glucuronic acid units within disaccharide building blocks. CS is a key functional component in proteoglycans of cartilaginous tissues. Owing to its numerous biological roles, CS is widely explored in the pharmaceutical market as nutraceutical ingredient commonly utilized against arthritis, osteoarthrosis, and sometimes osteoporosis. Tissues like shark cartilage and bovine trachea are common sources of CS. Nonetheless, a new CS type has been introduced and investigated in the last few decades in what regards its medical potentials. It is named fucosylated chondroitin sulfate (FucCS). This less common CS type is isolated exclusively from the body wall of sea cucumbers. The presence of fucosyl branching units in the holothurian FucCS gives to this unique GAG, therapeutic properties in various pathophysiological systems which are inexistent in the common CS explored in the market. Examples of these systems are coagulation, thrombosis, hemodialysis, atherosclerosis, cellular growth, angiogenesis, fibrosis, tumor growth, inflammation, viral and protozoan infections, hyperglycemia, diabetes-related pathological events and tissue damage. This report aims at describing the medical benefits gained upon
 
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