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A unique therapeutic approach to emesis and itch with a proanthocyanidin-rich genonutrient
Mark JS Miller, Brian K Reuter, John L Wallace, Keith A Sharkey
Journal of Translational Medicine , 2008, DOI: 10.1186/1479-5876-6-3
Abstract: Emesis was induced in ferrets with morphine-6-glucuronide (0.05 mg/kg sc) in the presence of Zangrado (3 mg/kg, ip) and the cannabinoid receptor 1 antagonist, AM 251 (5 mg/kg, ip). Topical Zangrado (1%) was assessed for anti-pruretic actions in the 5-HT-induced scratching model in rats and evaluated in capsaicin-induced gastric hyperemia as measured by laser doppler flow. In the ApcMinmouse model of precancerous adenomatosis polyposis, mice received Zangrado (100 μg/ml in drinking water) from the age of 6 – 16 weeks for effects on polyp number. In RAW 264.7 cells Zangrado was examined for effects on lipopolysaccharide-induced nitrite production.Zangrado was a highly effective anti-emetic, reducing morphine-induced vomiting and retching by 77%. These benefits were not associated with sedation or hypothermia and were not reversed by cannabinoid receptor antagonism. Itch responses were blocked in both the morphine and 5-HT models. Zangrado did not exacerbate the ApcMincondition rather health was improved. Capsaicin-induced hyperemia was blocked by Zangrado, which also attenuated the production of nitric oxide by activated macrophages.Zangrado is an effective anti-emetic and anti-itch therapy that is devoid of common side-effects, cannabinoid-independent and broadly suppresses sensory afferent nerve activation. This complementary medicine represents a promising new approach to the management of nausea, itch and irritable bowel syndrome.The latex of the Amazonian traditional medicine Croton palanostigma and related Croton species is traditionally used in the treatment of inflammation, pain, itch, and a number of gastrointestinal afflictions that are common in the rainforest [1]. This traditional medicine is derived from a fast growing tree that is known by different names in various countries: in Peru it is called sangre de grado and in Ecuador, sangre de drago. We have found substantial scientific support for a number of these ethnomedical applications [2-4]. A central
Chondroprotective Activity of Murraya exotica through Inhibiting β-Catenin Signaling Pathway  [PDF]
Longhuo Wu,Haiqing Liu,Rui Zhang,Linfu Li,Jialin Li,Haibo Hu,Hao Huang
Evidence-Based Complementary and Alternative Medicine , 2013, DOI: 10.1155/2013/752150
Abstract: Osteoarthritis (OA) is a degenerative joint disease that affects millions of people. Currently, there is no effective drug treatment for it. The purpose of this study is to investigate the chondroprotective effects of Murraya exotica (L.) on OA. The rat OA models were duplicated to prepare for separating OA chondrocytes, synovial fluid (SF), and serum containing M. exotica (50?mg/kg, 100?mg/kg, and 200?mg/kg), M. exotica showed the activity of decreasing the contents of TNF-α and IL-1β in SF and the chondrocyte apoptosis in a dose-dependent manner. To investigate the probable mechanism, quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting were used to determine gene expression and protein profiles, respectively. The results reveal that M. exotica can downregulate mRNA and protein expressions of β-catenin and COX-2 and reporter activity significantly. Conclusively, M. exotica exhibits antiapoptotic chondroprotective activity probably through inhibiting β-catenin signaling. 1. Introduction Osteoarthritis (OA) is a progressive joint disorder, which remains the leading cause of chronic disability in aged people. It had been elucidated that the signaling pathways directing joint formation and homeostasis were the key molecular players in OA [1]. Wnt proteins play central roles in a variety of developmental processes and events, including organogenesis, cell differentiation, morphogenesis, and tissue remodeling [2]. In the canonical Wnt/β-catenin signaling pathway, Wnt protein binds to cell-surface frizzled and the coreceptor low density lipoprotein receptor-related protein 5 and 6 (LRP-5/6), leading to inhibition of β-catenin phosphorylation by glycogen synthase kinase 3 beta (GSK-3β) and proteasome-mediated degradation; stabilized β-catenin translocates into the nucleus, where it interacts with resident lymphoid enhancer factor/T-cell (LEF/TCF) transcription factors to activate target genes [3]. Cumulating studies mainly based on experimental animal models for OA have suggested an important procatabolic role for Wnt/β-catenin signaling in the pathogenesis of OA [2, 4]. Direct genetic evidence for β-catenin in OA had not been reported, because tissue-specific activation of the β-catenin gene (target by Col2a1-Cre) was embryonic lethal. In Col2a1-CreERT2 ? mice, overexpression of β-catenin protein was detected by immunostaining in the 3th month, reduction of Safranin O and Alcian blue staining in the 5th month, and cell cloning, surface fibrillation, vertical clefting, and osteophyte formation were observed in the 8th month. In
Chondroprotective Potential of Fruit Extracts of Phyllanthus emblica in Osteoarthritis  [PDF]
Venil N. Sumantran,Asavari Kulkarni,Rucha Chandwaskar,Abhay Harsulkar,Bhushan Patwardhan,Arvind Chopra,Ulhas V. Wagh
Evidence-Based Complementary and Alternative Medicine , 2008, DOI: 10.1093/ecam/nem030
Abstract: There is a need for effective nutraceuticals for osteoarthritis care. The fruit of Phyllanthus emblica is used as a powerful rejuvenator in Ayurvedic medicine. This study measured the chondroprotective potential of P. emblica (‘Amalaki’) fruits in vitro. We used aqueous extracts of unprocessed P. emblica fruit powder (powder A), and the powder obtained after hot water extraction and drying of powder A (powder B). Chondroprotection was measured in three different assay systems. First, we tested the effects of both fruit powders on the activities of the enzymes hyaluronidase and collagenase type 2. Second, an in vitro model of cartilage degradation was set-up with explant cultures of articular knee cartilage from osteoarthritis patients. Cartilage damage was assayed by measuring glycosaminoglycan release from explants treated with/without P. emblica fruit powders. Aqueous extracts of both fruit powders significantly inhibited the activities of hyaluronidase and collagenase type 2 in vitro. Third, in the explant model of cartilage matrix damage, extracts of glucosamine sulphate and powder B (0.05 mg/ml) exhibited statistically significant, long-term chondroprotective activity in cartilage explants from 50% of the patients tested. This result is important since glucosamine sulphate is the leading nutraceutical for osteoarthritis. Powder A induced a statistically significant, short-term chondroprotective activity in cartilage explants from all of the patients tested. This is the first study to identify and quantitate new chondroprotective activities of P. emblica fruits. These data provide pilot pre-clinical evidence for the use of P. emblica fruits as a chondroprotective agent in osteoarthritis therapy.
Selection of reliable reference genes for qPCR studies on chondroprotective action
Stefan Toegel, Wenwen Huang, Claudia Piana, Frank M Unger, Michael Wirth, Mary B Goldring, Franz Gabor, Helmut Viernstein
BMC Molecular Biology , 2007, DOI: 10.1186/1471-2199-8-13
Abstract: CPA treatment of C-28/I2 chondrocytes significantly affected the expression level of many reference genes (p < 0.05). According to their expression stability, geNorm analysis revealed rankings of the 3 most stable genes (from most stable to least stable) as follows: GAPDH, B2M and SDHA in glucosamine treated samples and HPRT1, GAPDH and B2M in curcumin or diacerein treated samples. Interestingly, ACTB was one of the most variably expressed genes throughout all experiments.Our study points out the problem of relying on commonly used reference genes without an accurate validation process. For normalization purposes in gene profiling studies on glucosamine action, the genes GAPDH, B2M and SDHA are recommended as single reference genes depending on the expression level of the target gene or more favourably in combination. For experiments with curcumin and diacerein the use of HPRT1, GAPDH and B2M should be considered.Osteoarthritis (OA) is a chronic, degenerative disorder of unknown cause characterized by gradual loss of articular cartilage. It is the most common of all joint diseases and represents a major social and economic burden since its prevalence increases with age [1]. Currently, classic therapeutic approaches are still limited to symptom relieving drugs or surgical intervention. Chondroprotection with drugs possessing disease-modifying qualities represents an alternative concept in the treatment of OA and its clinical potential has been the subject of numerous studies, both clinical and in-vitro [2-10]. Examples of chondroprotective agents (CPA) are glucosamine, chondroitin sulphate, curcumin, diacerein, rhein, and avocado/soybean unsaponifiables. However, medical opinion about the applicability and clinical efficacy of CPA in OA remains divided. In the case of glucosamine, for example, numerous clinical reports have indicated beneficial effects such as symptom relief in OA [2,3]. On the other hand, several reviews have provided criticism of study designs or p
Protective Effect of Proanthocyanidin against Diabetic Oxidative Stress
Takako Yokozawa,Eun Ju Cho,Chan Hum Park,Ji Hyun Kim
Evidence-Based Complementary and Alternative Medicine , 2012, DOI: 10.1155/2012/623879
Abstract: We investigated the antidiabetic potential of proanthocyanidin and its oligomeric form in STZ-induced diabetic model rats and db/db type 2 diabetic mice. Proanthocyanidin ameliorated the diabetic condition by significant decreases of serum glucose, glycosylated protein, and serum urea nitrogen as well as decreases of urinary protein and renal-AGE in STZ-induced diabetic rats and decrease of serum glucose as well as significant decrease of glycosylated protein in db/db type 2 diabetic mice. The suppression of ROS generation and elevation of the GSH/GSSG ratio were also observed in the groups administered proanthocyanidin. Moreover, proanthocyanidin, especially its oligomeric form, affected the inflammatory process with the regulation of related protein expression, iNOS, COX-2 and upstream regulators, NF-κB, and the IκB-α. In addition, it had a marked effect on hyperlipidemia through lowering significant levels of triglycerides, total cholesterol, and NEFA. Moreover, expressions in the liver of SREBP-1 and SREBP-2 were downregulated by the administration of proanthocyanidins. The protective effect against hyperglycemia and hyperlipidemia in type 1 and 2 diabetic models was significantly strong in the groups administered the oligomeric rather than polymeric form. This suggests that oligomers act as a regulator in inflammatory reactions caused by oxidative stress in diabetes.
Chondroprotective Effect of Zerumbone on Monosodium Iodoacetate Induced Osteoarthritis in Rats  [PDF]
F.J. Al-Saffar,S. Ganabadi,S. Fakurazi,H. Yaakub
Journal of Applied Sciences , 2010,
Abstract: The objective of this investigation was to evaluate chondroprotective effect of zerumbone, a purified compound of Zingiber zerumbet Smith against monosodium iodoacetate (MIA) induced knee osteoarthritis (OA) in the rat. The effect on the articular cartilage was examined and compared with celecoxib (Celebrex ), a Non-Steroidal Anti-Inflammatory Drug (NSAID). Forty adult male Sprague Dawley rats were divided into four groups (n=10 for each). All animals were injected with MIA intraarticularly in their right knee joints to induce OA. Rats from first and second groups were treated with zerumbone in a same dose but with two different concentrations. Rats in the third group were treated with celecoxib and served as positive control whereas the fourth group were treated with corn oil and served as negative control. Evaluation of OA changes in the knees was assessed with the aid of both radiography and histopathology score. Macroscopic as well as microscopic examinations revealed curative effect of zerumbone in a dose dependent manner on the osteoarthritic knee joints. Apart from this, our data also revealed very poor anti-OA property of celecoxib. We concluded that oral administration of zerumbone in a dose of 2 mL kg-1 b.wt. of 0.4% w/v diluted with corn oil for a period of 4 weeks has some chondroprotective effects.
Associations of Proanthocyanidin Intake with Renal Function and Clinical Outcomes in Elderly Women  [PDF]
Kerry L. Ivey, Joshua R. Lewis, Wai H. Lim, Ee M. Lim, Jonathan M. Hodgson, Richard L. Prince
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0071166
Abstract: Background Progression to chronic renal failure involves accelerated atherosclerosis and vascular calcification. Oxidative stress and endothelial dysfunction play a role in renal failure pathophysiology. In addition to improving vascular health and function, proanthocyanidins have been shown to exert renoprotective effects in animal models. Thus we hypothesize that proanthocyanidins may contribute to the maintenance of healthy renal function. Objective Determine the association of habitual proanthocyanidin intake with renal function and the risk of clinical renal outcomes in a population of elderly women. Design 948 women aged over 75 y, free of prevalent renal disease at baseline, were randomly selected from ambulant Caucasian women. Proanthocyanidin consumption was determined using a validated food frequency questionnaire and the United States Department of Agriculture proanthocyanidin food content database. Fasting serum cystatin C and creatinine were assessed at baseline. Renal failure hospitalisations and deaths were assessed over 5 years of follow-up through the Western Australia Data Linkage System. Results Compared to participants with low consumption, participants in the highest tertile of proanthocyanidin intake had a 9% lower cystatin C concentration (P<0.001). High proanthocyanidin consumers were at 50% lower risk of moderate chronic kidney insufficiency, and 65% lower risk of experiencing a 5-year renal disease event (P<0.05). These relationships remained significant following adjustment for renal disease risk factors and diet-related potential confounders. Conclusion Increased consumption of proanthocyanidins was associated with better renal function and substantially reduced renal associated events, which has been supported by mechanistic and animal model data. Proanthocyanidin intake should be further examined as a dietary contributor to better renal health.
Photo-Irradiation of Proanthocyanidin as a New Disinfection Technique via Reactive Oxygen Species Formation  [PDF]
Keisuke Nakamura, Midori Shirato, Hiroyo Ikai, Taro Kanno, Keiichi Sasaki, Masahiro Kohno, Yoshimi Niwano
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0060053
Abstract: In the present study, the bactericidal effect of photo-irradiated proanthocyanidin was evaluated in relation to reactive oxygen species formation. Staphylococcus aureus suspended in proanthocyanidin aqueous solution was irradiated with light from a laser at 405 nm. The bactericidal effect of photo-irradiated proanthocyanidin depended on the concentration of proanthocyanidin, the laser irradiation time, and the laser output power. When proanthocyanidin was used at the concentration of 1 mg/mL, the laser irradiation of the bacterial suspension could kill the bacteria with a >5-log reduction of viable cell counts. By contrast, bactericidal effect was not observed when proanthocyanidin was not irradiated. In electron spin resonance analysis, reactive oxygen species, such as hydroxyl radicals, superoxide anion radicals, and hydrogen peroxide, were detected in the photo-irradiated proanthocyanidin aqueous solution. The yields of the reactive oxygen species also depended on the concentration of proanthocyanidin, the laser irradiation time, and the laser output power as is the case with the bactericidal assay. Thus, it is indicated that the bactericidal effect of photo-irradiated proanthocyanidin is exerted via the reactive oxygen species formation. The bactericidal effect as well as the yield of the oxygen radicals increased with the concentration of proanthocyanidin up to 4 mg/mL, and then decreased with the concentration. These findings suggest that the antioxidative activity of proanthocyanidin might prevail against the radical generation potency of photo-irradiated proanthocyanidin resulting in the decreased bactericidal effect when the concentration is over 4 mg/mL. The present study suggests that photo-irradiated proanthocyanidin whenever used in an optimal concentration range can be a new disinfection technique.
Interleukin-4 downregulates the cyclic tensile stress-induced matrix metalloproteinases-13 and cathepsin b expression by rat normal chondrocytes
Doi,Hideyuki,Nishida,Keiichiro,Yorimitsu,Masanori,Komiyama,Takamitsu
Acta Medica Okayama , 2008,
Abstract: Mechanical stress plays a key role in the pathogenesis of cartilage destruction seen in osteoarthritis (OA). We investigated the effect of cyclic tensile stress (CTS) on the anabolic and catabolic gene expression of rat cultured normal chondrocytes using the Flexercell strain unit. The effects of interleukin (IL)-4, a chondroprotective cytokine, on the changes in gene expression induced by CTS were also investigated. CTS (7% elongation at 0.5 Hz) for 24 h did not affect the expression of aggrecan and type II collagen, whereas CTS significantly upregulated matrix metalloproteinase (MMP)-13 and cathepsin B mRNA expression by chondrocytes. IL-1beta expression was also signifi cantly upregulated by CTS up to 12 h. The upregulation of MMP-13 was observed at 3 h, which was earlier than that of IL-1beta. Furthermore, pre-treatment with IL-4 (10 ng/ml) suppressed both MMP-13 and cathepsin B induction by mechanical stress, as well as CTS-induced IL-1beta expression. Our results suggest that IL-4 might have a therapeutic value in the treatment of OA by downregulation of mechanical stress-induced MMP-13 and cathepsin B expression by chondrocytes.
Tissue inhibitors of metalloproteinases
Gillian Murphy
Genome Biology , 2011, DOI: 10.1186/gb-2011-12-11-233
Abstract: The naturally occurring inhibitory activities of the matrix metalloproteinases (MMPs) were initially identified in many cell and tissue culture studies, carried out over several decades. Between 1985 and 1996, however, four members of the tissue inhibitor of metalloproteinases (TIMP) family were definitively identified at the gene level in mammals. In fact, orthologs of the TIMPs are widely distributed across the animal kingdom and have now been identified in species as widely separated as Trichoplax, Hydra, molluscs, worms and insects, as well as in vertebrates such as fish and birds. Plants do have metzincins, but no plant TIMP ortholog has been identified.TIMP1 was originally cloned in 1985 when it was found to have an erythroid potentiating activity [1] and to be an inhibitor of metalloproteinases [2]. TIMP2 was cloned in 1990 by Stetler-Stevenson et al. [3], TIMP3 by Pavloff and colleagues in 1992 [4], and TIMP4 in 1996 [5]. These proteins act as significant regulators of the activities of MMPs and, in some instances, of other metalloendopeptidases of the metzincin clan, namely the disintegrin metalloproteinases (ADAM) and the disintegrin metalloproteinases with thrombospondin motifs (ADAMTS). TIMPs inhibit with a 1:1 molar stoichiometry. Their importance in modulating the ability of a cell to control its extracellular environment, from the remodeling of the extracellular matrix to the interaction of cells via adhesion and signaling molecules such as growth factors has long been appreciated [6], but the significance of TIMPs as both proteinase inhibitors and signaling molecules in their own right is only just beginning to be documented [7].The four mammalian TIMPs are thought to be products of gene duplication because there is a single gene in insects, but orthologs of all four proteins are not found in all vertebrates. The TIMP proteins share a similar domain structure, composed of an amino-terminal domain and a carboxy-terminal sub-domain. TIMP1 and TIMP3 see
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