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Glycyrrhizin exhibits potential chemopreventive activity on 12-O-tetradecanoyl phorbol-13-acetate-induced cutaneous oxidative stress and tumor promotion in Swiss albino mice

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Abstract

Glycyrrhizin and its aglycone, glycyrrhetic acid has been found useful for various therapeutic purposes. Glycyrrhizin has been shown to possess many physiological functions like anti-inflammatory activity, detoxification and inhibition of carcinogenic promoters. 12-O-Tetradecanoyl phorbol-13-acetate (TPA), a well-known phorbal ester is known for its tumor promotion activity. The induction of inflammation in skin mediated by TPA is believed to be governed by cyclooxygenase (COX), lipoxygenase and ornithine decarboxylase (ODC). These markers of inflammatory responses are important for skin tumor promotion. In our present study, we studied the chemopreventive effect of glycyrrhizin on TPA (20 nmol/0.2 mL acetone/animal, topically)-induced oxidative stress and hyperproliferation markers in skin. TPA enhanced lipid peroxidation with reduction in the level of catalase, glutathione, glutathione peroxidase, glutathione reductase and glutathione-s-transferase. TPA treatment also enhanced ODC activity and [3H] thymidine incorporation into cutaneous DNA. Prophylactic treatment of mice with glycyrrhizin (2.0 & 4.0 mg/0.2 mL acetone/animal, topically) resulted in a significant decrease in cutaneous microsomal lipid peroxidation (P < 0.001) and recovery of cutaneous glutathione content (P < 0.001) and its dependent enzymes. A significant inhibition in ODC activity and DNA synthesis (P < 0.001) was also observed. Thus, the results demonstrate that pretreatment with glycyrrhizin is protective against TPA-induced oxidative stress and tumor promotion in Swiss albino mice.

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... Glycyrrhizin, a conjugate of one molecule of Glycyrrhetinic acid and two molecules of Glucuronic acid, is the main constituent of G. glabra [25]. It is considered to be the most common of the Asiatic folk medicines that acts as an anti-in�ammatory agent on neutrophil functions including ROS generation [25]. ...
... Glycyrrhizin, a conjugate of one molecule of Glycyrrhetinic acid and two molecules of Glucuronic acid, is the main constituent of G. glabra [25]. It is considered to be the most common of the Asiatic folk medicines that acts as an anti-in�ammatory agent on neutrophil functions including ROS generation [25]. us, Glycyrrhizin can be considered as a quenching agent of free radicals and a blocking agent of lipid peroxidation chain reactions. ...
... us, Glycyrrhizin can be considered as a quenching agent of free radicals and a blocking agent of lipid peroxidation chain reactions. Tested on animal model, Glycyrrhizin showed an effective chemopreventive, antioxidant, and antiproliferative activity [25]. Extract of Mulberry (Morus alba) exhibited super oxide scavenging activity that is involved in the protection against autooxidation [26,27]. ...
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The fact that the skin is the most visible organ makes us aware of the ageing process every minute. The use of plant extracts and herbs has its origins in ancient times. Chronological and photo-ageing can be easily distinguished clinically, but they share important molecular features. We tried to gather the most interesting evidence based on facts about plants and plant extracts used in antiaging products. Our main idea was to emphasize action mechanisms of these plant/herbal products, that is, their "strategies" in fighting skin ageing. Some of the plant extracts have the ability to scavenge free radicals, to protect the skin matrix through the inhibition of enzymatic degradation, or to promote collagen synthesis in the skin. There are some plants that can affect skin elasticity and tightness. Certainly, there is a place for herbal principles in antiaging cosmetics. On the other hand, there is a constant need for more evaluation and more clinical studies in vivo with emphasis on the ingredient concentration of the plant/herbal products, its formulation, safety, and duration of the antiaging effect.
... An important ingredient of root extraction from liquorice is the water soluble acid, glycyrrhizin (Fig. 1), which consists of glucuronic acid and glycyrrhetinic acid (9). A prior study has indicated that glycyrrhizin is one of the most effective ingredients of liquorice, which has anti-ulcer, anti-allergic, anti-oxidant, immunomodulatory, anti-viral and anti-cancer effects (10). Furthermore, it has the functions of liver protection and membrane stabilization. ...
... Wang et al reported that glycyrrhizic acid attenuated reactive oxygen species production in the kidneys of diabetic mice (23). Rahman and Sultana (10) reported that glycyrrhizin inhibited 12-O-tetradecanoyl phorbol-13-acetate-induced cutaneous oxidative stress in Swiss albino mice. ...
Article
Glycyrrhizin, which is a type of perennial leguminous caudex, has been used in various Asian countries, including P.R. China, India and Japan, for thousands of years. The present study was designed to investigate the protective effect of glycyrrhizin on myocardial ischemia/reperfusion (I/R) injury through oxidative stress, inducible nitric oxide synthase (iNOS), and inflammatory reactions via high-mobility group box 1 (HMGB1) and mitogen-activated protein kinase (MAPK) expression. Sprague-Dawley rats were divided into five groups: Sham; myocardial I/R injury + non-treated; myocardial I/R injury + 2 mg/kg glycyrrhizin; myocardial I/R injury + 4 mg/kg glycyrrhizin; and myocardial I/R injury + 10 mg/kg glycyrrhizin. Pre-treatment with glycyrrhizin significantly reduced infarct size and inhibited creatine kinase, creatine kinase-MB, lactate dehydrogenase and cardiac troponin T activities in rats with myocardial I/R injury. Furthermore, glycyrrhizin treatment significantly suppressed oxidative stress, iNOS protein expression and inflammatory reactions in rats with myocardial I/R injury. Additionally, treatment with glycyrrhizin significantly decreased the release of HMGB1 from the cerebral cortex into the serum in rats with myocardial I/R injury. Notably, glycyrrhizin significantly suppressed p-ERK, p-p38 MAPK and p-c-Jun N-terminal kinase protein expressions, and promoted extracellular signal-regulated kinase protein expression in rats with myocardial I/R injury. Collectively, the present study indicates that the protective effect of glycyrrhizin may reduce myocardial I/R injury through oxidative stress, iNOS and inflammatory reactions, via HMGB1 and MAPK expression.
... Glycyrrhizin, the main sweet-tasting constituent of G. uralensis, has been reported to scavenge free radicals and block the chain reaction of lipid peroxidation (Binic et al., 2013). Moreover, its antioxidant, anti-inflammatory, chemopreventive, and antiproliferative activity have been reported (Rahman et al., 2007;Visavadiya et al., 2009;Binic et al., 2013).However, information on the cosmeceutical activity of G. uralensis is limited. G. uralensis extract in most research has been mainly prepared in methanol. ...
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Aim: The aim of the present study was to investigate the antioxidant, anti-melanogenic and anti-wrinkle activity of Glycyrrhiza uralensis (G. uralensis) for cosmeceutical application. Methodology: The free radical scavenging activity of 1,3-butylene glycol (1,3-BG) extract of G. uralensis was analyzed using 1,1-diphenyl-2-picrylhydrazyl (DPPH), 2,2-Azinobis-(3-ethylbenzothiazoline-6- sulfonic acid) (ABTS) and oxygen radical absorbance capacity (ORAC) assays. The anti-melanogenesis and anti-wrinkle effects of G. uralensis extract were also analyzed by tyrosinase, zymography and collagen assays. Results: The EC of 1,3-BG extract of G. uralensis, determined by DPPH and ABTS assays, was 0.59% 50 and 1.17%, respectively.The ORAC value of the extract was 41.56 μM trolox equivalent. The G. uralensis extract inhibited in vitro mushroom tyrosinase activity with an IC of 0.6%, and it also reduced melanin 50 contents in mouse melanoma cells. In addition, the G. uralensis extract notably inhibited matrix metalloproteinase-2 activity via zymography. Approximately, 60% collagen production enhancement was observed upon treatment with the extract, suggesting its anti-wrinkle potential. Interpretation: The 1,3-BG extract of G. uralensis may be utilized as a cosmeceutical ingredient, offering anti-oxidant, brightening and anti-wrinkle effects.
... , GA reduced the induction factor of H 2 O 2 with IC 50 34.61 µM. Earlier, there are reports revealing that GA protected human hepatoma cell line against aflatoxin-induced oxidative stress [25] and the chemopreventive activity of GA on 12-O-tetradecanoyl phorbol-13-acetate-induced cutaneous oxidative stress and tumor promotion in Swiss albino mice. [26] In Comet assay, it reduced the tail moment induced by H 2 O 2 with IC 50 34.95 µM. In another study, comet assay was utilized to evaluate DNA protection capability of GA and revealed that intraperitoneal administration of GA to mice protected cellular DNA from gamma-radiationinduced damage. [27] The ability of silver nanoparticlesglycyr ...
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Background: The chemopreventive effects of certain phytoconstituents can be exploited for their use as functional foods, dietary supplements and even as drugs. The natural compounds, acting as anti-genotoxic and free radical scavenging compounds, may serve as potent chemopreventive agents. These can inhibit DNA modulatory activities of mutagens and help preventing pathological processes. Objectives: Present study on Glycyrrhiza glabra L., a promising medicinal plant, widely used in traditional medicine, focused on the bioassay-guided fractionation of its extracts for the isolation of certain phytochemicals with anti-genotoxic potential against oxidative mutagens. Materials and methods: The methanol extract of Glycyrrhiza glabra rhizomes was subjected to column chromatography, and isolated fraction was evaluated for its anti-genotoxic and antioxidant potential using SOS chromotest, Comet assay, and DPPH radical scavenging assay. Results: GLG fraction, which was characterized as Glycyrrhizic acid, inhibited the genotoxicity of oxidative mutagens viz., H(2)O(2) and 4NQOquite efficiently. In SOS chromotest, using E.coli PQ37 tester strain, it inhibited induction factor induced by H(2)O(2) and 4NQO by 75.54% and 71.69% at the concentration of 121.46 μM,respectively. In Comet assay, it reduced the tail moment induced by H(2)O(2) and 4NQO by 70.21% and 69.04%, respectively, at the same concentration in human blood lymphocytes. The isolated fraction also exhibited DPPH free radical scavenging activity and was able to scavenge 85.95% radicals at a concentration of 120 μM. Conclusion: Glycyrrhizic acid is a potential modulator of genotoxins as well as efficient scavenger of free radicals.
... Those molecules which have high betweenness might exert important pharmacological effects as they play key roles in the biological network (Jeong et al., 2001;Goñ i et al., 2008). For example, 18b-glycyrrhetinic acid exhibits anti-inflammatory effects, and glycyrrhizic acid exhibits detoxification and inhibition of carcinogenic promoters (Mollica et al., 2007;Rahman and Sultana, 2007). Liquiritin, a major flavonoid compound in licorice, has been reported to exert antioxidative and antiviral activities (Hatano et al., 1988;Vaya et al., 1997). ...
... This study showed the crude product had the stronger activity of inhibiting death rate caused by chloral hydrate than that of processed product. It is reported that glycyrrhizin cloud relief acute intoxication caused by food and drug, and its content in crude licorice is higher than that in processed licorice (Li and Tong, 2007;He et al., 2009;Rahman and Sultana, 2007). Our study showed that the content and decocting quantity of glycyrrhizin in licorice descended after processing, and honey did not possess obvious intoxication action. ...
Article
In traditional Chinese medicine (TCM), licorice is usually processed with honey and traditionally used in decoction form. However, the influence of honey-roasting on the main pharmacological activities and the water-soluble active constituents of licorice has not been reported. The aim of the present study is to determine whether honey-roasting can modify the main pharmacological activities and the active constituents of licorice. According to licorice clinical application and processing method, the mainly related pharmacological activities of crude licorice, processed licorice and refined honey, such as enhancing immune function, relieving cough, eliminating phlegm and detoxication, were compared. The results showed that honey-roasting obviously reinforced the licorice activity of enhancing Pi-deficiency mice's immune function, and significantly weaken the licorice activity of relieving cough, removing phlegm and detoxication. However, honey didn't show the significant activity of relieving cough, removing phlegm and detoxication. The influence of honey-roasting on the chemical compositions in licorice slice and licorice decoction was investigated by using HPLC. The results showed that the content and the decocting quantity of mainly 5 active glycosides in licorice, i.e. liquiritin apioside, liquiritin, licuraside, isoliquiritin and glycyrrhizin, obviously changed after processing; glycyrrhizin and liquiritin obviously decomposed during honey-roasting. In conclusion, honey-roasting obviously modified the main pharmacological activities and the water-soluble compositions of licorice. The modification was not cause by honey only. This finding may shed some light on understanding the differences in the therapeutic values of crude and processed licorice.
... Our studies have demonstrated chemopreventive effects of natural agents in skin carcinogenesis, hepatocarcinogenesis, and renal carcinogenesis and colon cancer. [14][15][16][17][18][19] We have selected 3 plants-namely, Trigonella foenumgraecum, Eclipta alba, and Calendula officinalis-with established medicinal properties, including anticancer properties. The seeds of T foenumgraecum have been demonstrated to inhibit mammary hyperplasia induced by DMBA by induction of apoptosis 20 and reduction of tumor cell growth in the Ehrlich ascites carcinoma model by immune augmentation. ...
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Cancer is the final outcome of a plethora of events. Targeting the proliferation or inducing programmed cell death in a proliferating population is a major standpoint in the cancer therapy. However, proliferation is regulated by several cellular and immunologic processes. This study reports the inhibition of proliferation by augmenting immune surveillance, silencing acute inflammation, and inducing p53-mediated apoptosis of skin cancer by 3 promising medicinal extracts. We used the well-characterized model for experimental skin carcinogenesis in mice for 32 weeks to study the chemopreventive effect of the methanolic extracts of TRIGONELLA FOENUMGRAECUM, ECLIPTA ALB: , and CALENDULA OFFICINALI: . All 3 extracts reduced the number, incidence, and multiplicity of tumors, which was confirmed by the pathologic studies that showed regressed tumors. There was a significant reduction in the PCNA+ nuclei in all treatment groups 32 weeks after the initiation. Mechanistic studies revealed that proliferative population in tumors is diminished by the restoration of the endogenous antioxidant defense, inhibition of the stress-related signal-transducing element NFκB, reduction of inflammation, enhancement of immunosurveillance of the genetically mutated cells, along with silencing of the cell cycle progression signals. Finally, all 3 medicinal extracts induced stable expression of p53 within the tumors, confirmed by the CFDA-Cy3 apoptosis assay. Results of our study confirm that these extracts not only limit the rate of proliferation by inhibition of the processes integral to cancer development but also induce stable cytoplasmic expression of p53-mediated apoptosis, leading to fewer and regressed tumors in mice.
... Glycyrrhizae radix includes glycyrrhzin, flavonoid, saponin, coumarin, essential oil, phytosterol, tannin, and other substances. Glycyrrhizin (approximately 6 -10%), a major ingredient of Glycyrrhizae radix has chemopreventive activities on tumor promotion (Rahman et al., 2007) and anti-inflammatory effects (Takei et al., 2006). In this study, KMP6 and hesperidin inhibited PMACI-induced inflammatory cytokine expression on HMC-1 cells. ...
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The prevalence of allergic disease has been increasing over the past few decades in the majority of Western industrialized nations. There are some socioeconomic disparities regarding allergic disease status and management. Pyeongwee-San (KMP6) is Korean medicine for the treatment of gastrointestinal tract disease. It is known that KMP6 has an improving effect on the spleen and stomach functions in traditional Korean medical theory. Here, we hypothesized that KMP6 could be used to regulate the inflammatory reaction. We show the molecular mechanisms of Pyeongwee-San (KMP6) on inflammatory reactions. A molecular docking simulation showed that hesperidin, component of KMP6, regulate the enzymatic activity by interaction in the active site of caspase-1. KMP6 control the activity of caspase-1 in activated human mast cell line (HMC-1 cells). KMP6 reduced the expression of receptor interacting protein (RIP)-2 in HMC-1 cells. Thymic stromal lymphopoietin protein production and mRNA expression were inhibited by KMP6. In the activated HMC-1 cells, KMP6 suppressed the activation of mitogen-ativated protein kinase and nuclear factor-kappaB. In addition, KMP6 significantly inhibited the expression of inflammatory cytokines. Our findings indicate that KMP6 may attenuate allergic reactions via the regulation of caspase-1/RIP-2 signaling pathway. These studies will help advance the social welfare system.
... at glycyrrhizin and its metabolite glycyrhhetinic acid inhibit Smad3-mediated type 1 collagen gene transcription and suppress experimental murine liver fibrosis. Glycyrrhetinic acid did not affect gene expression of TGF-β receptors or Smad proteins, but inhibited nuclear accumulation of Smad3 in activated hepatic stellate cells (Moro et al., 2008). Rahman and Sultana (2007) demonstrated the chemopreventive activity on 12-O-tetradecanoyl phorbol-13- acetate-induced coetaneous oxidative stress and tumor promotion in Swiss albino mice. Studies using 1249 patients, in 2006, found that a long-term glycyrrhizin injection therapy could reduce hepatocellular carcinogenesis rate in patients with IFN-resistant activ ...
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Cancer is a major public health problem in India and many other parts of the world. Its two main characteristics are uncontrolled cell growth and metastasis. Natural products represent a rich source of compounds that have found many applications in various fields of medicines and therapy including cancer therapy. Effective ingredients in several plant-derived medicinal extracts are terpenoid compounds and many terpenes have biological activities and are used for the treatment of human diseases. This review attempted to collect all available published scientific literature of eight naturally occurring terpenoids and their effect on inhibition of tumor progression. The present review is about eight potent naturally occurring terpenoids that have been studied for their pharmacological properties in our lab and this review includes 130 references compiled from all major databases. Literature survey revealed that triterpenoids, such as glycyrrhizic acid, ursolic acid, oleanolic acid, and nomilin, the diterpene andrographolide, and the monoterpenoids like limonene and perillic acid had shown immunomodulatory and antitumor activities. All of them could induce apoptosis in various cancer cells by activating various proapoptotic signaling cascades. Many of these terpenoids found to inhibit metastatic progression and tumor-induced angiogenesis. The molecular mechanisms that involved in these activities include inhibition of various oncogenic and anti-apoptotic signaling pathways and suppression or nuclear translocation of various transcription factors including nuclear factor kappa B (NF-κB). The chemopreventive and chemoprotective effects of these compounds point toward their possible role in modern anticancer therapies.
... The ability of glycyrrhizin to inhibit inflammatory events, such as oedema, apoptosis, iNOS expression and NFB, was recently reported (Marianecci et al., 2012). The chemopreventive effect of glycyrrhizin on TPA-induced oxidative stress and skin hyperproliferation markers was also probed (Rahman & Sultana, 2007). Other studies demonstrated that the whole liquorice extract can be as effective as corticosteroids in the treatment of dermatitis, eczema and psoriasis. ...
Article
Liquorice extract, obtained by percolation in ethanol of Glycyrrhiza glabra L. roots, was incorporated in liposomes and hyalurosomes, new phospholipid-sodium hyaluronate vesicles, and their protective effect against oxidative stress skin damages was probed. As a comparison, raw glycyrrhizin was also tested. All the vesicles were small in size (≤100 nm), with a highly negative zeta potential ensuring long-term stability, and able to incorporate a high amount of the extract. In vitro tests showed that the liquorice extract loaded in vesicles was able to scavenge DPPH free radical (80% inhibition) and to protect 3T3 fibroblasts against H 2 O 2-induced oxidative stress, restoring the normal conditions. By contrast, glycyrrhizin showed poor antioxidant activity, and was not able to efficiently counteract the oxidative effect of H 2 O 2. In addition, the incorporation of the liquorice extract into the vesicular systems promoted the proliferation and migration of 3T3 fibroblasts, favouring the closure of the scratched area. In vivo anti-inflammatory tests on mice confirmed the ability of the proposed nanosystems to improve the local efficacy of the extract, favouring the re-epitelization process.
... GA, the major ingredient has been reported to have inhibitory effects on lipid peroxidation of membranes, scavenge free radicals, protect -SH group of Glutathione (GSH) and stimulate glutathionetransferases and hence subsiding the myocardial injury induced by ischemia-reperfusion and provided protection against myocardial ischemia in rats [210,211]. Ojha et al. (2013) [212] revealed that pretreatment with G. glabra remarkably diminished myocardial injury induced by ischemic-reperfusion by significantly restoring antioxidant activities in the heart as manifested by enhanced levels of SOD, CAT and GSH-Px enzymes. It has also exhibited prevention of myocardial GSH depletion, inhibition of lipid peroxidation, favoured desired perfused hemodynamic modulation and left ventricular contractile activity of left ventricular wall accompanied by myocardial salvaging effect [193,206]. ...
Article
The feeding trial was conducted with 15 weaned male Corriedale lambs of 3 months age and 13.0± 0.46 kg body weight, dividing into 3 equal groups and fed on iso-nitrogenous ration for 90 days to assess the effect of grain-less ration with or without Mulberry leaf meal on growth, nutrient utilization, blood profile, wool yield and its characteristics. Ration T1 contained maize grain, in T2 and T3 ration, maize grain was completely replaced with wheat bran, while in T3 ration, 20% of ground nut cake (GNC) was replaced by leaf meal. The replacement of maize grain by wheat bran and partial replacement of GNC (20%) by Mulberry leaves did not have any significant effect on intake and digestibility of nutrients, live weight gain, cost of production, blood profile, wool yield and its characteristics. It was concluded that maize grain at 100% level and GNC at 20% level can be replaced with wheat bran and Mulberry leaves respectively, without any adverse effect on the performance of lambs.
... 14 Thus, Glycyrrhizin is considered as quenching agent of free radicals and also as blocking agent of lipid peroxidation chain reactions. Glycyrrhizin showed chemopreventive, antioxidant, and antiproliferative activity when tested on animal model [14] . Glycyrrhizin (a tribasic acid), can form a variety of salts. ...
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There is an increasing demand for herbal medicines, health products, pharmaceuticals. Glycyrrhiza glabra Linn is a plant used in traditional medicine across the world for its ethnopharmacological value. It is found to contain important phytoconstituents such as glycyrrhizin, glycyrrhizinic acid, glabrin A and B and isoflavones. It is effectively used as anti-inflammatory, anti-bacterial, anti-fungal, anti-diabetic, anti-viral, anti-ulcer, antitussive, anti-oxidant, skin whitening, anti-diuretic agent. The present article is an effort to compile the available literature on Glycyrrhiza glabra with respect to its traditional uses, bioactive constituents and pharmacologic activities. This may be useful in discovering potential therapeutic effects and developing new formulations.
... Glycyrrhizin and its aglycone glycyrrhetic acid (GA) are used for various therapeutic purposes in Chinese traditional medicine practice [81]. GA is the hydrophilic part of glycyrrhizin, an active compound found in licorice (Glycyrrhiza glabra), which is a conjugate of two molecules of glucuronic acid and GA. ...
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Cisplatin (CSP) is a chemotherapeutic agent commonly used to treat a variety of malignancies. The major setback with CSP treatment is that its clinical efficacy is compromised by its induction of organ toxicity, particular to the kidneys and ears. Despite the significant strides that have been made in understanding the mechanisms underlying CSP-induced renal toxicity, advances in developing renoprotective strategies are still lacking. In addition, the renoprotective approaches described in the literature reveal partial amelioration of CSP-induced renal toxicity, stressing the need to develop potent combinatorial/synergistic agents for the mitigation of renal toxicity. However, the ideal renoprotective adjuvant should not interfere with the anticancer efficacy of CSP. In this review, we have discussed the progress made in utilizing plant-derived agents (phytochemicals) to combat CSP-induced nephrotoxicity in preclinical studies. Furthermore, we have also presented strategies to utilize phytochemicals as prototypes for the development of novel renoprotective agents for counteracting chemotherapy-induced renal damage.
... Glycyrrhiza uralensis contains glycyrrhizin, liquiritin, and glycyrrhizic acid (Guo et al., 2007). Glycyrrhizic acid has been shown to exert anti-inflammatory and detoxification effects and to inhibit carcinogenic promoters (Rahman and Sultana, 2007). This substance is also reported to inhibit the binding of NF-B to its target elements (Cherng et al., 2006 ) and to suppress tripterene-inducible ICAM- 1 expression in a concentration-dependent manner (Zhang et al., 2006 ). ...
Article
Unlabelled: Xia-bai-san (XBS) is a traditional Chinese medicine that has been used clinically for centuries in Asian countries to treat some types of common cold and asthma-like diseases similar to infantile pneumonia and childhood bronchitis. In previous studies, XBS was found to suppress the inflammatory process induced in lungs of mice treated with lipopolysaccharide (LPS). Purpose: The present study was undertaken to examine the effects of XBS on LPS-inducible production of inflammatory cytokines, up-regulation of intercellular cell adhesion molecule-1 (ICAM-1), and activation of nuclear factor NF-kappaB in cultured human lung cells. Principal results: Extracts of four raw herbs (Cortex mori, Cortex lycii, Radix glycyrrhizae, and Fructus oryzae) were used to prepare the decoction. XBS decreased the histological damage and up-regulation of ICAM-1 observed in lungs of mice treated with lipopolysaccharide (LPS). In cultured human pulmonary epithelial A549 cells, XBS and its components Morus alba and Glycyrrhiza uralensis suppressed the up-regulation of IL-8 and ICAM-1 in response to LPS. Production of TNF-alpha, IL-1beta, IL-6 and IL-8 by LPS-treated human THP-1 monomyelocytes was also suppressed by XBS. A549 cells expressed ICAM-1 in response to medium from LPS-treated THP-1 cells; expression was decreased by XBS. The adhesion of THP-1 cells to LPS-treated A549 cells were inhibited in the presence of XBS. Activation of NF-kappaB by LPS in A549 cells was suppressed by XBS, Morus alba, and Glycyrrhiza uralensis through inhibition of IkappaB phosphorylation; the concentrations at which suppression occurred were identical to those at which production of inflammatory cytokines and up-regulation of ICAM-1 were inhibited. Major conclusions: These findings support the hypothesis that XBS, Morus alba, and Glycyrrhiza uralensis inhibit the inflammatory process in lung tissue through suppression of the IkappaB signaling pathway. XBS may prove helpful in the management of asthma, various allergic disorders, sepsis, or any other condition associated with pulmonary inflammation.
... A previous study showed that the DNA mismatch repair system is inactivated by oxidative stress (33). The antioxidant effect of glycyrrhizic acid in mice (34) suggests that suppression of oxidative stress by glycyrrhizic acid could be one of the mechanisms that resulted in the activation of repair enzymes much earlier than with UV radiation alone; thus it is possible that thymine dimers were removed much earlier in glycyrrhizic acidtreated animals than 1 h, the time we used in our study. More studies are needed employing different times to assess whether glycyrrhizic acid causes a faster repair of UV-radiation-induced DNA damage, ultimately leading to a strong reduction in thymine dimer-positive cells. ...
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Glycyrrhizic acid (GL) has been shown to possess anti-inflammation, antiviral, and chemoprotective activity against tumors. We assessed the protective effects of GL in UVB-induced skin tumor formation in SKH-1 hairless mice and the early molecular biomarkers. Mice irradiated at 180 mJ/cm2 twice per week elicited 100% tumor incidence in 20 weeks. Feeding of GL prior to UVB irradiation caused a strong protection against photocarcinogenesis in terms of delay in tumor appearance, multiplicity, and size. It took 24 weeks to get 100% tumor incidence in GL plus UVB treated-group; the first tumor appearance in UVB-treated animals occurred at 16th week, which was delayed by 3 weeks in GL plus UVB-treated group. Feeding of GL for 2 weeks before a single UVB (180mJ/cm2) irradiation resulted in a strong and significant decrease in UVB-induced thymine dimer-positive cells (p < 0.004), proliferative cell nuclear antigen PCNA (p < 0.01), terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, and apoptotic sunburn cells (p < 0.01) together with an increase in p53 and p21/Cip1-positive cell population in epidermis (p < 0.02 ∼ 0.003). Simultaneously, GL also significantly inhibited NF-κB, cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), and nitric oxide (NO) levels (p < 0.01-0.004). Taken together, these results suggest that GL causes a strong protective effect against photocarcinogenesis via down-regulation of cell proliferative controls, involving thymine dimer, PCNA, apoptosis, transcription factors NF-kB and of inflammatory responses involving COX-2, PGE2, and NO, while up-regulation of p53, p21/Cip1 to prevent DNA damage. These results provide a focus for the rational development of GL as a novel chemopreventive agent against UV-induced human skin cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2483. doi:10.1158/1538-7445.AM2011-2483
... Both glycyrrhizin and glycyrrhetic acid can exist in two sterioisomeric forms (18a and 18b). Glycyrrhizin has been reported to be effective against lipid peroxidation reactions by acting as a blocking agent (Rahman & Sultana, 2007). Apart from triterpenoids, 1-5% of dried roots consist of 300 other flavonoids which have successfully been isolated from Glycyrrhiza species (Li, Asada, & Yoshikawa, 2000). ...
Article
In the current study, antioxidant potential of licorice extracts was determined through different assays. For optimum recovery of bioactive components, three solvents (ethanol, methanol, and ethyl acetate) were employed at different ratios with water (25:75, 50:50, and 75:25) and supercritical fluid extracts (SFE) were obtained at varying pressures (3,500, 4,500, and 5,500 psi). Results exhibited that the extraction of antioxidant compounds from licorice increased with increasing solvent concentration. Among solvent extracts, 75% ethanolic extract showed highest total phenolic content (TPC), total flavonoids content (TF), and antioxidant activity. The supercritical CO2 extract obtained at 5,500 psi pressure exhibited highest values for TPC, TF, and antioxidant capacity. It was evident from HPLC analysis that the highest recovery of major bioactive components (glycyrrhizin and glabridin) was obtained through supercritical CO2 extraction at elevated pressures. Practical applications Licorice is a rich source of biologically active components with history of medicinal use. The current study provides an approach to maximize the recovery of desired components from licorice that can be used in different formulations with antioxidant potential.
... Glycyrrhizin represents about 10-25% of liquorice root extract. It is considered to be the most commonly used of the folkmedicines in Asia.Its structure is a saponin compound 16,17 . Thus due of the existence of these different secondary metabolites such as flavonoids, alkaloids, and saponins in its aquatic-root extract, it exhibits potent antibacterial activity 18,19 , also it has a role as antiviral agent against many viruses 20,21 . ...
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There are incrementsto the need ofthe usage of new non-chemical medicines, pharmaceuticalsand health products. Plantsare traditionallyused as medicine over the world for their pharmacological values. They effectively used as anti-fungal,antiviral,anti-bacterial, anti-inflammatory, anti-diabetic, anti-oxidant anti-ulcer, andantitussive. Thisstudy aimsto investigate the effects of plant extracts (Glycyrrhiza glabra, Cuminum cyminum, Zingiber officinale,Origanum majorana and Petroselinum crispum) against different types of gram-positive and negative bacterial isolates. Antimicrobial activity of tested aqueous extracts by well-diffusion methodagainst various bacterial isolates were done, to estimate their antibacterial activity. Results showed that the aquatic extracts of different plants produce a good antibacterial effects when compared with the synthetic antibiotic ciprofloxacin. As all bacterial isolates in this study where sensitive to these extracts with variable ranges of inhibition zones ranging from 18-32mm in diameter. Thus we can concluded that the aquatic extracts of Glycyrrhiza glabra, Cuminum cyminum, Zingiber officinale,Origanum majorana and Petroselinum crispum can be beneficial as treatment of UTI-causing bacteria.
... GA, the major ingredient has been reported to have inhibitory effects on lipid peroxidation of membranes, scavenge free radicals, protect -SH group of Glutathione (GSH) and stimulate glutathionetransferases and hence subsiding the myocardial injury induced by ischemia-reperfusion and provided protection against myocardial ischemia in rats [210,211]. Ojha et al. (2013) [212] revealed that pretreatment with G. glabra remarkably diminished myocardial injury induced by ischemic-reperfusion by significantly restoring antioxidant activities in the heart as manifested by enhanced levels of SOD, CAT and GSH-Px enzymes. It has also exhibited prevention of myocardial GSH depletion, inhibition of lipid peroxidation, favoured desired perfused hemodynamic modulation and left ventricular contractile activity of left ventricular wall accompanied by myocardial salvaging effect [193,206]. ...
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Background Glycyrrhiza glabra L. (Family: Fabaceae) is one of the important traditional medicinal plant used extensively in folk medicine. Introduction It is known for its ethanopharmacological value in curing a wide variety of ailments. Glycyrrhizin, an active compound of G. glabra, possesses anti-inflammatory activity due to which it is mostly used in traditional herbal medicine for the treatment and management of chronic diseases. Methodology The present review is focused extensively on the pharmacology, pharmacokinetics, toxicology and potential effects of Glycyrrhizic Acid (GA). A thorough literature survey was conducted to identify various studies that reported on the GA on PubMed, Science Direct and Google Scholar.
... Glycyrrhizin demonstrated chemopreventive, antioxidant, and antiproliferative effects in an animal model. 16 Flavonoids present in licorice roots include liquirtin, rhamnoliquiritigenin, licopyranocoumarin, glisoflavone, licoarylcoumarin, and coumarin-GU-12. 17 Dry roots yield five novel flavonoids: glucoliquiritinapioside, shinflavanone, shinpterocarpin, prenyllicoflavone A, and 1methoxyphaseolin. ...
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Plants have long been valued for their medicinal properties. The secret to efficient treatment is finding the right herb. The purpose of this review is to provide an updated overview of Glycyrrhiza glabra L., “the guardian of herbs” regarding its traditional uses, phytochemistry, and emphasizing the relevance of a few key characteristics of this plant. This review covers a combination of all aspects from an aphrodisiac point of view that were missed by previous articles. This article is presented to include all of the most recent information on its phytochemical and pharmacological effects, which were investigated using a variety of approaches. The plant can be a suitable candidate to manage the long fought erectile dysfunction in men. The extract and the constituents have been found effective in inducing NO signaling pathway that has beneficial effects in initiation and maintenance of erection. It is an age-old plant that belongs to the family Fabaceae. G. glabra (Licorice) has been used in folk medicine all over the world for its ethnomedicinal characteristics, and has historically been recognized as a preventative treatment for stomach ulcers, according to pharmacological research. It comprises a wide range of biological actions, including antibacterial, anti-inflammatory, antiviral, antioxidant, as well as others, for which it has been used to treat a variety of disorders ranging from simple cough to hepatitis, as well as more serious conditions like SARS and cancers. This study presents a critical, and thorough assessment of the current understanding of G. glabra composition and therapeutic potential. This article concludes that G. glabra is actually a potent herb that can cure almost all illnesses. .
... A previous study showed that the DNA mismatch repair system is inactivated by oxidative stress (33). The antioxidant effect of glycyrrhizic acid in mice (34) suggests that suppression of oxidative stress by glycyrrhizic acid could be one of the mechanisms that resulted in the activation of repair enzymes much earlier than with UV radiation alone; thus it is possible that thymine dimers were removed much earlier in glycyrrhizic acidtreated animals than 1 h, the time we used in our study. More studies are needed employing different times to assess whether glycyrrhizic acid causes a faster repair of UV-radiation-induced DNA damage, ultimately leading to a strong reduction in thymine dimer-positive cells. ...
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Glycyrrhizic acid has been shown to possess anti-inflammation, antiviral and chemoprotective activity against tumors. We evaluated the protective effects of glycyrrhizic acid in UVB-radiation-induced skin tumor formation in SKH-1 hairless mice and the early molecular biomarkers of these effects. Mice irradiated at 180 mJ/cm² twice per week showed 100% tumor incidence in 20 weeks. Feeding with glycyrrhizic acid prior to UVB irradiation caused delays in tumor appearance, multiplicity and size. Feeding with glycyrrhizic acid for 2 weeks before a single UVB irradiation (180 mJ/cm²) resulted in significant decrease in UVB-radiation-induced thymine dimer-positive cells, expression of proliferative cell nuclear antigen (PCNA), terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive cells, and apoptotic sunburn cells together with an increase in p53- and p21/Cip1-positive cell populations in epidermis. Simultaneously, glycyrrhizic acid also significantly inhibited NF-κB, cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), and nitric oxide (NO) levels. Thus glycyrrhizic acid ameliorates UVB-radiation-induced tumorigenesis via downregulation of cell proliferation controls involving thymine dimer, PCNA, apoptosis and transcription factor NF-κB and of inflammatory responses involving COX-2, PGE2 and NO while upregulating of p53 and p21/Cip1 to prevent DNA damage and facilitate DNA repair.
... Cuscuta reflexa (Giant dodder) in cell lines [5], Swiss albino mice [6], human red blood cells [7] and human cancer cell lines [8]. Ashwagandha or Indian ginseng Withania somnifera has immunomodulatory and anti-cancer effects [9][10][11][12][13][14]. Glycyrrhiza glabra (Liquorice) expresses promising antimicrobial, cytotoxic and anti-cancer effects [15,16]. Also Terminalia bellerica known as Bahera or Beleric has been found to possess anti-cancer effects [17,18]. ...
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UNANI MEDICINE AND CANCER Christer Sundqvist. Prepublished article, 2020 Petrafoundation, Helsinki, Finland https://www.petrafoundation.com/en/foundation Unani medicine is an alternative medical system originating in ancient Greece almost 2500 years back. It is now practiced primarily in India. Herbal remedies, dietary practices and alternative therapies characterize Unani medicine. Let us study what it can offer for a cancer patient.
... Glycyrrhizin, one of the most effective ingredients of the root extraction of Glycyrrhiza glabra L., is consisted of glucuronic acid and glycyrrhetinic acid and possesses anti-allergic, anti-oxidant, anti-ulcer, anti-viral, anti-cancer, and immunomodulatory effects (296,297). It also protects the liver and stabilizes the cell membrane. ...
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Percutaneous coronary intervention (PCI) is one of the most effective reperfusion strategies for acute myocardial infarction (AMI) despite myocardial ischemia/reperfusion (I/R) injury, causing one of the causes of most cardiomyocyte injuries and deaths. The pathological processes of myocardial I/R injury include apoptosis, autophagy, and irreversible cell death caused by calcium overload, oxidative stress, and inflammation. Eventually, myocardial I/R injury causes a spike of further cardiomyocyte injury that contributes to final infarct size (IS) and bound with hospitalization of heart failure as well as all-cause mortality within the following 12 months. Therefore, the addition of adjuvant intervention to improve myocardial salvage and cardiac function calls for further investigation. Phytochemicals are non-nutritive bioactive secondary compounds abundantly found in Chinese herbal medicine. Great effort has been put into phytochemicals because they are often in line with the expectations to improve myocardial I/R injury without compromising the clinical efficacy or to even produce synergy. We summarized the previous efforts, briefly outlined the mechanism of myocardial I/R injury, and focused on exploring the cardioprotective effects and potential mechanisms of all phytochemical types that have been investigated under myocardial I/R injury. Phytochemicals deserve to be utilized as promising therapeutic candidates for further development and research on combating myocardial I/R injury. Nevertheless, more studies are needed to provide a better understanding of the mechanism of myocardial I/R injury treatment using phytochemicals and possible side effects associated with this approach.
... Glycyrrhizin present in the roots of G. glabra is considered as quenching agent of free radicals and also as blocking agent of lipid peroxidation chain reactions. Glycyrrhizin showed chemopreventive, antioxidant, and anti-proliferative activity when tested on animal model [28]. ...
Article
Objective: The present study attempts to estimate the total flavonoid and phenolic content and to evaluate the free radical scavenging activity of the roots of Glycyrrhiza glabra Leguminosae family.Methods: The various extracts, namely, petroleum ether, chloroform, ethyl acetate, aqueous, and methanol of G. glabra root were evaluated by 2, 2-diphenyl-1-picryl-hydrazyl (DPPH), hydroxyl radicals, superoxide, 2,2’-azino-bis-3-ethyl benzthiazoline-6-sulphonic acid (ABTS), and non-radicals such as hydrogen peroxide (H2O2) and nitric oxide (NO) and assays. Total flavonoid and phenol contents were estimated as per the standard procedure.Results: The effect of the methanolic extract of G. glabra root was found to be more in scavenging the free radicals such as DPPH, hydroxyl, H2O2, superoxide, NO, and ABTS when compared to other extracts. The presence of flavonoids and phenol in the plant is responsible for the free radical scavenging effects.Conclusion: This in vitro assessment of the antioxidant properties of the various extracts of G. glabra roots validates and confirms its free-radical scavenging activity. Thus, the present data suggest that the G. glabra root extract can be used as a good source of natural antioxidants for health benefits.
... It consists of the glucuronic acid as well as the glycyrrhetinic acid [10]. e research study conducted by [11] demonstrates that the glycyrrhizin is a successful element in the liquorice that comprises of antiallergic, antioxidant, immunomodulatory, anticancer, antiulcer, and antiviral properties. e risk of lethal myocardial infarction and evolution of heart failure is intensified because of diabetes [12,13]. ...
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Introduction: Cardiovascular disorders are one of the prominent causes of risks of mortality which accounts for high rate of the deaths at a global level. The risk of deadly myocardial infraction grows because of diabetes which even causes the development of heart failure. Objective: The objective of this study was to understand and study the effect of glycyrrhizin on diabetes suffering rats with myocardial remodeling. Materials and methods: Streptozotocin was used for induction of diabetes, and 8-12 weeks later, the assessment of inflammation, fibrosis, and cardiac damage was evaluated. Histopathological analysis and immunohistochemistry was performed to analyze the effect in various groups. Western blotting was performed to understand the proteins expressed in diabetes, and also, their expression was noted in treatment groups. Results: There was a significant rise in TNF-α, dense fibrosis, and collagen deposits in the STZ diabetes group. The effects of hyperglycemia were significantly improved in the glycyrrhizin-treated group. DAPI, BrDu, and caspase staining was also performed to understand apoptosis in tissues where the diabetic groups reported significant apoptosis, while the effects were significantly lower in the treated group. Conclusion: All the observations indicate that glycyrrhizin has cardioprotective action in diabetic rats with myocardial remodeling and is due to the inhibition of the NF-κB signaling pathway in the myocardial layer.
Article
Glycyrrhiza Radix is a commonly used Chinese herbal medicine, derived from the dried roots and rhizomes of Glycyrrhiza uralensis, G. glabra and G. inflata. The main bioactive constituents of licorice are triterpene saponins and flavonoids. There are various types of pharmacological properties of licorice are proved, including antiulcer, antiinflammation, spasmolysis, antioxidative, contravariance, antiviral, anticancer activities, hepatoprotective, eliminating phlegm and reinforcing remembrance effects. Triterpene saponins are the main components of Glycyrrhiza Radix and its pharmacological activities are comparatively thorough and clear. In recent years, licorice flavonoids, proved to have a variety of pharmacological activities, become one of the hot of pharmacological studies. In this review, we summarized the latest five-year progress in pharmacological activities of licorice extract, its triterpenoid saponins and flavonoids, and experimental researches indicated that licorice had both accommodation and protection activity on the digestive system, respiratory system, nervous system, and endocrine system, etc.
Article
Monoammonium glycyrrhizinate (MAG) was the aglycone of glycyrrhizin derived from licorice. In this study, the anti-inflammatory effects of MAG on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice and the possible mechanisms involved in this protection were investigated. Pretreatment with MAG prior to the administration of intratracheal LPS significantly induced a decrease in lung wet weight/dry weight ratio, in total leukocyte number and neutrophil percent in the BALF, and in myeloperoxidase (MPO) activity of lung in dose-dependent manners. At the same time, pretreatment with MAG also significantly improved the super oxide dismutase (SOD) activity and induced the malondialdehyde (MDA) content in the bronchoalveolar lavage fluid (BALF). Importantly, pretreatment with MAG prevented an increase in cyclic adenosine monophosphate-phosphodiesterase (cAMP-PDE) activity of lung in a dose-dependent manner. In addition, it can up-regulate the interleukin-10 (IL-10) level and down-regulate the tumor neurosis factor-α (TNF-α) level in the lung tissue of ALI mice. These results showed that anti-inflammatory effects of MAG against the LPS-induced ALI may be due to its ability of primary inhibition of cAMP-PDE activity, oxidative stress and its regulation of cytokine effects. Thus the results support that use of MAG is beneficial in the treatment of ALI and ARDS.
Article
The present study investigated the neuroprotective potential of Diammonium Glycyrrhizinate (DG) in focal cerebral ischemic-reperfusion (IR) injury in mice. The middle cerebral artery occlusion (MCAO) model of the mouse was used. Mice were treated with DG (20mg/kg per day, intraperitoneal injection) or saline as control, from the beginning of the reperfusion to 7 days. The focal cerebral IR injury resulted in significant neurological deficits, infarct size, and brain water content (BWC) at 1 day, 3 days and 7 days after MCAO. A significant increase in various inflammatory mediators like interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS) and nuclear factor-κB (NF-κB) and astrocytic glial fibrillary acidic protein (GFAP) was also observed in the IR challenged brains. The DG treatment significantly improved neurofunction, decreased infarct size, and suppressed edema in the focal cerebral IR injury. The neuroprotective effect of DG was found to be associated with significant reduction in the IL-1, TNF-α, COX-2, iNOS, NF-κB and GFAP levels. In summary, this study suggested that DG has a neuroprotective effect on cerebral IR injury and this effect is likely related to DG's anti-inflammatory function.
Article
Extracellular cytokine function of the non-histone nuclear protein high-mobility group box 1 (HMGB1) has recently been recognized as an important drug target for novel anti-inflammatory therapeutics. Accumulating evidence supports the mechanistic involvement of the alarmin HMGB1 in skin response to microbial infection and ultraviolet-induced solar damage. Moreover, HMGB1 modulation of inflammatory signaling and tissue remodeling is now emerging as a causative factor in wound repair, autoimmune dysregulation, and skin carcinogenesis, representing cutaneous pathologies that affect large patient populations with unmet therapeutic needs. Recent structure-based drug discovery efforts have aimed at increasing the number of small molecule- and biologics-based prototype therapeutics targeting HMGB1. Small molecule drugs that may provide therapeutic benefit through HMGB1-directed mechanisms involve HMGB1 inhibitory ligands, Toll-like receptor antagonists, RAGE antagonists, alpha7 nicotinic acetylcholine receptor agonists, G2A antagonists, serine protease inhibitors, and alpha-dicarbonyl-based soft electrophiles. Using some of these agents, pharmacological modulation of HMGB1-associated cutaneous pathology has been achieved with an acceptable toxicity profile, and preclinical proof-of-concept experimentation has demonstrated feasibility of developing HMGB1-modulators into novel systemic and topical therapeutics that target cutaneous inflammatory dysregulation.
Article
Present study evaluated the cardioprotective effect of Glycyrrhiza glabra against ischemia-reperfusion injury (I-R) induced by ligation of left anterior descending coronary artery (LADCA) in rats. Ligation of LADCA for 45min followed by 60min of reperfusion has induced significant (p<0.05) heart dysfunction evidenced by significant (p<0.05) decrease in mean arterial pressure (MAP), heart rate (HR), contractility; (+)LVdP/dtmax and relaxation; (-)LVdP/dtmax along with increased left ventricular end diastolic pressure (LVEDP). Ligation induced I-R injury also significantly (p<0.05) decreased myocyte injury enzymes, creatine phosphokinase-MB (CK-MB) isoenzyme and lactate dehydrogenase (LDH) as well as antioxidant enzymes; superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px). Furthermore, I-R injury also induced lipid peroxidation evidenced by significant (p<0.05) increase in malondialdehyde (MDA) formation and histological perturbations concomitant to depletion of glutathione (GSH) from heart. However, pretreatment with G. glabra significantly (p<0.05) prevented the depletion of the antioxidant enzymes; SOD, CAT, GSH-Px and myocyte injury marker enzymes; CK-MB isoenzyme and LDH. Pretreatment with G. glabra also prevented GSH depletion and inhibited lipid peroxidation in heart. In addition to improving biochemical indices of myocardial function, G. glabra also significantly (p<0.05) reinstated MAP, HR, (±)LVdP/dtmax and attenuated abrupt rise in LVEDP. Histopathological preservation evidenced by reduced infiltration of cells and myonecrosis depicted the myocardial salvaging effect of G. glabra. Taken together, results of the present study clearly suggest the cardioprotective potential of G. glabra against myocardial infarction by amelioration of oxidative stress and favorable modulation of cardiac function.
Article
Pyungwi-san (PWS, Heii-san in Japanese) is a mixture of six herbs and is traditionally used in Northeast Asia (especially Korea and Japan) for the treatment of gastrointestinal disorder, such as dyspepsia and inappetance induced by gastric dilatation and gastrointestinal catarrh. Although PWS is a widely used herbal prescription in Korea and Japan, little information is available in the literature on the safety and toxicity of PWS. As part of a safety evaluation of PWS, the present study evaluated the potential genotoxicity of PWS using a standard battery of test. We prepared PWS using a water extraction method and simultaneously extracted three compounds from PWS using high performance liquid chromatography. The PWS extract that was obtained was assayed for genotoxicity using the standard three tests recommended by the Korea Food and Drug Administration. These tests included the bacterial reverse mutation test (Ames test), the chromosomal aberration test using China hamster lung cells, and the micronucleus test using ICR mice. The Ames test showed that the PWS extract did not induce an increase in the number of revertant colonies compared with vehicle control at any dose in all of tester strains. In the micronucleus test, no significant increase was observed in micronucleated polychromatic erythrocytes (MNPCEs) at any dose of PWS extract compared with vehicle control. Conversely, chromosomal aberration test showed that the PWS extract at a dosage of 4500 μg/mL induced an increase in the number of chromosomal aberrations in the 6 h group with metabolic activation compared with the vehicle control. PWS extract exhibits genotoxicity, based on the results of the chromosomal aberration test. Thus, further detailed experiments will be needed to identify the ingredient responsible for inducing this genotoxicity and to determine its mechanism.
Article
Glycyrrhizic acid (GA) is a main sweetening component of licorice roots and has been found to be associated with multiple therapeutic properties. In this study, we used GA as a protective agent against the clastogenic and nephrotoxic effects of cisplatin (CP). Mice were given a prophylactic treatment of GA orally at doses of 75 and 150mg/kg body weight for seven consecutive days before the administration of a single intraperitoneal dose of CP at 7mg/kg body weight. The modulatory effects of GA on CP-induced nephrotoxicity and genotoxicity were investigated by assaying oxidative stress biomarkers, lipid peroxidation, serum kidney toxicity markers, DNA fragmentation, alkaline unwinding, and micronuclei and by histopathological examination of the kidneys. A single intraperitoneal dose of cisplatin in mice enhanced renal lipid peroxidation, xanthine oxidase, and H(2)O(2) generation; depleted glutathione content, activities of the anti-oxidant enzymes glutathione peroxidase, glutathione reductase, catalase, glutathione-S-transferase and quinone reductase; induced DNA strand breaks and micronucleus formation (p<0.001); and majorly disrupted normal kidney architecture. Pretreatment with GA prevented oxidative stress by restoring the levels of antioxidant enzymes at both doses. A significant dose-dependent decrease in DNA fragmentation, micronucleus formation (p<0.05), and the kidney toxicity markers BUN (p<0.001), creatinine (p<0.01), and LDH (p<0.001) and restoration of normal kidney histology was observed. Our study supports the claim that the phytochemical GA has the potential to attenuate the side effects of anticancer drug overdose.
Article
Subcritical water (SBW) extraction of licorice root (LR) was carried out at four different temperatures (50, 100, 200, and 300 °C) for 10, 30, or 60 min, and nutraceutical compound levels of the SBW extracts were evaluated. SBW treatment of LR increased the antioxidant activity of extracts. Higher radical scavenging activity, reducing power, and total phenol content of the LR extracts were found when SBW extraction was carried at 200 °C for 60 min or at 300 °C for more than 30 min. The main active compounds such as glycyrrhetic acid (GA) and glycyrrhizin (GL) showed different extraction patterns. GA and GL were present at maximum levels following SBW extraction at 100 °C for 30 and 60 min, respectively. However, liquiritin (LQ), another nutraceutical compound of LR, showed the highest levels following extraction at 300 °C for 60 min. The results indicated that the temperature and time of SBW extraction significantly affected the antioxidant activities and nutraceutical compound levels of LR extracts.
Article
Ethnopharmacological relevance Lung cancer is one of the most common malignant tumours and has become the leading cause of cancer-related deaths worldwide. Abnormal microcirculation during tumour growth leads to intermittent hypoxia (IH), which is responsible for promoting cancer cell proliferation and migration. Patients with advanced lung cancers show deficiency of both Qi and Yin Syndrome (DQYS) in TCM, and studies have confirmed that IH exposure is related to DQYS. Shashen-Maidong Decoction (SMD), has been widely applied clinically targeting DQYS and has a long history for treating lung cancer by nourishing the body's “zheng qi” and resisting “xie qi”. However, whether SMD could be beneficial to lung cancer under IH conditions remains unclear. Aim of the study This study aimed to clarify the effects and mechanism of SMD on non-small cell lung cancer (NSCLC) growth under IH conditions. Materials and methods C57 mice were injected subcutaneously into the right axilla with Lewis lung cancer (LLC) cells and exposed to IH conditions (21%–5% O2, 5 min/cycle, 8 h/day) for 21 days. SMDs were orally treated with different concentrations (2.6, 5.2 or 10.4 g/kg/day) 30 min before IH exposure. Tumour proliferation and migration were assessed by HE and IHC staining, and oxidative stress was assessed by DHE staining and MDA or SOD detection. IL-6, IL-1β and TNF-α levels were assessed by IHC staining, and the IL-6/JAK2/STAT3 signalling pathway was detected by western blotting. Results Our results showed that SMD treatment inhibited tumour growth and liver metastasis in LLC-bearing mice exposed to IH, decreased Ki67, CD31, VEGF, and MMP-2, and increased E-cadherin expression in tumourt tissue. SMD reduced ROS production, increased SOD levels and SOD-2 expression, and decreased MDA levels and NOX-2 expression. SMD decreased IL-6, IL-1β and TNF-α levels, reduced IL-6 expression and inhibited JAK2 and STAT3 phosphorylation. Additionally, SMD treatment improved DQYS and liver and kidney function in LLC-bearing mice under IH conditions. Conclusion Our research suggests that SMD treatment can inhibit tumour growth in mice exposed to IH. The antitumour effect of SMD may be related to attenuated oxidative stress and inflammation through inactivation of the IL-6/JAK2/STAT3 signalling pathway under IH conditions.
Article
Licorice (Glycyrrhiza uralensis Fisch) roots (LR) powders were far-infrared (FIR)-irradiated for 30 min at 120∼200C. After irradiation, a 50% ethanol extract of LR (LRE) (0.5 g/50 mL) was prepared, and total phenolic content (TPC), total flavanol content (TFC) and radical scavenging activity (RSA) were determined. The antioxidant activities of the LRE were significantly affected by FIR irradiation. For example, the FIR irradiation of LR at 120C increased the TPC, TFC and RSA of the LRE from 22.85 to 29.81 mg/g, 5.61 to 13.31 mg/g and 24.59 to 52.24%, respectively, as compared with the nonirradiated control. The main functional chemical components of LR such as glycyrrhizin, glycyrrhetic acid and liquiritin, were also significantly affected by irradiation. These results indicate that the FIR irradiation of LR affected the antioxidant activities and important chemical compositions of LRE and FIR irradiation can be used to improve the quality of LR. Licorice root (LR) has been widely used in traditional oriental medicine to treat bronchitis, cough, arthritis, adrenal insufficiency, and allergies. In this article, we report appropriate far-infrared (FIR) irradiation can increase antioxidant activity and functional chemical components of LR. For example, when LR was FIR irradiated at 120C increased the total phenolic content, total flavanol content and radical scavenging activity of the LR ethanol extract from 22.85 to 29.81 mg/g, 5.61 to 13.31 mg/g and 24.59 to 52.24%, respectively, as compared with the nonirradiated control. The results indicated that appropriate FIR-irradiation could be applied to increase quality of LR.
Article
Glycyrrhizic acid (GA) is the bioactive compound of licorice and has been used as a herbal medicine because of its anti-viral, anti-cancer, and anti-inflammatory properties. This study was designed to investigate the effects of GA on tumor growth, angiogenesis, and the mechanisms underlying the anti-angiogenic activities of GA. We observed that GA inhibited tumor growth and angiogenesis in mice. GA decreased angiogenic activities, such as the migration, invasion, and tube formation of endothelial cells. We also demonstrated that GA reduced the production of reactive oxygen species and activation of ERK in endothelial cells. Our findings suggest that GA is a promising anti-angiogenic therapeutic agent that targets the ERK pathway. Considering that angiogenesis is highly stimulated in the majority of cancers, GA could offer a potent therapeutic agent for cancer. Copyright © 2012 John Wiley & Sons, Ltd.
Article
Despite dramatic advances in cancer therapy, the overall prognosis of glioblastoma (GBM) remains dismal. Nuclear factor kappa-B (NF-κB) has been previously demonstrated to be constitutively activated in glioblastoma, and it was suggested as a potential therapeutic target. Glycyrrhizic acid (GA) has been proved to have cytotoxic effects in many cancer cell lines. However, its role in glioblastoma has not yet been addressed. Therefore, this study aimed to investigate the effects of GA on human glioblastoma U251 cell line. The effects of GA on proliferation of U251 cells were measured by CCK-8 assay and plate colony-forming test. Cellular apoptosis was detected by Hoechst 33258 fluorescent staining and flow cytometry with annexin V-FITC/PI dual staining. The expression of nuclear p65 protein, the active subunit of NF-κB, was determined by Western blot and immunofluorescence. Our results demonstrated that the survival rate and colony formation of U251 cells significantly decreased in a time- and dose-dependent manner after GA addition, and the apoptotic ratio of GA-treated groups was significantly higher than that of control groups. Furthermore, the expression of NF-κB-p65 in the nucleus was remarkably reduced after GA treatment. In conclusion, our findings suggest that GA treatment can confer inhibitory effects on human glioblastoma U251 cell line including inhibiting proliferation and inducing apoptosis, which is possibly related to the NF-κB mediated pathway.
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Chinese traditional herbs are used widely as feed supplements to improve the immune response and antioxidant capacity of livestock. Twenty early-weaned 4-month-old yak calves (72.3 ± 3.65 kg) were divided randomly into four groups (n = 5 per group); three groups were provided with supplementary 80 mL/kg DMI of the root water extracts of either Angelica sinensis, Codonopsis pilosula or Glycyrrhiza uralensis, and one group (control) was not provided with a supplement. Compared to control calves, calves consuming the three herbal extracts increased serum concentrations of albumin (ALB) and glutathione peroxidase (GSH-Px), but decreased serum concentrations of free fatty acids (FFAs) and malondialdehyde (MDA) (p < 0.05). Calves consuming A. sinensis decreased (p < 0.05) serum concentration of total cholesterol (TC), and increased (p < 0.05) serum concentration of total proteins (TP). Serum FFA concentrations increased (p = 0.004) linearly with time in the control group, but not in the groups consuming herbs. Serum metabolomic data demonstrated that A. sinensis and C. pilosula regulate mainly amino acid metabolism, while G. uralensis regulates mainly carbon and amino acid metabolism. It was concluded that the three herbal root extracts, as dietary supplements, improved energy and nitrogen metabolism, and enhanced the antioxidant capacity of yak calves.
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Licorice (Gancao in Chinese) has been used worldwide as a botanical source in medicine and as a sweetening agent in food products for thousands of years. Triterpene saponins and flavonoids are its main ingredients that exhibit a variety of biological activities, including hepatoprotective, antiulcer, anti-inflammatory, antiviral and anticancer effects among others. This review attempts to summarize the current knowledge on the anticancer properties and mechanisms of the compounds isolated from licorice and obtain new insights for further research and development of licorice. A broad spectrum of in vitro and in vivo studies have recently demonstrated that the mixed extracts and purified compounds from licorice exhibit evident anticancer properties by inhibition of proliferation, induction of cell cycle arrest, apoptosis, autophagy, differentiation, suppression of metastasis, angiogenesis, and sensitization of chemotherapy or radiotherapy. A combined treatment of licorice compounds and clinical chemotherapy drugs remarkably enhances anticancer effects and reduces the side effects of chemotherapeutics. Furthermore, glycyrrhizic acid and glycyrrhetinic acid in licorice have been indicated to present obvious liver-targeting effects in targeted drug delivery systems for hepatocellular carcinoma treatment.
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Cancer is one of the fastest growing diseases, with an estimated worldwide incidence of 10 million new cases per year. Mortality is high, with >7 million deaths per year. In the last two decades, great advances have been made in cancer therapy; however, the success rates still remain unsatisfactory. Current conventional anticancer therapies are associated with adverse effects, drug resistance, and cancer recurrence. In Unani system of medicine, Cancer is known as Sartān, an Arabic word which means "crab". In the classical Unani literature, Sartān (Cancer) has been mentioned with great description, causes, origin, expansion, metastasis and all of clinical presentations. Renowned physicians like Buqrat, Jalinoos, Razi, Ibn Sina, Tabri and Jurjani gave the details of Sartān and its management. Through this paper, an attempt has been made to highlight the strength of Unani medicine in Sartān.
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About the Book The book “Advances in Ethnobotany” is an attempt to integrate research work of different practicing ethnobotanist across India from laboratories of repute. This book is divided into three sections. In first section ethnobotanical works of Veligonda, Shivalik hills, and some other research works of North eastern states are described. A chapter is dedicated on research methodology in ethnobotany. Another chapter describes ethnobotany of orchidaceae. The second section deals with Pharmacological activities of Cyperus rotundus, bioactive metabolites from plant associated endophytic fungi, berries: source of natural antioxidant, phytochemistry of Murraya Koenigii and several other herbal drugs are explained in very lucid manner. The third section focuses on utilization and conservation of plants in which medicinal and economic importance of Rhododendron in Sikkim Himalaya, an efficient micropropagation protocol for Melissa officinalis, utilization of plant biodiversity for treatment and cure of diseases and many other relevant topics are discussed in length.This book will be very much helpful for Post Graduate students, researchers, scientists and doctors working in the field of Indian System of Medicine and academicians working in the field of Medical Botany, Herbal technology and Ethnobotany as well as other branches of Life sciences. This book will be equally helpful for students of pharmacognosy, pharmacology as well as environmentalist and conservationist. The editor has attempted to organise the book in such a way that it will be useful to everyone interested in the field of medicinal botany, pharmacy, ethno-medicine, ethnobotany, herbal therapy, naturopathy and green health therapy. This book will be equally helpful for students of pharmacognosy, pharmacology as well as environmentalist and conservationist .
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Herbal supplements are being tested as alternatives to antibiotics in enhancing the performance of livestock. The present study evaluated the effects of herbal root extracts from three traditional Chinese medicinal herbs as dietary supplements on dry matter intake (DMI), average daily gain (ADG), rumen fermentation and ruminal microbiota in early weaned yak calves (Poephagus grunniens). Twenty, four-month old weaned yak calves (72.3 ± 3.65 kg) were divided into four groups, matched for bodyweight and sex (n = 5 per group), and received either no supplement (control group) or 80 mL/kg DMI of herbal root extracts of Angelica sinensis, Codonopsis pilosula or Glycyrrhiza uralensis. The water extract (∼170 mL) was mixed with 300 g concentrate and offered to the calves each day for 60 days following a 14-day adaptation period. Dry matter intake did not differ among treatments, but ADG was highest for calves fed Codonopsis pilosula root extract (P = 0.026). Compared with control calves, calves fed root extract of Glycyrrhiza uralensis had a higher ruminal proportion of propionate (P = 0.034), calves fed root extracts of Codonopsis pilosula and Glycyrrhiza uralensis had higher ruminal proportions of isovalerate (P = 0.032) and calves fed root extract of Glycyrrhiza uralensis had a lower acetate:propionate ratio (P = 0.027) on d 30. Calves consuming Angelica sinensis and Codonopsis pilosula root extracts, and Glycyrrhiza uralensis root extract had lower ruminal NH3-N concentrations than control calves on d 60 (P < 0.05). The abundances of Bacteroidetes and Firmicutes comprised over 90% of the total phyla in the four groups. Yak calves consuming Glycyrrhiza uralensis root extract had the highest abundance of Bacteroidetes (P = 0.009) and lowest abundance of Firmicutes (P = 0.023). Calves consuming Codonopsis pilosula root extract had the highest abundances of Proteobacteria (P = 0.035) and Actinobacteria (P = 0.007), while calves consuming the three herbal root extracts tended to have lower abundances of Kiritimatiellaeota (P = 0.082), Spirochaetes (P = 0.081) and Synergistetes (P = 0.058) than control calves. In conclusion, consuming Codonopsis pilosula root extract increased ADG in early weaned yak calves, while consuming the three herbal root extracts increased ruminal proportions of propionate and isovalerate, and altered rumen microbiota. Supplementary Codonopsis pilosula proved to be the most beneficial of the three herbal roots for the early weaned calves.
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The article provides a general outline on descriptions of various types of cancers and their management from medicinal and ethnobotanical perspective underlying its scientific principles involved in treating these conditions with the use of natural products. The article reviews the available literature regarding researches on anti-cancerous traditional and ayurvedic herbs and also includes how these plants are used to control and cure various types of cancers.
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Glycyrrhizin is a major constituent of Kanzo, a popular herbal medicine used in food and cosmetics. Glycyrrhizin alone did not stimulate nitric oxide (NO) or prostaglandin E2 (PGE2) production by RAW 264.7 cells, but modified lipopolysaccharide (LPS)-stimulated NO and PGE2 production in a bimodal fashion: it was stimulatory at lower concentrations, whereas it was inhibitory at higher concentrations. Electron-spin resonance spectroscopy showed that glycyrrhizin slightly scavenged the superoxide anion generated by hypoxanthine-xanthine oxidase reaction, but did not scavenge the DPPH and NO radicals. The present study demonstrates the concentration-dependent action of glycyrrhizin on both PGE2 and NO production by activated macrophages.
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The purification of homogeneous glutathione S-transferases B and C from rat liver is described. Kinetic and physical properties of these enzymes are compared with those of homogeneous transferases A and E. The letter designations for the transferases are based on the reverse order of elution from carboxymethylcellulose, the purification step in which the transferases are separated from each other. Transferase B was purified on the basis of its ability to conjugate iodomethane with glutathione, whereas transferase C was purified on the basis of conjugation with 1,2-dichloro-4-nitrobenzene. Although each of the four enzymes can be identified by its reactivity with specific substrates, all of the enzymes are active to differing degrees in the conjugation of glutathione with p-nitrobenzyl chloride. Assay conditions for a variety of substrates are included. All four glutathione transferases have a molecular weight of 45,000 and are dissociable into subunits of approximately 25,000 daltons. Despite the similar physical properties and overlapping substrate specificities of these enzymes, only transferases A and C are immunologically related.
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Glutathione reductase from rat liver has been purified greater than 5000-fold in a yield of 20%. The molecular weights of the enzyme and its subunits were estimated to be 125,000 and 60,000, respectively, indicating that the native enzyme is a dimer. The enzyme molecular contains 2 FAD molecules, which are reducible by NADPH, GSH or dithioerythritol. The reduced flavin is instantaneously reoxidized by addition of GSSG. The steady state kinetic data are consistent with a branching reaction mechanism previously proposed for glutathione reductase from yeast (MANNERVIK, B. (1973) Biochem. Biophy. Res. Commun. 53, 1151-1158). This mechanism is also favored by the nonlinear inhibition pattern produced by NADP-+. However, at low GSSG concentrations the rate equation can be approximated by that of a simple ping pong mechanism. NADPH and the mixed disulfide of coenzyme A and GSH were about 10% as active as NADPH and GSSG, respectively, whereas some sulfenyl derivatives related to GSSG were less active as substrates. The pH activity profiles of these substrates differed from that of the NADPH-GSSG substrate pair.
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Using the electron spin resonance/spin trapping system, 4-pyridyl 1-oxide N-tert-butylnitrone (4-POBN)/ethanol, hydroxyl radical was detected as the alpha-hydroxyethyl spin trapped adduct of 4-POBN, 4-POBN-CH(CH3)OH, from phorbol 12-myristate 13-acetate-stimulated human neutrophils and monocytes without the addition of supplemental iron. 4-POBN-CH(CH3)OH was stable in the presence of a neutrophil-derived superoxide flux. Hydroxyl radical formation was inhibited by treatment with superoxide dismutase, catalase, and azide. Treatment with a series of transition metal chelators did not appreciably alter 4-POBN-CH(CH3)OH, which suggested that hydroxyl radical generation was mediated by a mechanism independent of the transition metal-catalyzed Haber-Weiss reaction. Kinetic differences between transition metal-dependent and -independent mechanisms of hydroxyl radical generation by stimulated neutrophils were demonstrated by a greater rate of 4-POBN-CH(CH3)-OH accumulation in the presence of supplemental iron. Detection of hydroxyl radical from stimulated monocyte-derived macrophages, which lack myeloperoxidase, required the addition of supplemental iron. The addition of purified myeloperoxidase to an enzymatic superoxide generating system resulted in the detection of hydroxyl radical that was dependent upon the presence of chloride and was inhibited by superoxide dismutase, catalase, and azide. These findings implicated the reaction of hypochlorous acid and superoxide to produce hydroxyl radical. 4-POBN-CH(CH3)OH was not observed upon stimulation of myeloperoxidase-deficient neutrophils, whereas addition of myeloperoxidase to the reaction mixture resulted in the detection of hydroxyl radical. These results support the ability of human neutrophils and monocytes to generate hydroxyl radical through a myeloperoxidase-dependent mechanism.
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To determine if singlet oxygen (O2(1 delta g)) is produced by neutrophils (PMNs) during the process of phagocytosis, glass beads were coated with a specific chemical trap for O2(1 delta g), 9,10-diphenylanthracene (DPA). Singlet oxygen, but not other reactive oxygen species, reacts rapidly with DPA at a rate of kr = 1.3 x 10(6) M-1 s-1 to form a stable product, DPA-endoperoxide (Corey, E. J., and Taylor, W. C. (1964) J. Am. Chem. Soc. 86, 3881-3882; Wasserman, H. H., Scheffer, J. R., and Cooper, J. L. (1972) J. Am. Chem. Soc. 94, 4991-4996; Turro, N. J., Chow, M.-F., and Rigaudy, J. (1981) J. Am. Chem. Soc. 103, 7218-7224). The production of DPA-endoperoxide was determined by ultraviolet spectroscopy as a decrease in DPA absorbance at 355 nm. The absorbance of DPA was normalized to the absorbance of perylene, which was included in the coating on the beads as a nonreactive, internal standard. In the present study, DPA- and perylene-coated beads were initially allowed to adhere to fibronectin-coated coverslips. PMNs were then added to the bead-coated coverslips and allowed to adhere and phagocytose the beads for 1 h at 37 degrees C. In some experiments, 4B-phorbol-12-myristate-13-acetate (PMA) (1 ng/2.5 x 10(7) cells/ml), a known activator of the PMN NADPH-oxidase, was added as a co-stimulant. The amount of O2(1 delta g) produced by phagocytically stimulated PMNs was calculated to be 11.3 +/- 4.9 nmol of O2(1 delta g)/1.25 x 10(6) cells. Low dose PMA co-stimulation increased the production of O2(1 delta g) to 14.1 +/- 4.1 nmol/1.25 x 10(6) cells. Averaged together these amounts represent approximately 19 +/- 5.0% of the total oxygen consumed by PMNs in response to DPA- and perylene-coated beads. The specificity of the DPA reaction with O2(1 delta g) was confirmed by warming to 120 degrees C, which releases O2(1 delta g) from the DPA-endoperoxide, regenerating the parent DPA compound (Wasserman et al., 1972; Turro et al., 1981) and the absorbance at 355 nm. In addition, beta-carotene, an avid quencher of O2(1 delta g), was included in the coating of some bead preparations; assays in which these beads were used showed no change in the absorbance at 355 nm. Singlet oxygen production by myeloperoxidase was also measured using the coated bead assay and the results suggest that this is a major pathway by which singlet oxygen is generated in phagocytically stimulated PMNs.(ABSTRACT TRUNCATED AT 400 WORDS)
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There has been a paucity of evidence showing that 12-O-tetradecanoyl-phorbol-13-acetate (TPA), a potent tumor promoter, causes DNA damage in vivo. We show that oxidized DNA bases are formed in the epidermis of TPA-treated SENCAR mice in a dose- and time-dependent manner. As measured by high-performance liquid chromatography and acetylation of nucleosides with [3H]acetic anhydride, these oxidized DNA derivatives include cis-thymidine glycol, 5-hydroxymethyl-2'-deoxyuridine, and 8-hydroxyl-2'-deoxyguanosine. Their maximal formation induced by a single TPA dose occurred within 6-8 h (a 2-5-fold increase). The level of 8-hydroxyl-2'-deoxyguanosine was the lowest (3.2/10(5) bases) and remained almost unchanged for 18 h; thymidine glycol (29.1/10(4) bases) and 5-hydroxymethyl-2'-deoxyuridine (17.3/10(4) bases) declined gradually but were still above controls at 24 h. Reapplication of TPA 20 h after the first dose (time of the maximal polymorphonuclear leukocyte infiltration) enhanced the net formation of 8-hydroxyl-2'-deoxyguanosine by 3.8-fold (P less than 0.05), of cis-thymidine glycol by 1.9-fold (P less than 0.001), and of 5-hydroxymethyl-2'-deoxyuridine by 2.0-fold (P less than 0.01), as compared to those maximally produced by a single TPA dose. Thus, the infiltration of polymorphonuclear leukocytes into TPA-treated mouse skin, which was corroborated by histological examination and the presence of polymorphonuclear leukocyte-specific myeloperoxidase, might play an important role in TPA-induced DNA oxidation in vivo. Our findings provide proof that tumor promoters can induce genetic modification in vivo that is oxidative in nature. Hence, formation of oxidized DNA bases may be responsible for the genetic effects of tumor promoters in carcinogenesis.
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Following a brief introduction of cellular response to stimulation comprising leukocyte activation, three major areas are discussed: (1) the neutrophil oxidase; (2) myeloperoxidase (MPO)-dependent oxidative microbicidal reactions; and (3) MPO-independent oxidative reactions. Topics included in section (A) are current views on the activation mechanism, redox composition, structural and topographic organization of the oxidase, and its respiratory products. In section (B), emphasis is placed on recent research on cidal mechanisms of HOCl, including the oxidative biochemistry of active chlorine compounds, identification of sites of lesions in bacteria, and attendant metabolic consequences. In section (C), we review the (bio)chemistry of H2O2 and .OH microbicidal reactions, with particular attention being given to addressing the controversial issue of probe methods to identify .OH radical and critical assessment of the recent proposal that MPO-independent killing arises from site-specific metal-catalyzed Fenton-type chemistry.
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Toxicity studies were conducted on Brassica rapa, Prunus amygdalus and Zingiber officinale, used as aphrodisiacs in Arab Medicine. During acute toxicity test observations were made for 24 h where all these plants showed no toxicity. The animals were treated for 3 months in chronic treatment. External morphological changes, visceral toxicity, haematological changes, effects on average body weight, vital organ weight, sperm contents, sperm motility and sperm abnormalities were recorded. The average body weight increase was significant in B. rapa and P. amygdalus treated animals. Haematological studies revealed reduction in WBC level in these groups. These changes were not significant in Z. officinale treated animals. In all three groups the visceral condition was normal and the percent lethality was insignificant as compared to the control. All these plant extracts significantly increased the sperm motility and sperm contents in the epididymides and vas deferens without producing any spermatotoxic effect.
Article
Red ginseng extract A and B are the active components of Panax ginseng. Red ginseng is a classical traditional Chinese medicine. Among Chinese herbs, red ginseng has been considered as one of the tonics. Many studies indicated that red ginseng could enhance immune function of the human body. The effects of red ginseng extracts on transplantable tumors, proliferation of lymphocyte, two-stage model and rat liver lipid peroxidation were studied. In a two-stage model, red ginseng extracts had a significant cancer chemoprevention. At 50-400 mg/kg, they could inhibit DMBA/Croton oil-induced skin papilloma in mice, decrease the incidence of papilloma, prolong the latent period of tumor occurrence and reduce tumor number per mouse in a dose-dependent manner. Red ginseng extract B could effectively inhibit the Fe2+/cysteine-induced lipid peroxidation of rat liver microsome, suggesting that red ginseng extract B has a stronger antioxidative effect than that of extract A. The results indicated that red ginseng extracts (50 approximately 400 mg/kg) could significantly inhibit the growth of transplantable mouse sarcoma S180 and melanoma B16. Red ginseng extracts A (0.5 mg/ml) and B (0.1 and 0.25 mg/ml) might effectively promote the transformation of T lymphocyte, but there was no influence on lymphocyte proliferation stimulated by concanavalin A. This suggests that red ginseng extracts have potent tumor therapeutic activity and improve the cell immune system.
Article
The induction of ornithine decarboxylase and S-adenosyl-L-methionine decarboxylase in mouse epidermis by various classes of tumor-promoting and nonpromoting compounds has been studied in order to determine the specificity of this response for tumor promotion. The effect of topical applications of a series of phorbol esters on these enzyme activities correlated well with their promoting abilities. Iodoacetic acid, anthralin, and Tween 60, all promoting compounds, also stimulated both of these enzyme activities after single and multiple applications. The hyperplastic agents acetic acid, cantharidin, and ethyl phenylpropriolate, however, had little effect on ornithine decarboxylase activity but a pronounced effect on epidermal S-adenosyl-L-methionine decarboxylase activity. The specificity of the ornithine decarboxylase response for tumor promotion was suggested by the results of the above experiments as well as the stimulatory effect of a completely carcinogenic dose of 7,12-dimethylbenz[a]anthracene; a lower initiating dose had no effect. In addition, epidermal tumors produced by a two-stage procedure showed consistently high levels of ornithine decarboxylase activity but variable levels of S-adenosyl-L-methionine decarboxylase activity.
Article
A number of systems that generate oxygen free radicals catalyze the oxidative modification of proteins. Such modifications mark enzymes for degradation by cytosolic neutral alkaline proteases. Protein oxidation contributes to the pool of damaged enzymes, which increases in size during aging and in various pathological states. The age-related increase in amounts of oxidized protein may reflect the age-dependent accumulation of unrepaired DNA damage that, in a random manner, affects the concentrations or activities of numerous factors that govern the rates of protein oxidation and the degradation of oxidized protein.
Article
Our laboratory has been studying cancer chemopreventive effects of polyphenolic fraction isolated from green tea (GTP). In prior studies we have shown that (a) GTP possesses antigenotoxic effects in various test systems; (b) topical application of GTP protects against UV radiation and chemical carcinogen-induced tumorigenesis in murine skin; and (c) feeding of GTP in drinking water p.o. to mice protects against carcinogen-induced forestomach and lung tumorigenesis. Recently, we showed that in a dose-dependent manner GTP inhibits tumor promoter-caused induction of epidermal ornithine decarboxylase activity in SENCAR mice (R. Agarwal et al., Cancer Res., 52: 3582-3588, 1992). In the present study, we assessed the effect of GTP on TPA-induced skin tumor promotion in 7,12-dimethylbenz(a)anthracene-initiated SENCAR mouse. Topical application of varying doses of GTP (1-24 mg) 30 min prior to that of each TPA application resulted in highly significant protection against skin tumor promotion in a dose-dependent manner. The animals pretreated with GTP showed substantially lower tumor body burden such as decrease in total number of tumors per group, number of tumors per animal, tumor volume per mouse, and average volume per tumor, as compared to the animals that did not receive GTP. Since TPA-induced epidermal cyclooxygenase and lipoxygenase activities and edema and hyperplasia are conventionally used markers of skin tumor promotion, we also assessed the effect of preapplication of GTP on these parameters. As quantitated by the formation of prostaglandin and hydroxy-eicosatetraenoic acid metabolites from, respectively, cyclooxygenase- and lipoxygenase-catalyzed metabolism of arachidonic acid, skin application of GTP to SENCAR mice resulted in significant inhibition of TPA-caused effects on these 2 enzymes. Prior application of GTP to mouse skin also resulted in 30-46% inhibition of TPA-induced epidermal edema and hyperplasia. The results of the present study suggest that GTP possesses anti-skin tumor-promoting effects, and that the mechanism of such effects may involve inhibition of tumor promoter-induced epidermal ornithine decarboxylase, cyclooxygenase and lipoxygenase activities, edema, and hyperplasia. Further studies are in progress to define which component present in GTP is responsible for its anti-skin tumor-promoting effects.
Article
The effect of glycyrrhizin on inflammatory mediators such as neutrophil functions including reactive oxygen species (ROS) generation was examined. Glycyrrhizin significantly decreased neutrophil-generated O2-, H2O2 and OH in a dose-dependent manner. However, the drug did not reduce any of the ROS generated in a cell-free, xanthine-xanthine oxidase system. The drug did not affect neutrophil chemotaxis or phagocytosis, either. The present study indicates that glycyrrhizin is not an ROS scavenger but exerts an anti-inflammatory action by inhibiting the generation of ROS by neutrophils, the most potent inflammatory mediator at the site of inflammation.
Article
Free radicals are found to be involved in both initiation and promotion of multistage carcinogenesis. These highly reactive compounds can act as initiators and/or promoters, cause DNA damage, activate procarcinogens, and alter the cellular antioxidant defense system. Antioxidants, the free radical scavengers, however, are shown to be anticarcinogens. They function as the inhibitors at both initiation and promotion/transformation stage of carcinogenesis and protect cells against oxidative damage. Altered antioxidant enzymes were observed during carcinogenesis or in tumors. When compared to their appropriate normal cell counterparts, tumor cells are always low in manganese superoxide dismutase activity, usually low in copper and zinc superoxide dismutase activity and almost always low in catalase activity. Glutathione peroxidase and glutathione reductase activities are highly variable. In contrast, glutathione S-transferase 7-7 is increased in many tumor cells and in chemically induced preneoplastic rat hepatocyte nodules. Increased glucose-6-phosphate dehydrogenase activity is also found in many tumors. Comprehensive data on free radicals, antioxidant enzymes, and carcinogenesis are reviewed. The role of antioxidant enzymes in carcinogenesis is discussed.
Article
Oxidant species such as superoxide radical (O.2-), hydrogen peroxide (H2O2), hydroxyl radical (HO.), and lipid peroxides (LOOH) are becoming increasingly implicated in human disease. However, the question of whether such oxidants are a major cause of tissue injury in human disease or are merely produced during such injury has been difficult to answer because of inadequate experimental techniques, and possibly because of an overemphasis on lipid peroxidation as a mechanism of oxidant injury. Recent developments in methodology, in our understanding of the primary mechanism of oxidant toxicity to cells, and in concepts of antioxidant protection are reviewed. Good evidence now exists for some role of oxidant damage to tissues in the pathology of several human diseases, including rheumatoid arthritis, reperfusion injury, immune injury to lung and kidney, and cerebral trauma or ischemia. These have led to promising suggestions for new therapeutic approaches.
Article
12-O-Tetradecanoylphorbol-13 acetate (TPA) or various acylglycerols were applied topically to CD-1 mice, and biochemical changes associated with tumor promotion in the epidermis were examined. The topical application of 5 mumol of sn-1,2-didecanoylglycerol caused a 40-fold increase in ornithine decarboxylase activity which was similar to that found after the topical application of 2 nmol of TPA. The time course for the induction of ornithine decarboxylase activity by TPA and the time course for its induction by sn-1,2-didecanoylglycerol were similar; both compounds produced rapid increases in ornithine decarboxylase activity with peak induction occurring 4-6 h after application of the inducing chemical. sn-1,2-Dioctanoylglycerol and sn-1-oleoyl-2-acetylglycerol also increased ornithine decarboxylase activity in mouse epidermis, but sn-1,2-dioleoylglycerol, 1,3-didecanoylglycerol and rac-1-monodecanoylglycerol were inactive at the dose tested. trans-Retinoic acid, a potent inhibitor of tumor promotion, markedly inhibited the epidermal induction of ornithine decarboxylase activity that resulted from the topical administration of sn-1,2-didecanoylglycerol or TPA. The effects of TPA and the acylglycerols on epidermal DNA synthesis in vivo were determined by measuring the incorporation of [3H]thymidine into epidermal DNA. The application of sn-1,2-didecanoylglycerol or TPA to mouse skin stimulated epidermal DNA synthesis. The maximum increase occurred 18 h after administration of the inducing chemical, and the increase in DNA synthesis was proportional to the dose of sn-1,2-didecanoylglycerol. Although sn-1,2-didecanoylglycerol, sn-1,2-dioctanoylglycerol and sn-1,2-dioleoylglycerol stimulated epidermal DNA synthesis, sn-1-oleoyl-2-acetylglycerol, 1,3-didecanoylglycerol and rac-1-monodecanoylglycerol had little or no effect. The increase in epidermal DNA synthesis induced by sn-1,2-didecanoylglycerol or TPA was inhibited by the simultaneous application of fluocinolone acetonide, a potent inhibitor of tumor promotion. The results indicate that several sn-1,2-diacylglycerols mimic TPA in vivo with respect to their effects on certain biochemical parameters associated with tumor promotion in mouse skin.
Article
The purification of homogeneous glutathione S transferases B and C from rat liver is described. Kinetic and physical properties of these enzymes are compared with those of homogeneous transferases A and E. The letter designations for the transferases are based on the reverse order of elution from carboxymethylcellulose, the purification step in which the transferases are separated from each other. Transferase B was purified on the basis of its ability to conjugate iodomethane with glutathione, whereas transferase C was purified on the basis of conjugation with 1,2 dichloro 4 nitrobenzene. Although each of the 4 enzymes can be identified by its reactivity with specific substrates, all of the enzymes are active to differing degrees in the conjugation of glutathione with p nitrobenzyl chloride. Assay conditions for a variety of substrates are included. All four glutathione transferases have a molecular weight of 45,000 and are dissociable into subunits of approximately 25,000 daltons. Despite similar physical properties and overlapping substrate specificities of these enzymes, only transferases A and C are immunologically related.
Article
This laboratory has previously postulated that bromobenzene-induced hepatic necrosis results from the formation of a reactive metabolite that arylates vital cellular macromolecules. Accordingly, the severity of liver necrosis has been compared with the formation of metabolites of bromobenzene and with covalent binding of metabolites in vivo and in vitro after various pretreatment regimens that alter hepatotoxicity. These data provide direct kinetic evidence that 3,4-bromobenzene oxide is the reactive hepatotoxic metabolite. The studies also demonstrate that the hepatotoxic metabolite is preferentially conjugated (detoxified) with glutathione, thereby depleting glutathione from the liver. Liver necrosis and arylation of cellular macromolecules occur only when glutathione is no longer available. Thus, a dose threshold exists for bromobenzene-induced hepatic necrosis.
Article
Whole tissue reduced glutathione (GSH) concentration was found to be lowest in rabbit renal inner medulla and progressively higher in outer medulla and cortex. Activities of cytosolic glutathione reductase in inner medulla and outer medulla were similar, and each was only approximately 50% of that of cortex. Whole tissue and microsomal gamma-glutamyl transpeptidase activities were high in cortex and outer medulla but were low in inner medulla. Cytosolic activity of selenium-dependent glutathione peroxidase ( GPx -I) was similar in both outer medulla and inner medulla but was only 50% of that of cortex. Activity of cytosolic selenium-independent glutathione peroxidase ( GPx -II) was highest in cortex and lowest in inner medulla (approximately 15% of cortex and approximately 50% of outer medulla). Cytosolic glutathione S-transferase activity with 1-chloro-2,4-dinitrobenzene as substrate was high in all three regions of kidney. With 1,2-dichloro-4-nitrobenzene and 1,2-epoxy-(4-nitrophenoxy)propane as substrates, cytosolic glutathione S-transferase activities were very low in cortex, outer medulla, and inner medulla. Microsomal activities of glutathione reductase, GPx -I, GPx -II and glutathione S-transferases were much lower than activities of corresponding cytosolic enzymes. Activities of the glutathione peroxidases in renal inner medulla would hence be expected to cause little interference to prostaglandin endoperoxide synthetase mediated cooxidative activation of paracetamol. It has been demonstrated that the paracetamol metabolite can react rapidly with GSH, forming not only glutathione conjugate but also paracetamol itself and oxidized glutathione. Low GSH concentrations, as well as low activities of glutathione reductase, GPx -I, GPx -II, and gamma-glutamyl transpeptidase, may therefore render the inner medullary region of kidney particularly vulnerable to paracetamol-related analgesic nephropathy.
Article
Arachidonic acid plays a central role in a biological control system where such oxygenated derivatives as prostaglandins, thromboxanes, and leukotrienes are mediators. The leukotrienes are formed by transformation of arachidonic acid into an unstable epoxide intermediate, leukotriene A4, which can be converted enzymatically by hydration to leukotriene B4, and by addition of glutathione to leukotriene C4. This last compound is metabolized to leukotrienes D4 and E4 by successive elimination of a gamma-glutamyl residue and glycine. Slow-reacting substance of anaphylaxis consists of leukotrienes C4, D4, and E4. The cysteinyl-containing leukotrienes are potent bronchoconstrictors, increase vascular permeability in postcapillary venules, and stimulate mucus secretion. Leukotriene B4 causes adhesion and chemotactic movement of leukocytes and stimulates aggregation, enzyme release, and generation of superoxide in neutrophils. Leukotrienes C4, D4, and E4, which are released from the lung tissue of asthmatic subjects exposed to specific allergens, seem to play a pathophysiological role in immediate hypersensitivity reactions. These leukotrienes, as well as leukotriene B4, have pro-inflammatory effects.
Article
Studies were carried out to determine the effects of lung and liver cytosol on pulmonary and hepatic mierosomal lipid peroxidation, to determine the cytosolic concentrations of various substances which affect lipid peroxidation, and to determine which of these substances is responsible for the effects of the cytosol on lipid peroxidation. Lung cytosol inhibits both enzymatic (NADPH-induced) and nonenzymatic (Fe2+-induced) lung microsomal lipid peroxidation. In contrast, liver cytosol stimulates lipid peroxidation in hepatic microsomes during incubation alone, enhances Fe2+-stimulated lipid peroxidation, and has no effect on the NADPH-induced response. Substances which are known to be involved in inhibition of lipid peroxidation, including glutathione, glutathione reductase, glutathione peroxidase, and superoxide dismutase, are found in greater concentrations in liver cytosol than in lung cytosol. However, ascorbate is found in approximately equal concentrations in pulmonary and hepatic cytosol. Most of the effects of the cytosol on lipid peroxidation seem to be due to ascorbate and glutathione. For example, ascorbate, in concentrations found in lung cytosol, inhibits lung microsomal lipid peroxidation to about the same extent as the cytosol. The effects of liver cytosol on hepatic microsomal lipid peroxidation can be duplicated by concentrations of ascorbate and glutathione normally found in the cytosol; i.e., ascorbate stimulates and glutathione inhibits lipid peroxidation with the net effect being similar to that of liver cytosol. The results indicate that ascorbate has opposite effects on pulmonary and hepatic microsomal lipid peroxidation and suggest that ascorbate plays a major role in protecting pulmonary tissue against the harmful effects of lipid peroxidation.
Article
Literature on case reports, clinical studies and biochemical mechanisms of the sweet-tasting compound glycyrrhizic acid in liquorice was critically reviewed to provide a safety assessment of its presence in liquorice sweets. A high intake of liquorice can cause hypermineralocorticoidism with sodium retention and potassium loss, oedema, increased blood pressure and depression of the renin-angiotensin-aldosterone system. As a consequence, a number of other clinical symptoms have also been observed. Glycyrrhizic acid is hydrolysed in the intestine to the pharmacologically active compound glycyrrhetic acid, which inhibits the enzyme 11 beta-hydroxysteroid dehydrogenase (in the direction of cortisol to cortisone) as well as some other enzymes involved in the metabolism of corticosteroids. Inhibition of 11 beta-hydroxysteroid dehydrogenase leads to increased cortisol levels in the kidneys and in other mineralocorticoid-selective tissues. Since cortisol, which occurs in much larger amounts than aldosterone, binds with the same affinity as aldosterone to the mineralocorticoid receptor, the result is a hypermineralocorticoid effect of cortisol. The inhibitory effect on 11 beta-hydroxysteroid dehydrogenase is reversible; however, the compensatory physiological mechanisms following hypermineralocorticoidism (e.g. depression of the renin-angiotensin system) may last several months. It is not possible, on the basis of existing data, to determine precisely the minimum level of glycyrrhizic acid required to produce the described symptoms. There is apparently a great individual variation in the susceptibility to glycyrrhizic acid. In the most sensitive individuals a regular daily intake of no more than about 100 mg glycyrrhizic acid, which corresponds to 50 g liquorice sweets (assuming a content of 0.2% glycyrrhizic acid), seems to be enough to produce adverse effects. Most individuals who consume 400 mg glycyrrhizic acid daily experience adverse effects. Considering that a regular intake of 100 mg glycyrrhizic acid/day is the lowest-observed-adverse-effect level and using a safety factor of 10, a daily intake of 10 mg glycyrrhizic acid would represent a safe dose for most healthy adults. A daily intake of 1-10 mg glycyrrhizic acid/person has been estimated for several countries. However, an uneven consumption pattern suggests that a considerable number of individuals who consume large amounts of liquorice sweets are exposed to the risk of developing adverse effects.
Article
This article summarizes available data on the chemopreventive efficacies of tea polyphenols, curcumin and ellagic acid in various model systems. Emphasis is placed upon the anticarcinogenic activity of these polyphenols and their proposed mechanism(s) of action. Tea is grown in about 30 countries and, next to water, is the most widely consumed beverage in the world. Tea is manufactured as either green, black, or oolong; black tea represents approximately 80% of tea products. Epidemiological studies, though inconclusive, suggest a protective effect of tea consumption on human cancer. Experimental studies of the antimutagenic and anticarcinogenic effects of tea have been conducted principally with green tea polyphenols (GTPs). GTPs exhibit antimutagenic activity in vitro, and they inhibit carcinogen-induced skin, lung, forestomach, esophagus, duodenum and colon tumors in rodents. In addition, GTPs inhibit TPA-induced skin tumor promotion in mice. Although several GTPs possess anticarcinogenic activity, the most active is (–)-epigallocatechin-3-gallate (EGCG), the major constituent in the GTP fraction. Several mechanisms appear to be responsible for the tumor-inhibitory properties of GTPs, including enhancement of antioxidant (glutathione peroxidase, catalase and quinone reductase) and phase II (glutathione-S-transferase) enzyme activities; inhibition of chemically induced lipid peroxidation; inhibition of irradiation-and TPA-induced epidermal ornithine decarboxylase (ODC) and cyclooxygenase activities; inhibition of protein kinase C and cellular proliferation; antiinflammatory activity; and enhancement of gap junction intercellular communication. Curcumin is the yellow coloring agent in the spice turmeric. It exhibits antimutagenic activity in the Ames Salmonella test and has anticarcinogenic activity, inhibiting chemically induced preneoplastic lesions in the breast and colon and neoplastic lesions in the skin, forestomach, duodenum and colon of rodents. In addition, curcumin inhibits TPA-induced skin tumor promotion in mice. The mechanisms for the anticarcinogenic effects of curcumin are similar to those of the GTPs. Curcumin enhances glutathione content and glutathione-S-transferase activity in liver; and it inhibits lipid peroxidation and arachidonic acid metabolism in mouse skin, protein kinase C activity in TPA-treated NIH 3T3 cells, chemically induced ODC and tyrosine protein kinase activities in rat colon, and 8-hydroxyguanosine formation in mouse fibroblasts. Ellagic acid is a polyphenol found abundantly in various fruits, nuts and vegetables. Ellagic acid is active in antimutagenesis assays, and has been shown to inhibit chemically induced cancer in the lung, liver, skin and esophagus of rodents, and TPA-induced tumor promotion in mouse skin. Ellagic acid functions through a variety of mechanisms, including inhibition of microsomal P-450 enzymes, stimulation of glutathione-S-transferase, scavenging the reactive metabolites of carcinogens, and direct binding to DNA, thus potentially masking sites that would normally interact with ultimate carcinogens. GTP, curcumin and ellagic acid exhibit potent antioxidant effects. This property, coupled with their other effects, make them effective chemopreventives against both the initiation and promotion/progression stages of carcinogenesis.
Article
l-Ornithine decarboxylase (ODC) is essential for polyamine synthesis and growth in mammalian cells; it provides putrescine that is usually converted into the higher polyamines, spermidine and spermine. Many highly specific and potent inhibitors of ODC are based on the lead compound alpha-difluoromethylornithine (DFMO), which is an enzyme-activated irreversible inhibitor. DFMO is accepted as a substrate by ODC and is decarboxylated, leading to the formation of a highly reactive species that forms a covalent adduct with either cysteine-360 (90%) or lysine-69 (10%). Both modifications inactivate the enzyme. ODC activity is normally very highly regulated at both transcriptional and post-transcriptional levels according to the growth state of the cell and the intracellular polyamine content. Experimental over-production of ODC can be caused by either transfection with plasmids containing the ODC cDNA with part of the 5'-untranslated region (5'UTR) deleted under the control of a very strong viral promoter, or transfection of plasmids that cause the overproduction of eIF-4E, reported to be a limiting factor in the translation of mRNAs with extensive secondary structures in the 5'UTR. In both cases, unregulated overexpression of ODC transforms NIH 3T3 cells to a neoplastic state. Along with studies showing that many tumor promoters increase ODC activity and that a number of preneoplastic conditions and tumor samples show high levels of ODC, these results suggest that ODC may act as an oncogene in an appropriate background. This provides a rationale for the possible use of ODC inhibitors as chemopreventive agents.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
Autooxidation of polyphenolic metabolites of benzene, such as hydroquinone (HQ), catechol (CT), 1,2,4-benzenetriol (BT) and pyrogallol (PG), produced several kinds of active oxygen species (AOS). BT and PG induced DNA breaks in the absence of metal ions, especially when producing AOS such as H2O2, O2-, HO. or 1 delta gO2. HQ and CT did not result in double-strand DNA breaks, except when ferrous ion was added, indicating the participation of the Fenton reaction. Polyphenolic fractions isolated from green tea (GTP) exerted inhibitory effects on the autooxidation of BT and suppressive effects on H2O2 or HO. generated from phenolic metabolites of benzene in the presence of S9 or an in vivo system. Additionally, although the activities of antioxidant and phase II enzymes were elevated by both GTP and phenolic metabolites of benzene, GTP counteracted the lowering GSH caused by phenolic metabolites of benzene in rat liver. The above results suggest that GTP and phenolic metabolites of benzene are antagonistic in their response to AOS, especially hydroxyl radical.
Article
There is considerable emphasis on identifying potential chemopreventive agents present in food consumed by the human population. Ginger rhizome (Zingiber officinale), known commonly as ginger, is consumed worldwide in cookeries as a spice and a flavoring agent. In prior in vitro studies, it has been shown that the water or organic solvent extract of ginger possesses antioxidative and antiinflammatory properties. In this study, we evaluated whether ethanol extract of ginger (GE) possesses anti-tumor-promoting effects in a mouse skin tumorigenesis model. Because skin tumor promoters induced epidermal ornithine decarboxylase (ODC), cyclooxygenase, and lipoxygenase activities, and edema and hyperplasia are conventionally used markers of skin tumor promotion, first, we assessed the effect of GE on these parameters. Preapplication of GE onto the skin of SENCAR mice resulted in significant inhibition of 12-0-tetradecanoylphorbol-13-acetate (TPA)-caused induction of epidermal ODC, cyclooxygenase, and lipoxygenase activities and ODC mRNA expression in a does-dependent manner. Preapplication of GE to mouse skin also afforded significant inhibition of TPA-caused epidermal edema (56%) and hyperplasia (44%). In long-term tumor studies, topical application of GE 30 min prior to that of each TPA application to 7,12-dimethylbenz(a)anthracene-initiated SENCAR mice resulted in a highly significant protection against skin tumor incidence and its subsequent multiplicity. The animals pretreated with GE showed substantially lower tumor body burdens compared with non-GE-treated controls. The results of our study, for the first time, provide clear evidence that GE possesses anti-skin tumor-promoting effects, and that the mechanism of such effects may involve inhibition of tumor promoter-caused cellular, biochemical, and molecular changes in mouse skin.
Article
Glycyrrhizin (GL), an anti-inflammatory compound isolated from Glycyrrhiza glabra, was identified as a new thrombin inhibitor: (a) It prolonged plasma recalcification and thrombin and fibrinogen clotting times, and (b) it inhibited thrombin-induced, but not collagen-, PAF- or convulxin-induced platelet aggregation. On the other hand, GL did not block thrombin's amidolytic activity upon S-2238. Furthermore, the fluorescence emission intensity of dansyl-thrombin was increased upon GL binding. Moreover, GL displaced hirudin as an inhibitor of thrombin-catalyzed hydrolysis of S-2238. Our data provide evidence that GL is a selective inhibitor of thrombin (the first one isolated from plants) that is able to exert its anti-thrombin action by interacting with the enzyme's anion binding exosite 1. A pharmacophoric search identified GL as a sialyl Lewis X (SLe[X]) mimetic compound able to inhibit selectin binding to SLe(X). However, SLe(X) did not affect thrombin clotting activities, which indicates a lack of its interaction with thrombin and distinguishes both molecules. It is suggested that the anti-inflammatory effect of GL may be due to its effective anti-thrombin action.
Article
Detoxication enzymes protect cells from a wide variety of xenobiotics and endogenous toxins. Current data suggest that the balance between the Phase I carcinogen-activating enzymes and the Phase II detoxifying enzymes is critical to determining an individual's risk for cancer. Human deficiencies in Phase II enzyme activity, specifically glutathione-S-transferase (GST), have been identified and associated with increased risk for colon cancer. The increased frequency of the GST M1 null genotype among individuals with primarily smoking-related cancers has been documented. Induction of Phase II enzymes by naturally occurring or synthetic agents represents a promising strategy for cancer prevention. Both the required characteristics of potential chemopreventive agents and the role of the antioxidant response element in the monofunctional induction of Phase II enzymes have been discussed. The synthetic dithiolthione oltipraz induces a battery of Phase II enzymes and inhibits chemically induced tumors in a variety of target organs. Its ability to induce Phase II enzymes in human colon tissue and blood lymphocytes has been reported. Other promising inducers with chemopreventive activity include the isothiocyanates and polyphenols. These data collectively support the future development of Phase II enzyme inducers as clinical chemopreventive agents.
Article
The chemopreventive effect of topical application of 4'-demethyl epipodophyllotoxin (DMEP), an antimitotic agent, on a two-stage skin carcinogenesis model in Swiss Albino mice induced by 9, 10-dimethylbenz[a]anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA) was investigated. Two topical applications with 0.24% DMBA over 1 week, followed later by 5 nmol of TPA twice weekly produced 100% incidence of tumors in these animals by 18 weeks. Treatment of animals with DMEP (until the end of the experiment), 30 min before TPA treatment, significantly reduced the tumor incidence, tumor volume and the conversion efficiency of papillomas to squamous cell carcinomas. The tumor formation and growth was also delayed by DMEP pre-treatment. Application of DMEP protected against the losses provoked in levels of glutathione and activity of catalase and superoxide dismutase in skin and liver of animals by the application of DMBA/TPA. Thus, DMEP might possibly be exerting its chemopreventive activity by acting as an antioxidant.
Article
Procyanidins present in grape seeds are known to exert anti-inflammatory, anti-arthritic and anti-allergic activities, prevent skin aging, scavenge oxygen free radicals and inhibit UV radiation-induced peroxidation activity. Since most of these events are associated with the tumor promotion stage of carcinogenesis, these studies suggest that grape seed polyphenols and the procyanidins present therein could be anticarcinogenic and/or anti-tumor-promoting agents. Therefore, we assessed the anti-tumor-promoting effect of a polyphenolic fraction isolated from grape seeds (GSP) employing the 7,12-dimethylbenz[a]anthracene (DMBA)-initiated and 12-O-tetradecanoylphorbol 13-acetate (TPA)-promoted SENCAR mouse skin two-stage carcinogenesis protocol as a model system. Following tumor initiation with DMBA, topical application of GSP at doses of 0.5 and 1.5 mg/mouse/application to the dorsal initiated mouse skin resulted in a highly significant inhibition of TPA tumor promotion. The observed anti-tumor-promoting effects of GSP were dose dependent and were evident in terms of a reduction in tumor incidence (35 and 60% inhibition), tumor multiplicity (61 and 83% inhibition) and tumor volume (67 and 87% inhibition) at both 0.5 and 1.5 mg GSP, respectively. Based on these results, we directed our efforts to separate and identify the individual polyphenols present in GSP and assess their antioxidant activity in terms of inhibition of epidermal lipid peroxidation. Employing HPLC followed by comparison with authentic standards for retention times in HPLC profiles, physiochemical properties and spectral analysis, nine individual polyphenols were identified as catechin, epicatechin, procyanidins B1-B5 and C1 and procyanidin B5-3'-gallate. Five of these individual polyphenols with evident structural differences, namely catechin, procyanidin B2, procyanidin B5, procyanidin C1 and procyanidin B5-3'-gallate, were assessed for antioxidant activity. All of them significantly inhibited epidermal lipid peroxidation, albeit to different levels. A structure-activity relationship study showed that with an increase in the degree of polymerization in polyphenol structure, the inhibitory potential towards lipid peroxidation increased. In addition, the position of linkage between inter-flavan units also influences lipid peroxidation activity; procyanidin isomers with a 4-6 linkage showed stronger inhibitory activity than isomers with a 4-8 linkage. A sharp increase in the inhibition of epidermal lipid peroxidation was also evident when a gallate group was linked at the 3'-hydroxy position of a procyanidin dimer. Procyanidin B5-3'-gallate showed the most potent antioxidant activity with an IC(50) of 20 microM in an epidermal lipid peroxidation assay. Taken together, for the first time these results show that grape seed polyphenols possess high anti-tumor-promoting activity due to the strong antioxidant effect of procyanidins present therein. In summary, grape seed polyphenols in general, and procyanidin B5-3'-gallate in particular, should be studied in more detail to be developed as cancer chemopreventive and/or anticarcinogenic agents.
Article
The antioxidant, antimutagenic and anticarcinogenic activities of green tea and its polyphenols have been reported. As bioactivation of the precarcinogens and detoxification of ultimate carcinogens are mainly carried out by hepatic metabolizing enzymes, we have investigated the modulation of these enzyme activities subsequent to tea consumption in rats. Female Wistar rats were divided into eight groups (n = 5). Six groups were given aqueous solutions (2%, w/v) of six different teas (New Zealand green tea, Australian green tea, Java green tea, Dragon green tea, Gunpowder green tea or English Breakfast black tea) as the sole source of fluid. One group was given a standard green tea extract (0.5%, w/v) while the control group had free access to water. At the end of four-weeks treatment, different cytochrome P450 (CYP) isoform and phase II enzyme activities were determined by incubation of the liver microsomes or cytosols with appropriate substrates. CYP 1A2 activity was markedly increased in all the tea treatment groups (P < 0.05). CYP 1A1 activity was increased significantly in most of the groups except for the Madura, Gunpowder, and Java green tea-treatment groups. Cytosolic glutathione-S-transferase activity was significantly increased (P< 0.05) in the New Zealand, Gunpowder, and Java green tea-treatment groups. The microsomal UDP-glucuronosyl transferase activity remained unchanged or was moderately increased in most of the groups. The balance between the phase I carcinogen-activating enzymes and the phase II detoxifying enzymes could be important in determining the risk of developing chemically-induced cancer.
Article
Eleven serratane-type triterpenoids isolated from the stem bark of Picea jezoensis (Sieb. et Zucc.) Carr. var. jezoensis (Pinaceae) and the stem bark of Picea jezoensis (Sieb. et Zucc.) Carr. var. hondoensis (Mayer) Rehder (Pinaceae) and three synthetic analogs were studied for their possible inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA). 21-Episerratenediol, serratenediol, diepiserratenediol, 3 beta-hydroxyserrat-14-en-21-one, 3 alpha-methoxy-21 beta-hydroxyserrat-14-en-16-one, 3 beta-methoxyserrat-14-en-21 beta-yl acetate, 3 alpha-methoxyserrat-14-en-21 beta-yl acetate and 3 beta-methoxyserrat-14-en-21 alpha-yl acetate demonstrated strong inhibitory effects on the EBV-EA activation without showing any cytotoxicity, their effects being stronger than that of a representative control, oleanolic acid. Furthermore, 21-episerratenediol exhibited a remarkable inhibitory effect on skin tumor promotion in an in vivo two-stage mouse skin carcinogenesis test using 7,12-dimethylbenz[a]anthracene as an initiator and TPA as a promoter. The result of the present investigation indicated that 21-episerratenediol might be valuable as a potent cancer chemopreventive agent.
Article
Since 1922 when Wu proposed the use of the Folin phenol reagent for the measurement of proteins (l), a number of modified analytical pro- cedures ut.ilizing this reagent have been reported for the determination of proteins in serum (2-G), in antigen-antibody precipitates (7-9), and in insulin (10). Although the reagent would seem to be recommended by its great sen- sitivity and the simplicity of procedure possible with its use, it has not found great favor for general biochemical purposes. In the belief that this reagent, nevertheless, has considerable merit for certain application, but that its peculiarities and limitations need to be understood for its fullest exploitation, it has been studied with regard t.o effects of variations in pH, time of reaction, and concentration of react- ants, permissible levels of reagents commonly used in handling proteins, and interfering subst.ances. Procedures are described for measuring pro- tein in solution or after precipitation wit,h acids or other agents, and for the determination of as little as 0.2 y of protein.
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