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Cat's Claws and shark
cartilage/ Una de Gato y Cartílago de Tiburón.
Data-Médicos
~ Una de gato y Cartílago de Tiburón ~
EDITORIAL ESPAÑOL
EDITORIAL ENGLISH
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Sheng Y [Find other
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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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Reinhard KH [Find other
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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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Lemaire I; Assinewe V;
Cano P; Awang DV; Arnason JT [Find other articles with these Authors]
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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Keplinger K; Laus G; Wurm
M; Dierich MP; Teppner H [Find other articles with these Authors]
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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Sheng Y; Pero RW; Amiri A;
Bryngelsson C [Find other articles with these Authors]
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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Santa Maria A; Lopez A;
Diaz MM; Alban J; Galan de Mera A; Vicente Orellana JA; Pozuelo JM [Find other
articles with these Authors]
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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Wurm M; Kacani L; Laus G;
Keplinger K; Dierich MP [Find other articles with these Authors]
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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Proc West Pharmacol Soc 1998;41:123-4 (ISSN: 0083-8969) Salazar EL; Jayme V [Find
other articles with these Authors]
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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]
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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Rizzi R, Re F, Bianchi A,
De Feo V, de Simone F, Bianchi L, Stivala LA
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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Aquino R, De Feo V, De
Simone F, Pizza C, Cirino G
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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Aquino R, De Simone F,
Vincieri FF, Pizza C, Gacs-Baitz E
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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Aquino R, De Simone F,
Pizza C, Conti C, Stein ML
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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Senatore A, Cataldo A,
Iaccarino FP, Elberti MG
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PHYSIOLOGY:
INDICATIONS:
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Ernst E, Cassileth BR
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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Sorrell JM, Carrino DA,
Baber MA, Asselineau D, Caplan AI
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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Renckens CN, van Dam FS
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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Sheu JR, Fu CC, Tsai ML,
Chung WJ
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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Felzenszwalb I, Pelielo de
Mattos JC, Bernardo-Filho M, Caldeira-de-Araujo A
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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Horsman MR, Alsner J,
Overgaard J
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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Miller DR, Anderson GT,
Stark JJ, Granick JL, Richardson D
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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Sivakumar P, Chandrakasan
G
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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Dupont E, Savard PE,
Jourdain C, Juneau C, Thibodeau A, Ross N, Marenus K, Maes DH, Pelletier G,
Sauder DN
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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Newman V, Rock CL, Faerber
S, Flatt SW, Wright FA, Pierce JP
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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Fontenele JB, Araujo GB,
de Alencar JW, Viana GS
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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Ashar B, Vargo E
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Fontenele JB, Viana GS,
Xavier-Filho J, de-Alencar JW
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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Gomes EM, Souto PR,
Felzenszwalb I
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.
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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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Moller HJ, Moller-Pedersen
T, Damsgaard TE, Poulsen JH
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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Alves ML, Straus AH,
Takahashi HK, Michelacci YM
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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Fernaud-Espinosa I,
Nieto-Sampedro M, Bovolenta P
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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de Waard P, Vliegenthart
JF, Harada T, Sugahara K
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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Sugahara K, Ohi Y, Harada
T, de Waard P, Vliegenthart JF
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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Lafont F, Rouget M,
Triller A, Prochiantz A, Rousselet A
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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Oikawa T, Ashino-Fuse H,
Shimamura M, Koide U, Iwaguchi T
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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Uchiyama H, Kikuchi K,
Ogamo A, Nagasawa K
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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Matsushima T, Nakashima Y,
Sugano M, Tasaki H, Kuroiwa A, Koide O
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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Cockin GH, Huckerby TN,
Nieduszynski IA
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Takagi M, Parmley RT,
Denys FR, Yagasaki H, Toda Y
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Rama S, Chandrakasan G
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Lee A, Langer R
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Yutaka T, Okada S, Kato T,
Inui K, Yabuuhi H
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Mathews MB, Decker L
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Michelacci YM, Dietrich CP
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