Article

Constituents isolated from Cordyceps militaris suppress enhanced inflammatory mediator's production and human cancer cell proliferation

Authors:
  • ALPS Biotech. Co. Ltd. National Biotechnology Research Park Nangang Taipei Taiwan
  • National Taiwan University of Sport, Taichung, Taiwan
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Abstract

The purpose of this study is to isolate the pure compounds from the extracts of Cordyceps militaris obtained through solid-state cultivation process, and evaluate their anti-inflammatory and anticancer properties. Silica gel column chromatographic purification of Cordyceps militaris extracts resulted in the isolation of 10 pure compounds (1-10). The compounds 1-10 were examined for their growth inhibitory properties against nitric oxide (NO), tumor necrosis factor (TNF)-alpha and interleukin (IL)-12 enhanced production from LPS/IFN-gamma-stimulated macrophages. Additionally, the anti-proliferation effects of 1-10 on human cancer cell lines, colon (colon 205), prostate (PC-3), and hepatoma (HepG2) cells were also analyzed. Compound 8 displayed potent growth inhibition on NO, TNF-alpha and IL-12 production with an IC(50) value of 7.5, 6.3, and 7.6 microg/ml, respectively. A similar inhibitory trend on these inflammatory mediators was observed for 3, 7, 9 and 10 with an IC(50) values ranging from 10.8 to 17.2 microg/ml. On the other hand, compounds 3 and 8 were potent anti-proliferative agents with an IC(50) value of 35.6 and 32.6 microg/ml toward PC-3 and colon 205 cell lines, respectively. The compounds 1 and 2 showed potent anti-proliferation in PC-3 and colon 205 cells, while only 3 displayed such effect in HepG2 cells. The present study provides scientific supporting information for the ethnopharmacological use of Cordyceps militaris as an anti-inflammatory and anticancer agent.

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... Recently, a cultivation process for C. militaris was successfully established [4]. This mushroom has received attention as a health supplement to improve longevity, endurance, and human health and as an alternative medicine to ameliorate diseases including stroke, sore throat, tuberculosis, epilepsy, and cancer [5][6][7]. Many active compounds such as mannitol, ergosterol, polysaccharides, and cordycepin have been identified from C. militaris, and studies with these compounds showed diverse pharmacological 2 Evidence-Based Complementary and Alternative Medicine activities with antiviral, antioxidative, antidiabetic, antiinflammatory, antiplatelet aggregation, and anticancer effects [8][9][10][11][12]. ...
... A few studies on the anticancer activity of C. militaris have been reported [5][6][7]. However, the precise reasons for cancer suppression by C. militaris have not been elucidated. ...
... Cordyceps sinensis species inhibits growth of U937 leukemia, A549 lung cancer, and B16 melanoma cells [24][25][26]. Cordyceps militaris inhibits growth of HepG2 liver hepatocellular carcinoma cells [5]. Therefore, previous results indicate that Cordyceps species have potent anticancer activity against diverse cancer types including leukemia, melanoma, lung carcinoma, and liver carcinoma. ...
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Cordyceps militaris is used widely as a traditional medicine in East Asia. Although a few studies have attempted to elucidate the anticancer activities of C. militaris, the precise mechanism of C. militaris therapeutic effects is not fully understood. We examined the anticancer activities of C. militaris ethanolic extract (Cm-EE) and its cellular and molecular mechanisms. For this purpose, a xenograft mouse model bearing murine T cell lymphoma (RMA) cell-derived cancers was established to investigate in vivo anticancer mechanisms. MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay, immunoblotting analysis, and flow cytometric assay were employed to check in vitro cytotoxicity, molecular targets, and proapoptotic action of Cm-EE. Interestingly, cancer sizes and mass were reduced in a C. militaris-administered group. Levels of the phosphorylated forms of p85 and AKT were clearly decreased in the group administered with Cm-EE. This result indicated that levels of phosphoglycogen synthase kinase 3β (p-GSK3β) and cleaved caspase-3 were increased with orally administered Cm-EE. In addition, Cm-EE directly inhibited the viability of cultured RMA cells and C6 glioma cells. The number of proapoptotic cells was significantly increased in a Cm-EE treated group compared with a control group. Our results suggested that C. militaris might be able to inhibit cancer growth through regulation of p85/AKT-dependent or GSK3β-related caspase-3-dependent apoptosis.
... as cordycepin, polysaccharides, adenosine derivatives, ophicordin, and L-tryptophan. Polysaccharides of C. militaris (CPS) are one of the major bioactive components which possess antioxidant [18,19], immunomodulatory [12,16], antitumor [20,21], and anti-inflammatory [21] activities. ...
... as cordycepin, polysaccharides, adenosine derivatives, ophicordin, and L-tryptophan. Polysaccharides of C. militaris (CPS) are one of the major bioactive components which possess antioxidant [18,19], immunomodulatory [12,16], antitumor [20,21], and anti-inflammatory [21] activities. ...
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Polysaccharides are an important class of bioactive components of medical mushroom and herbs and are now used as natural drugs or dietary supplements on a global scale. In this paper, we aimed to increase the polysaccharide production of Cordyceps militaris and the antioxidant activities of fermented rice by solid-state fermentation. The media components and culture condition were optimized by orthogonal design and mono-factor tests using rice as the raw material. The optimal media consisted of (g/L): rice (50), fructose (7), glycerin (7), peptone (1), MgCl2 (0.11), VB1 (0.05), VB2 (0.05), CaCl2 (1.5), corn bran (6), and a water–materials ratio of 100%. The fermentation condition was as follows: inoculum volume of 5.5% (v/w), rice weight of 50 g in one bowl with a diameter of 120 mm and a depth of 90 mm, incubation temperature of 26 °C, and incubation time of seven days. Under the optimized condition, the maximal C. militaris polysaccharide content and free radical scavenging ratio were 68.3 mg/g dry substrate and 98.9%, respectively. This study provides a new strategy for the production of healthy food from traditional food.
... The functional components found in C. militaris include polysaccharides, cordycepin, cordycepic acid, superoxide dismutase (SOD) and fibrinolytic enzyme (CMase) [2,3]. A number of reports have indicated that C. militaris fruit body possessed antitumor, antivirus, antifungal, antiphlogosis, antiarrhythmic, immunomodulatory, blood pressure reduction, and fibrinolytic activities [4][5][6][7]. Because of its attractive beneficial effects and rarity in nature, C. militaris is considered as one of the most expensive mushrooms in China. ...
... Because of its attractive beneficial effects and rarity in nature, C. militaris is considered as one of the most expensive mushrooms in China. In order to obtain sufficient quantities of the fruiting bodies for commercial applications, efforts have been made to develop cultivation techniques, including solid state fermentation for the formation of fruit body of C. militaris, or submerged culture for harvesting mycelium, which both can be utilized as ingredients in functional foods and supplements [5,7,8]. Soybean curd residue (SCR) is the byproduct produced by tofu and soymilk factories in East Asia. ...
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Cordyceps militaris is an edible and medicinal fungus that has been traditionally used as a crude drug for treatment of human disease. Meanwhile, the functional nutrient substances in C. militaris possess various physiological activities. In addition, re-utilizing the soybean curd residue as solid medium for producing edible and medicinal fungus is an efficient and commercial method to dispose of the soybean curd residue waste materials. In this study, soybean curd residue was utilized as solid medium raw material for fermentation by C. militaris mycelium. The crude polysaccharide (CSCPS) from fermented soybean curd residue and C. militaris mycelium mixture showed potent bioactivities, including antioxidant, antitumor and immunomodulatory activities. Based on five antioxidant assays, the CSCPS showed powerful antioxidant capacities at OH•, DPPH and ABTS radical scavenging assays. The CSCPS significantly activated the proliferation of RAW 264.7, and protected it from DOX-induced and LPS-stimulated cell damage. Furthermore, the CSCPS inhibited the proliferation of HT1080, Hela, A549, U-2 OS and MDA-MB-231 cells.
... Regarding its exploitation in the pharmaceutical sector, BSG has been used as a culture medium for Cordyceps militaris (Gregori 2014) to produce cordycepin, a nucleoside analog with anti-tumor, anti-proliferative, anti-metastatic, insecticidal, and antibacterial activities (Gregori 2014). In addition, polysaccharides from C. militaris have shown significant antitumor activities against cervical and liver cancer cells in vitro (Yan et al. 2014), and extracts of its fruiting bodies show antioxidant, antibacterial, antifungal, and anti-tumor activities against human cell lines (Yan et al. 2014;Reis et al. 2013;Rao et al. 2010), and also anti-inflammatory (Rao et al. 2010), anti-fibrotic (Nan et al. 2001), anti-obesity , and anti-angiogenetic (Yoo et al. 2004) and insulinsecreting (Choi et al. 2004) activities. Thus, the use of BSG for cordycepin production by C. militaris has been shown to be a very effective technique for the production of high-value food and feed additives (Gregori 2014). ...
... Regarding its exploitation in the pharmaceutical sector, BSG has been used as a culture medium for Cordyceps militaris (Gregori 2014) to produce cordycepin, a nucleoside analog with anti-tumor, anti-proliferative, anti-metastatic, insecticidal, and antibacterial activities (Gregori 2014). In addition, polysaccharides from C. militaris have shown significant antitumor activities against cervical and liver cancer cells in vitro (Yan et al. 2014), and extracts of its fruiting bodies show antioxidant, antibacterial, antifungal, and anti-tumor activities against human cell lines (Yan et al. 2014;Reis et al. 2013;Rao et al. 2010), and also anti-inflammatory (Rao et al. 2010), anti-fibrotic (Nan et al. 2001), anti-obesity , and anti-angiogenetic (Yoo et al. 2004) and insulinsecreting (Choi et al. 2004) activities. Thus, the use of BSG for cordycepin production by C. militaris has been shown to be a very effective technique for the production of high-value food and feed additives (Gregori 2014). ...
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Brewers’ spent grain (BSG) is the most abundant by-product of brewing. Due to its microbiological instability and high perishability, fresh BSG is currently disposed of as low-cost cattle feed. However, BSG is an appealing source of nutrients to obtain products with high added value through microbial-based transformation. As such, BSG could become a potential source of income for the brewery itself. While recent studies have covered the relevance of BSG chemical composition in detail, this review aims to underline the importance of microorganisms from the stabilization/contamination of fresh BSG to its biotechnological exploitation. Indeed, the evaluation of BSG-associated microorganisms, which include yeast, fungi, and bacteria, can allow their safe use and the best methods for their exploitation. This bibliographical examination is particularly focused on the role of microorganisms in BSG exploitation to (1) produce enzymes and metabolites of industrial interest, (2) supplement human and animal diets, and (3) improve soil fertility. Emerging safety issues in the use of BSG as a food and feed additive is also considered, particularly considering the presence of mycotoxins. Key points • Microorganisms are used to enhance brewers’ spent grain nutritional value. • Knowledge of brewers’ spent grain microbiota allows the reduction of health risks. Graphical abstract
... In ( Rao et al., 2010 ) Tuber magnatum (Phenols) in vitro COX-1 & 12-LOX ( Beara et al., 2014 ) Cordyceps sinensis (Peptide) Brain Ischaemia TNF-& IL-1 Qian et al., 2012 ) Honey Brown (both Agaricus bisporus ), Enoki ( Flammulina velutipes ), Shiitake ( Lentinus edodes ), and Oyster mushroom ( Pleurotus ostreatus ) preparations were evaluated for their anti-inflammatory properties in IFNand LPS-activated murine RAW264.7 macrophages. All mushroom extracts exhibited potent inhibition of NO production, Oyster, Shiitake and Enoki mushrooms also exhibited potent inhibition of TNF-secretion ( Gunawardena et al., 2014 ). ...
... In LPS-induced murine RAW264.7 macrophages, Erinarols H and J, and 2 of the ergostane-type sterols showed inhibitory activity against TNF-expression while three ergostane-type sterols and Erinarols J exhibited significant inhibitory effects against NO production ( Li et al., 2015 ). Similarly, ergosterol isolated from the extracts of Cordyceps militaris exhibited strong inhibition on NO, TNF-, and IL-12 production in vitro ( Rao et al., 2010 ). ...
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Background : Mushrooms include a wide variety of bioactive compounds that have been linked to therapeutic and nutritional benefits, making them a potential source of new medications and functional foods. Objective : This study reviewed the inhibitory effects of mushrooms on the inflammation process through the modulation of the pro-inflammatory mediators and associated signaling pathways. Methods : A literature search in PubMed and Google Scholar was conducted for the relevant original research and review articles on the anti-inflammatory effects of mushrooms. Related articles published in English were selected, studied and discussed. Results : As revealed by the selected articles, bioactive molecules which include peptides, polysaccharides, terpenes, sterols, fatty acids, and phenols have been extracted from the powder, concentrate, and different solvent extracts of edible mushrooms. These bioactive molecules have shown significant efficacy in inhibiting the major pro-inflammatory biomarkers and associated pathways in in vivo and in vitro settings. Conclusion : This review demonstrated that mushrooms significantly inhibit the production of pro-inflammatory mediators and can be developed for clinical use as anti-inflammatory agents. Further research is required to establish the comparative efficacy between mushrooms and NSAID especially in the in-vivo inhibitory activity against the production of cyclooxygenase and pro-inflammatory cytokines.
... Another study reported the antiproliferative potential of a polysaccharide from C. militarism against adenocarcinomic human alveolar basal epithelial cells (A549) cells, with an IC 50 of 39.08 µg/mL [38]. Additionally, the report confirm the inhibitory effects of C. militaris polysaccharides on colon 205, NCI-H460, PC-3 cell lines [40,41]. These components also inhibited tumor in animal model [42]. ...
... The pharmaceutical substance that adverts these pathways can reduce inflammatory processes in living beings. Various reports have shown that C. militaris reduces NF-κB-regulated inflammation and related responses in a variety of experiments [40,120,136,148,151]. Various inflammatory genes, such as COX-2 IL-8, IL-6, and TNF-α, are activated by the NF-κB transcription factor, which is susceptible to oxidative stress. ...
Article
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Cordyceps militaris (C. militaris) is a medicinal mushroom possessing a variety of biofunctionalities. It has several biologically important components such as polysaccharides and others. The diverse pharmacological potential of C. militaris has generated interest in reviewing the current scientific literature, with a particular focus on prevention and associated molecular mechanisms in inflammatory diseases. Due to rising global demand, research on C. militaris has continued to increase in recent years. C. militaris has shown the potential for inhibiting inflammation-related events, both in in vivo and in vitro experiments. Inflammation is a multifaceted biological process that contributes to the development and severity of diseases, including cancer, colitis, and allergies. These functions make C. militaris a suitable functional food for inhibiting inflammatory responses such as the regulation of proinflammatory cytokines. Therefore, on the basis of existing information, the current study provides insights towards the understanding of anti-inflammatory activity-related mechanisms. This article presents a foundation for clinical use, and analyzes the roadmap for future studies concerning the medical use of C. militaris and its constituents in the next generation of anti-inflammatory drugs.
... An entomopathogenic species, Cordyceps militaris (L.:Fr.) Link (Clavicipitaceae, Ascomycetes) is one of the traditional Chinese medicinal mushrooms, It has been reported that the extract of C. militaris fruiting bodies showed angiogenesis ( Yoo et al., 2004), anti-inflammatory ( Won and Park, 2005;Rao et al., 2010), antiasthma ( Hsu et al., 2008), anti-tumor ( Rao et al., 2010) and antidiabetic ( Cheng et al., 2012). C. militaris contain some noticeable bioactive compounds such as cordycepin (3'-deoxyadenosine), mannitol, and adenosine. ...
... An entomopathogenic species, Cordyceps militaris (L.:Fr.) Link (Clavicipitaceae, Ascomycetes) is one of the traditional Chinese medicinal mushrooms, It has been reported that the extract of C. militaris fruiting bodies showed angiogenesis ( Yoo et al., 2004), anti-inflammatory ( Won and Park, 2005;Rao et al., 2010), antiasthma ( Hsu et al., 2008), anti-tumor ( Rao et al., 2010) and antidiabetic ( Cheng et al., 2012). C. militaris contain some noticeable bioactive compounds such as cordycepin (3'-deoxyadenosine), mannitol, and adenosine. ...
... Cordycepin and ergosterol isolated from C. militaris have shown antiproliferative activity against human colon cancer cells. Proliferative activity was associated with antiinflammatory activity [85]. ...
... It was proven through in vitro experiment that cordycepin and ergosterol from C. militaris inhibit the release of inflammatory mediators: NO, TNF-α and IL-12, which correlates with antiproliferative activity in colon tumor cells [85]. ...
Article
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Cordyceps spp. mushrooms have a long tradition of use as a natural raw material in Asian ethnomedicine because of their adaptogenic, tonic effects and their ability to reduce fatigue and stimulate the immune system in humans. This review aims to present the chemical composition and medicinal properties of Cordyceps militaris fruiting bodies and mycelium, as well as mycelium from in vitro cultures. The analytical results of the composition of C. militaris grown in culture media show the bioactive components such as cordycepin, polysaccharides, -aminobutyric acid (GABA), ergothioneine and others described in the review. To summarize, based on the presence of several bioactive compounds that contribute to biological activity, C. militaris mushrooms definitely deserve to be considered as functional foods and also have great potential for medicinal use. Recent scientific reports indicate the potential of cordycepin in antiviral activity, particularly against COVID-19.
... The anticancer effects of C. militaris have been reported in very few research studies. The exact anti-cancer mechanism of C. militaris was not clear and established [23][24][25]. In our research, the synthesized gold nanoparticles with C. militaris were used to study the appropriate mechanisms that induce the apoptosis in the HCC (HepG2) cells. ...
... Cordyceps sinensis species halt the growth of leukaemia, melanoma, and lung cancer cells [26][27][28]. Rao et al. [23] proved that the C. militaris halt the exponential growth of HepG2 liver HCC cells. ...
Article
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Hepatocellular carcinoma is the most common liver cancer among different types of cancers. Cordyceps Militaris mushroom species traditionally used as an alternative medicine in china for centuries. Gold nanoparticles plays vital role in the development of the anticancer drugs. In our research, we investigated the gold nanoparticles with C. Militaris on the hepatocellular carcinoma HepG2 cells. The synthesized gold nanoparticles stability and integrity was studied at different time intervals. The gold nanoparticles potentially halt the growth of the HepG2 cells at the IC50 concentration between 10 μg and 12.5 μg/ml. The HR-TEM and XRD revealed the size and shape of the synthesized gold nanoparticles. The size of the gold nanoparticles was about 15 20 nm and the shape of gold nanoparticles was face-center-cubic structure. The FT-IR results proved that the gold nanoparticles contain hydroxyl and alkynes groups. The gold nanoparticles extract develops ROS and cause damage to the mitochondrial membrane potential in the hepatocellular carcinoma HepG2 cells. The gold nanoparticles extract tends to initiate the apoptosis by activating the Bax, Bid, caspases and inhibits the activation anti-apoptotic bcl-2 in the HepG2 cells. Our results concluded that the gold nanoparticles with C. Militaris would be an efficient chemotherapeutic drug against the hepatocellular carcinoma cells.
... This mushroom has a long history of applications against inflammatory processes in cases of cancer-related complications [35]. The study by Rao et al. (2010) provided scientific supporting information for the ethnopharmacological use of Cordyceps militaris in Taiwan as an anti-inflammatory and anti-cancer agent [36]. Coetzee and Wyk (2009) reported the ethnomycological potential of Calvatia species, namely C. cyathiformis, C. craniiformis, C. excipuliformis, C. Gigantean, and C. utriformis in the treatment of breast cancer [37]. ...
... This mushroom has a long history of applications against inflammatory processes in cases of cancer-related complications [35]. The study by Rao et al. (2010) provided scientific supporting information for the ethnopharmacological use of Cordyceps militaris in Taiwan as an anti-inflammatory and anti-cancer agent [36]. Coetzee and Wyk (2009) reported the ethnomycological potential of Calvatia species, namely C. cyathiformis, C. craniiformis, C. excipuliformis, C. Gigantean, and C. utriformis in the treatment of breast cancer [37]. ...
Article
Background: Nowadays medicines derived from natural sources have drawn much attention as potential therapeutic agents in the suppression and treatment of cancer because of their low toxicity and fewer side effects. Objective: The present review aims to assess the currently available knowledge on the ethnomedicinal uses and pharmacological activities of bioactive compounds obtained from medicinal mushrooms towards cancer treatment. Methods: Literature search has been conducted for the collection of research papers from universally accepted scientific databases. These research papers and published book chapters were scrutinized to retrieve information on ethnomedicinal uses of mushrooms, different factors involved in cancer cell proliferation, clinical and in silico pharmaceutical studies made for possible treatments of cancer using mushroom derived compounds. Overall 241 articles were retrieved and reviewed from the year of 1970 to 2020, out of which 98 relevant articles were finally considered for preparation of this review. Results: This review presents an update on the natural bioactive substances derived from medicinal mushrooms and their role in inhibiting the factors responsible for cancer cell proliferation. Along with it, the present review also provides information on the ethnomedicinal uses, solvents used for extraction of anticancer metabolites, clinical trials, and in silico studies that were undertaken towards anticancer drug development from medicinal mushrooms. Conclusion: The present review provides an extensive knowledge on various anticancer substances obtained from medicinal mushrooms, their biological actions and in silico drug designing approaches which could form a basis for the development of natural anticancer therapeutics.
... It was shown that basidiocarp extracts of various G. lucidum strains are significantly efficient in the inhibition of human papillomavirus 16 and in such a way in the prevention of cervix cancer appearance, than in the inhibition of colon, cervix, and lung adenocarcinoma cell line growth, in the reduction of viability of the stomach carcinoma cells, as well as in the combat against prostate cancer Sadava et al. 2009;Ćilerdžić et al. 2014;Milovanović et al. 2015b). Strong antiproliferative effect on colon adenocarcinoma cells was also caused by G. applanatum and G. tsugae fruiting body and mycelium extracts Milovanović et al. 2015b), as well as by Hericium erinaceus, Cordyceps militaris, Clitocybe alexandri, and Inonotus obliquus fruiting bodies as well as Lenzites betulinus and Funalia trogii mycelia extracts (Hu et al. 2009;Rao et al. 2010;Vaz et al. 2010;Kim et al. 2011;Rashid et al. 2011;Milovanović et al. 2015c). I. obliquus extracts are also effective against melanoma; C. sinensis against hepatoma; C. alexandri against lung, breast, and stomach cancers; and F. trogii against prostate and breast cancers (Youn et al. 2009;Vaz et al. 2010;Rashid et al. 2011;Wang et al. 2016). ...
... Besides these effects, Ph. linteus extracts are also very efficient in the inhibition of proliferation of liver, breast, bladder, stomach, and lung cancer cells, in the reduction of tumor size, and in the Chu et al. (2002), and Milovanović et al. (2015c) prevention of metastases (Sliva 2010). Inhibition of hepatoma and breast cancer can be also caused by Cordyceps militaris, Coprinus comatus, and Antrodia camphorata (Chang et al. 2008;Rao et al. 2010;Asatiani et al. 2011;Yang et al. 2011). ...
Chapter
Cancer is the second cause of morbidity and mortality worldwide, i.e., half of the men and more than a third of women of the world population get sick with some type of cancer during a lifetime, and one-quarter of all adults die of this disease. Common treatments, chemo- and radiotherapy, are not highly effective, give satisfactory results only in the treatment of early cancer development stages or have no any effect on some cancer types, and commonly cause numerous side effects. Therefore, alternative medicine based on various natural sources attracts great attention nowadays. Although mushrooms, their extracts, and isolated metabolites cannot be considered drugs, they are a type of important dietary supplement, i.e., functional food or nutraceuticals, and could be used as auxiliary natural cytostatics. They are highly selective, i.e., not toxic or almost nontoxic to normal cells, do not cause any side effects, and even reduce harmful effects caused by conventional treatments, and finally, resistance to them cannot be developed. Mushroom extracts or biologically active compounds isolated from them affect cytotoxic activity on a few mechanisms: stimulation of immune system; antioxidative, antimutagenic, and anti-inflammatory activity; regulation of expression of regulators of some cell processes; cell cycle arrest and apoptosis; disturbance of DNA synthesis and structure; changes in morphology and mobility of malignant cells; and antiangiogenic activity.
... Considering the relationship between the structure and cytotoxic activity of pentacyclic triterpenoids, it is seen that C3 hydroxyl group, C17 carboxyl group, and Δ 12,13 double bonds may be important active groups for bioactivity of pentacyclic triterpenoids, and hydroxyl groups in C2 or C23 may decrease bioactivity (Gao, He, Bi, Wu, & Altman, 2016). Previously, cytotoxicity against MCF-7 of Compounds 2 (IC 50 : 57.5 ± 2.0 µg/ml), 3 (IC 50 : of Compound 3 (IC 50 : 90.9 ± 3.2 µg/ml), 4 (IC 50 : 45.2 ± 2.5 µg/ml) and 7 (14.7 ± 8.5% growth inhibition at 20 µM) were studied (Ekon et al., 2015;Mo et al., 2004;Nguyen et al., 2005;Rao, Fang, Wu, & Tzeng, 2010;Torres et al., 2017;Vinh et al., 2017;Wei, Ma, Liu, Huang, & Liao, 2018;Xu et al., 2011;Zhao et al., 2016). This is the first report about cytotoxic activity against MCF-7 of Compounds 1, 5, 6, 7, 9 and cytotoxic activity against PC-3 of Compounds 1, 2, 10. ...
Article
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Chromatographic purification of Fuscoporia torulosa extracts resulted in the isolation and characterization of a new steroid, 5α,8α‐epidioxyergosta‐6,22‐dien‐3β‐il‐palmitate (1) and 10 known compounds (2–11). The structures of compounds were elucidated by IR, NMR, MS analyses, and comparison with literature data. Cytotoxic activities against MCF‐7 (breast cancer), PC‐3 (prostate cancer), and 3T3 (nontumor) of the extracts and cytotoxic, antioxidant, cholinesterase, and tyrosinase inhibitory activities of all isolated compounds were evaluated. The methanol extract and Compound 8 showed the best cytotoxicity against MCF‐7, whereas the hexane extract and Compound 4 displayed the highest cytotoxicity against PC‐3. Compounds 10 and 11 displayed higher antioxidant activity than α‐tocopherol and butylated hydroxyanisole (BHA) which are used as standards in ABTS•+, DPPH•, and cupric reducing antioxidant capacity (CUPRAC) assays. Also, cholinesterase inhibitory activity against acetylcholinesterase (AChE) and butrylcholinesterase (BChE), Compounds 4 and 8 were determined as the most active compounds. Among all isolated compounds, Compound 11 exhibited the highest tyrosinase inhibitory activity. Practical applications Mushrooms have various important medicinal properties. A detailed study was made to identify the bioactive constituents of Fuscoporia torulosa mushroom and a new (1) and 10 known compounds (2–11) were isolated. Compounds 10 and 11 showed higher antioxidant activity than standards. The methanol extract and Compound 8 exhibited high cytotoxic activity against MCF‐7. Compound 8 indicated potent BChE inhibitory activity. This study suggests that natural compounds isolated from F. torulosa mushroom could be used as promising anticancer, antioxidant, and anticholinesterase agents.
... 4 In vivo and in vitro evidence has shown that mushrooms have the potential to prevent several kinds of cancers (e.g., those of the breast, bladder, colon and lung), including prostate cancer. Extracts of mushrooms such as Agaricus blazei Murill, 5 Agaricus bisporus, 6 Trametes versicolor, 7 Cordyceps militaris 8 and Coprinus comatus 9 were suggested to inhibit cell proliferation in human prostate cancer cell lines and to restrict prostate tumorigenic progression from the hormone-dependent to the hormonerefractory state. ...
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In vivo and in vitro evidence has shown that mushrooms have the potential to prevent prostate cancer. However, the relationship between mushroom consumption and incident prostate cancer in humans has never been investigated. In the present study, a total of 36,499 men, aged 40-79 years, who participated in the Miyagi Cohort Study in 1990 and in the Ohsaki Cohort Study in 1994 were followed for a median of 13.2 years. Data on mushroom consumption (categorized as <1, 1-2 and ≥3 times/week) was collected using a validated food frequency questionnaire. Cox proportional hazards regression analysis was used to estimate multivariate hazard ratios (HRs) and 95% confidence intervals (CIs) for prostate cancer incidence. During 574,397 person-years of follow-up, 1,204 (3.3%) cases of prostate cancer were identified. Compared to participants with mushroom consumption <1 time/week, frequent mushroom intake was associated with a decreased risk of prostate cancer (1-2 times/week: HRs [95% CIs] = 0.92 [0.81, 1.05]; ≥3 times/week: HRs [95% CIs] = 0.83 [0.70, 0.98]; p-trend = 0.023). This inverse relationship was especially obvious among participants aged ≥50 years and did not differ by clinical stage of cancer and intake of vegetables, fruit, meat and dairy products. The present study showed an inverse relationship between mushroom consumption and incident prostate cancer among middle-aged and elderly Japanese men, suggesting that habitual mushroom intake might help to prevent prostate cancer.
... This will be discussed later. Examples include evaporation and cold precipitation followed by Dowex-I-chloride column filtering [Kredich & Guarino 1960]; hydrothermal reflux [Wang et al. 2004]; butanol, hexane, and ethyl acetate solvent extractions from dried stroma [Kim et al. 2006;Rao et al. 2010]; ionexchange resin/silica gel chromatography [Jiansheng 2008]; water, ethanol, and ultrasonic extraction methods [Zhang et al. 2012]; and microwave-assisted extraction [Chen et al. 2012;Tuli et al. 2017]. ...
Article
Cordyceps militaris is a widespread entomopathogenic fungus found in Europe, Asia, and North America, with a large number of insect hosts, predominantly lepidopteran larvae (caterpillars). This species is well known for its production of the nucleoside analogue cordycepin (3’-deoxyadenosine). Co-produced with its protector molecule pentostatin, cordycepin is a polyadenylation inhibitor, via its active modified form as cordycepin triphosphate. Pentostatin protects cordycepin from degradation to 3’-deoxyinosine by inhibition of the enzyme adenosine deaminase. It has been shown to have anti-inflammatory effects and hence has been the subject of much pharmacological research. Until recently, very little was known about the role of cordycepin in the ecology of the fungus, or why its production is favoured by natural selection. There are also gaps in the understanding of the process of infection of the host by the fungus, which is directly followed by sexual development and the formation of stromata bearing sexual fruiting bodies and spores (ascospores). Understanding these areas could have implications for biological control of insect pests. Indeed, the related species Beauveria bassiana and Metarhizium anisopliae have been used as bioinsecticides, precluding the use of harmful chemical insecticides. Culture degeneration is a phenomenon defined previously as a reduction in the production of cordycepin by C. militaris. Experiments comparing a degenerated strain of an isolate of C. militaris with its parental control strain were performed, involving the use of gene expression analysis and metabolomics. Reduced cordycepin production in the degenerated strain was shown to be accompanied by declines in sexual development-related gene expression, and reduced production of other metabolites involved in the citrate cycle and purine metabolism. This suggested a link between cordycepin production, primary metabolism, and sexual development. We hypothesised that the production of cordycepin by C. militaris aids the infection of the insect by suppression of the host immune system, and that pentostatin, by providing molecular protection, enhances this effect. In a caterpillar infection assay system involving the injection of spores into the model species Galleria mellonella (greater wax moth) caterpillars, the lower cordycepin-producing degenerated strain was shown to produce a significantly-decreased pathogenic response, marked by reduced fungal growth in the host. When spores of the degenerated strain were supplemented by cordycepin and pentostatin, fungal emergence rates and levels significantly increased, restoring the infection performance of the degenerated strain to that of the parental control. Assays of insect gene expression were also performed, and cordycepin was demonstrated to suppress the upregulation of immune response genes in both Drosophila melanogaster Schneider 2 cells and G. mellonella haemolymph cells. Pentostatin enhanced the effects of low cordycepin concentrations in both models. These findings support the hypothesis that cordycepin has an important role in aiding insect infection by the fungus via immune suppression, and that the effect of cordycepin on host cell responses is maintained by pentostatin. Biosynthesis genes (Cns genes) for cordycepin and pentostatin are located in the same gene cluster. We hypothesised that cordycepin-pentostatin co-production was a rare trait, and its evolution had been resultant partly due to horizontal gene transfer between different species. This was due to the lack of cordycepin in other Cordyceps species, and genetic evidence of its production only found previously in two other, distantly-related species. Bioinformatics work involving tBLASTn searches through the sequenced genomes of over two and a half thousand fungal species uncovered evidence of homologous Cns gene clusters in five new species. This together with consideration of protein structures suggests that the development of cordycepin-pentostatin co-production has occurred by convergent evolution involving duplication and subfunctionalisation of genes involved in the purine synthesis pathway, and/or through horizontal gene transfer.
... CM has been suggested as an efficacious medicine for eternal youth for its protective effects on mitochondria, testosterone stimulation, and aging [17,18]. CM is known to possess anti-oxidant, anti-inflammatory, and anti-cancer activities [19][20][21][22]. Among the components of CM, adenosine and cordycepin have been found to play important roles in modulating hepatosteatosis and atherosclerosis [23][24][25]. ...
Article
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Nonalcoholic fatty liver diseases (NAFLD) is characterized by accumulation of lipid droplets in the liver. The objective of this study was to evaluate protective effects of fermented Cordyceps militaris extract by Pediococcus pentosaceus ON188 (ONE) against hepatosteatosis and obesity in mice fed a high-fat diet (HFD). Eight-week-old male C57BL/6J mice were fed HFD mixed with ONE for four weeks and its effects on hepatosteatosis and obesity were examined. Although ONE did not change food intake, it reduced body weights of mice at administration dose of 200 mg/kg/day. Activities of lactate dehydrogenase (LDH), aspartate transaminase (AST), and alanine transaminase (ALT) as plasma parameters were reduced by ONE in a dose-dependent manner. Hepatic lipid droplets and triglyceride (TG) levels were also reduced by ONE due to upregulation of fatty acid oxidizing genes such as carnithine palmitoyltransferase (CPT1) and peroxisomal proliferator activated receptor α(PPARα) mediated by induction of sphingosine kinase 2 (SPHK2). In epididymal fat tissue, sizes of adipocytes were significantly reduced by ONE in a dose-dependent manner. This is mainly due to suppression of lipogenesis and upregulation of adipocyte browning genes. Collectively, these results suggest that fermented ONE can activate fatty acid oxidation via SPHK2 in the liver. It can also suppress lipogenesis and activate browning in adipose tissue. Thus, ONE might have potential to be used for the development of functional foods against liver dysfunction and obesity.
... Although a variety of bioactive components, such as cordycepic acid, cordycepin, adenine, adenosine, etc., have been reported, the polysaccharides are usually regarded as one of the most abundant bioactive substances, with the highest content in C. militaris [3,4]. Modern research has shown that polysaccharides from C. militaris possess multiple biological properties, such as antioxidant [5][6][7], antitumor [8,9], immunoregulatory [10][11][12], anti-hyperlipidemic [13], anti-inflammatory activities [14], etc. ...
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The effects of different extraction temperatures (4 and 80 °C) on the physicochemical properties and antitumor activity of water soluble polysaccharides (CMPs-4 and CMPs-80) from Cordyceps militaris (C. militaris) were evaluated in this study. The results of gas chromatography (GC) and high-performance gel permeation chromatography (HPGPC) showed that a higher extraction temperature could degrade the polysaccharides with 188 kDa, mainly composed of glucose, and increase the dissolution rate of polysaccharides about 308 kDa, mainly consisting of rhamnose and galactose. In addition, the CMPs displayed the same sugar ring and category of glycosidic linkage based on Fourier-transform infrared spectroscopy (FTIR) analysis, however, their invisible structural difference occurred in the specific rotation and conformational characteristics according to the results of specific optical rotation measurement and Congo red test. In vitro antitumor experiments indicated that CMPs-4 possessed stronger inhibitory effects on human esophagus cancer Eca-109 cells by inducing cell apoptosis more than CMPs-80 did. These findings demonstrated that the polysaccharides extracted with cold water (4 °C) could be applied as a novel alternative chemotherapeutic agent or dietary supplement with its underlying antitumor property.
... Both in vivo and in vitro experiments have demonstrated the anti-proliferative and apoptotic activities of C. militaris extract (CME) against human tumor cell lines. CME was demonstrated antitumor effects mainly through other various researched that suggested the induction of cell death and apoptosis, inhibition of angiogenesis, and suppression of invasion and metastasis by CME in human cancer cells [12][13][14][15]. Cordyceps militaris has recently received considerable attention as a potential source of anticancer drugs [16]. ...
Article
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Background: Cordyceps militaris (L.) Fr. (C. militaris) exhibits pharmacological activities, including antitumor properties, through the regulation of the nuclear factor kappa B (NF-κB) signaling. Tumor Necrosis Factor (TNF) and TNF-α modulates cell survival and apoptosis through NF- κB signaling. However, the mechanism underlying its mode of action on the NF-κB pathway is unclear. Methods: Here, we analyzed the effect of C. militaris extract (CME) on the proliferation of ovarian cancer cells by confirming viability, morphological changes, migration assay. Additionally, CME induced apoptosis was determined by apoptosis assay and apoptotic body formation under TEM. The mechanisms of CME were determined through microarray, immunoblotting and immunocytochemistry. Results: CME reduced the viability of cells in a dose-dependent manner and induced morphological changes. We confirmed the decrease in the migration activity of SKOV-3 cells after treatment with CME and the consequent induction of apoptosis. Immunoblotting results showed that the CME-mediated upregulation of tumor necrosis factor receptor 1 (TNFR1) expression induced apoptosis of SKOV-3 cells via the serial activation of caspases. Moreover, CME negatively modulated NF-κB activation via TNFR expression, suggestive of the activation of the extrinsic apoptotic pathway. The binding of TNF-α to TNFR results in the disassociation of IκB from NF-κB and the subsequent translocation of the active NF-κB to the nucleus. CME clearly suppressed NF-κB translocation induced by interleukin (IL-1β) from the cytosol into the nucleus. The decrease in the expression levels of B cell lymphoma (Bcl)-xL and Bcl-2 led to a marked increase in cell apoptosis. Conclusion: These results suggest that C. militaris inhibited ovarian cancer cell proliferation, survival, and migration, possibly through the coordination between TNF-α/TNFR1 signaling and NF-κB activation. Taken together, our findings provide a new insight into a novel treatment strategy for ovarian cancer using C. militaris.
... Only a few pertinent chemical investigations have been reported on the active components of C. militaris, including polysaccharides, amino acids, proteins and sterols (Chen et al. 2013;Fan & Lin 2013;Jiang et al. 2015;Hu et al. 2016). Pharmacological studies also confirmed that C. militaris possesses immune-modulatory, anti-tumour, anti-inflammatory, anti-oxidation and anti-bacterial activities (Yoo et al. 2004;Won & Park 2005;Rao et al. 2010;Wang, Wu et al. 2016). ...
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One new ribonucleotide, 5′-(3′′-deoxy-β-D-ribofuranosyl)-3′-deoxyadenosine (1), and 14 known compounds (2–15) were isolated from an ethanol extract of Cordyceps militaris. The chemical structures of these compounds were determined from 1D and 2D NMR (¹H-¹H COSY, HMBC, HMQC and NOESY) and HR-ESI-MS spectra, and results were compared with data from the literature. The effects of all isolated compounds were measured on NF-κB activation, with compound 2 exhibiting significant inhibitory activity against TNF-α-induced NF-κB reporter gene expression in HeLa cells from 3 to 100 μM.
... Furthermore, cordycepin has been shown to increase the expression of the interleukin-10 protein in human peripheral blood mononuclear cells, which is known to inhibit the secretion of proinflammatory and inflammatory cytokines (Moore et al., 1993;Armstrong et al., 1996;Cunha et al., 1992;Mertz et al., 1994;Dokka et al., 2001;Zhou et al., 2002). Rao et al. (2010) demonstrated that cordycepin is a potent inhibitor of free radical NO and cytokine (TNF-and IL-12) production. The study suggested that cordycepin might be useful for the prevention of cancer by acting as an anti-inflammatory agent. ...
Chapter
For thousands of years, natural products from medicinal mushroom are being used for the cure of different lethal diseases. Among the huge category of medicinal herbs, the genus Cordyceps is gaining special attention due to its broad spectrum of biological activity. Cordycepin, a nucleoside analogue, is the main bioactive ingredient of Cordyceps and known to mediate a variety of pharmacological effects. Many chemically modified cordycepin derivatives have been reported which have shown more potential therapeutic effects. With the advancement in fermentation techniques, it has been possible to produce the higher cordycepin product. The modern techniques enabled the researchers for an easy detection and extraction of cordycepin from fermentation medium. Being a nucleoside analogue, cordycepin can interfere with the DNA/RNA biosynthesis and acts as a potential candidate for the treatment of the dreadful diseases such as cancer. Besides, cordycepin have also been known to modulate a variety of signaling pathways involved in apoptosis, proliferation, metastasis, angiogenesis, and inflammation. This chapter will describe the chemistry, production, detection, and extraction strategies of cordycepin. In addition, variety of therapeutic applications of cordycepin with all possible molecular mechanisms of actions have also been summarized.
... The results of these investigations are summarized in and essential oils. In one report, authors demonstrated the isolation of ten pure compounds from C. militaris along with the evaluation of their biological activities by determining their effect on free radical NO and cytokines (TNF-α and IL-12) production [39]. Among the isolated compounds cordycepin, ergosterol, 3,4-O-isopropylidene-D-mannitol, D-mannitol and ergosterol peroxide showed the most potent activity through inhibiting inflammatory mediators production and human cancer cell proliferation. ...
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Cordyceps is treasured entomopathogenic fungi that have been used as antitumor, immunomodulating, antioxidant, and pro-sexual agent. Cordyceps, also called DongChongXiaCao in Chinese, Yartsa Gunbu (Tibetan), means winter worm-summer grass. Natural Cordyceps sinensis with parasitic hosts is difficult to be collected and the recent findings on its potential pharmacological functions, resulted in skyrocketing prices. Therefore, finding a mass-production method or an alternative for C. sinensis products is a top-priority task. In this review, we describe current status of Cordyceps research and its recent developments in Taiwan. The content and pharmacological activities of four major industrial species of Cordyceps (C. sinensis, C. militaris, C. cicadae and C. sobolifera) used in Taiwan, were reviewed. Moreover, we highlighted the effect of using different methods of fermentation and production on the morphology and chemical content of Cordyceps sp. Finally, we summarized the bottle-necks and challenges facing Cordyceps research as well as we proposed future road map for Cordyceps industry in Taiwan.
... The inhibitory activities of CM on MCF-7 and HepG2 cell growth have been reported in previous studies (28)(29)(30)(31); however, their associated mechanisms remain to be elucidated. The present study investigated the potential antitumor effects of CM on MCF-7 and HepG2 cells, and examined the possible underlying mechanisms. ...
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Cordyceps militaris (CM), an entomopathogenic fungus belonging to the class ascomycetes, possesses various pharmacological activities, including cytotoxic effects, on various types of human tumor cells. The present study investigated the anti‑hepatocellular carcinoma (HCC) and anti‑breast cancer effects of CM in in vitro and in vivo models. CM aqueous extract reduced cell viability, suppressed cell proliferation, inhibited cell migration ability, caused the over-release of lactate dehydrogenase, induced mitochondrial dysfunction and enhanced apoptotic rates in MCF‑7 and HepG2 cells. The expression levels of cleaved poly (ADP ribose) polymerase and caspase‑3, biomarkers of apoptosis, were increased following treatment with CM aqueous extract for 24 h. Furthermore, in the MCF‑7 and HepG2 cells, enhanced levels of B cell‑associated X protein and cleaved caspase‑8 were observed in the CM‑treated cells. Finally, the antitumor activities of CM in HCC and breast cancer were also confirmed in MCF‑7‑ and HepG2‑xengraft nude mice models. Collectively, the data obtained in the present study suggested that the cytotoxic effects of CM aqueous extract on HCC and breast cancer are associated with the caspase‑dependent mitochondrial pathway.
... Therefore, it has been shown to competitively inhibit the processes of synthesis and metabolism of DNA and RNA (Holbein et al. 2009;Tuli et al. 2013) and may further interfere with the activity of adenosine deaminase (Vodnala et al. 2013) (ADA) and the mTOR signaling pathway (Wong et al. 2010). Therefore, cordycepin exhibits a variety of pharmacological activities including immunological (Zhou et al. 2002), anticancer (Hunter et al. 2008;Noh et al. 2010), antioxidant, anti-inflammatory (Rao et al. 2010), anti-microbial (Sugar and Mccaffrey 1998;Ahn et al. 2000), antiviral (Müller et al. 1991), hypolipidemic (Guo et al. 2010) and hypoglycemic properties (Ma et al. 2015). Furthermore, some research groups have also shown that Cordyceps Shen Huang and Hui Liu contributed equally to this work. ...
Article
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Cordycepin is a purine nucleoside analog with potent and diverse biological activities. Herein, we designed two methods to synthesize cordycepin. One method mainly converted the 3′-OH group into an iodide group and further dehalogenation to yield the final product. Although this method presented a short synthetic procedure, the synthesis had a low overall yield, resulting in only 13.5% overall yield. To improve the overall yield of cordycepin, another synthetic route was studied, which consisted of four individual steps: (1) 5′-OH protection (2) esterification (3) -O-tosyl (-OTs) group removal (4) deprotection. The key step in the synthetic method involved the conversion of 5′-O-triphenylmethyladenosine to 3′-O-tosyl-5′-O-triphenylmethyladenosine, using LiAlH4 as reducing agent. The main advantages of this route were an acceptable total product yield and the commercial availability of all starting materials. The optimal reaction conditions for each step of the route were identified. The overall yield of cordycepin obtained from adenosine as the starting material was 36%.
... This biochemical synthesis of endogenous NO is governed by the family of nitric oxide synthase (NOS) enzymes through the stereospecific conversion of the natural amino acid Larginine to L-citrulline and NO. The three distinct mammalian isoforms of NOS are NOS1 (also known as neuronal or nNOS), NOS2 (inducible or iNOS), and NOS3 (endothelial or eNOS), each exhibiting a unique expression pattern and named for their location of initial isolation; nNOS is predominantly expressed by resident cells of the central and peripheral nervous system including both neuronal and non-neuronal cells (39,40), iNOS is expressed in inflammatory cells and can also be found in many other cell types in response to immunologic or inflammatory agents such as cytokines and lipopolysaccharides (41), and eNOS is predominantly expressed in endothelial cells. There is thus a regulation of NO synthesis that exists at the level of NOS transcription, post-translational modifications and specific cellular expression, as well as metabolic regulation at the level of NOS substrate availability (42). ...
Article
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The small free radical gas nitric oxide (NO) plays a key role in various physiological and pathological processes through enhancement of endothelial cell survival and proliferation. In particular, NO has emerged as a molecule of interest in carcinogenesis and tumour progression due to its crucial role in various cancer-related events including cell invasion, metastasis and angiogenesis. The dimethylarginine dimethylaminohydrolase (DDAH) family of enzymes metabolise the endogenous nitric oxide synthase (NOS) inhibitors, asymmetric dimethylarginine (ADMA) and monomethyl arginine (L-NMMA), and are thus key for maintaining homeostatic control of NO. Dysregulation of the DDAH/ADMA/NO pathway resulting in increased local NO availability often promotes tumour growth, angiogenesis and vasculogenic mimicry. Recent literature has demonstrated increased DDAH expression in tumours of different origins and has also suggested a potential ADMA-independent role for DDAH enzymes in addition to their well-studied ADMA-mediated influence on NO. Inhibition of DDAH expression and/or activity in cell culture models and in vivo studies has indicated the potential therapeutic benefit of this pathway through inhibition of both angiogenesis and vasculogenic mimicry, and strategies for manipulating DDAH function in cancer are currently being actively pursued by several research groups. This review will thus provide a timely discussion on the expression, regulation and function of DDAH enzymes in regard to angiogenesis and vasculogenic mimicry, and will offer insight into the therapeutic potential of DDAH inhibition in cancer based on preclinical studies.
... Cordyceps militaris extract exhibited antitumor effects mainly through the induction of apoptosis, inhibition of angiogenesis, and suppression of invasion and metastasis in cancer cells. [13][14][15] Cordyceps militaris has recently received considerable attention as a potential source of anticancer drugs. However, the molecular mechanism underlying the inhibitory effects of C. militaris on tumor cell growth remains unclear. ...
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This study aimed to investigate the effect of Cordyceps militaris extract on the proliferation and apoptosis of carboplatin- resistant SKOV-3 and determine the underlying mechanisms for overcoming carboplatin resistance in human ovarian cancer. We cultured the carboplatin-resistant SKOV-3 cells in vitro until the exponential growth phase and then treated with different concentrations of C. militaris for 24, 48, and 72 hours. We performed cell proliferation assay, cell morphological change assessment using transmission electron microscopy, apoptosis assay, and immunoblotting to measure the protein expression of caspase-3 and -8, poly (ADP-ribose) polymerase (PARP)-1, B-cell lymphoma (Bcl)-2, and activating transcription factor 3 (ATF3)/TP53 signaling-related proteins. As a result, C. militaris reduced the viability of carboplatin-resistant SKOV-3 and induced morphological disruptions in a dose- and time-dependent manner. The gene expression profiles indicated a reprogramming pattern of the previously known and unknown genes and transcription factors associated with the action of TCTN3 on carboplatin-resistant SKOV-3 cells. We also confirmed the C. militaris-induced activation of the ATF3/TP53 pathway. Immunoblotting indicated that cotreatment of C. militaris and carboplatin-mediated ATF3/TP53 upregulation induced apoptosis in the carboplatin-resistant SKOV-3 cells, which are involved in the serial activation of pro-apoptotic proteins, including Bcl-2, Bax, caspases, and PARP-1. Further, when the ATF3 and TP53 expression increased, the CHOP and PUMA expressions were upregulated. Consequently, the upregulated CHOP/PUMA expression activated the positive regulation of the apoptotic signaling pathway. In addition, it decreased the Bcl-2 expression, leading to marked ovarian cancer cells sensitive to carboplatin by enhancing apoptosis. We then corroborated these results using in vivo experiments. Taken together, C. militaris inhibits carboplatin-resistant SKOV-3 cell proliferation and induces apoptosis possibly through ATF3/TP53 signaling upregulation and CHOP/PUMA activation. Therefore, our findings provide new insights into the treatment of carboplatin-resistant ovarian cancer using C. militaris.
... These extracts exhibited antitumor effects mainly through the induction of apoptosis in tumor cells, inhibition of angiogenesis, and the suppression of invasion and metastasis. [24][25][26][27] Several reports over the past few years have shown that cordycepin (3′-deoxyadenosine), a major bioactive component extracted from C militaris, is reported to inhibit cell proliferation, [28][29][30] induce apoptosis, [31][32][33] inhibit platelet aggregation, regulate steroidogenesis, and reduce inflammation. 34 Moreover, cordycepin possesses antitumor activities. ...
Article
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This study aimed to investigate the effect of Cordyceps militaris extract on the proliferation and apoptosis of non–small cell lung cancer (NSCLC) cells and determine the underlying mechanisms. We performed a CCK-8 assay to detect cell proliferation, detection of morphological changes through transmission electron microscopy (TEM), annexin V–FITC/PI double staining to analyze apoptosis, and immunoblotting to measure the protein expression of apoptosis and hedgehog signaling–related proteins, with C militaris treated NSCLC cells. In this study, we first found that C militaris reduced the viability and induced morphological disruption in NSCLC cells. The gene expression profiles indicated a reprogramming pattern of genes and transcription factors associated with the action of TCTN3 on NSCLC cells. We also confirmed that the C militaris–induced inhibition of TCTN3 expression affected the hedgehog signaling pathway. Immunoblotting indicated that C militaris–mediated TCTN3 downregulation induced apoptosis in NSCLC cells, involved in the serial activation of caspases. Moreover, we demonstrated that the C militaris negatively modulated GLI1 transcriptional activity by suppressing SMO/PTCH1 signaling, which affects the intrinsic apoptotic pathway. When hedgehog binds to the PTCH1, SMO dissociates from PTCH1 inhibition at cilia. As a result, the active GLI1 translocates to the nucleus. C militaris clearly suppressed GLI1 nuclear translocation, leading to Bcl-2 and Bcl-xL down-regulation. These results suggested that C militaris induced NSCLC cell apoptosis, possibly through the downregulation of SMO/PTCH1 signaling and GLI1 activation via inhibition of TCTN3. Taken together, our findings provide new insights into the treatment of NSCLC using C militaris.
... Link [Cm]) that possess anticancer properties. [11][12][13][14][15][16][17][18][19][20] FDY003 inhibits cancer cell proliferation and survival and induces apoptosis in cancer cells in vitro and in vivo. 21 FDY003 exerts therapeutic effects by modulating the activities of key regulators in the apoptotic signaling pathway, such as Bcl-2associated X protein (Bax) and caspase-3, in colorectal cancer cells. ...
Article
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Increasing data support that herbal medicines are beneficial in the treatment of cervical cancer; however, their mechanisms of action remain to be elucidated. In the current study, we used a systems pharmacology approach to explore the pharmacological mechanisms of FDY003, an anticancer herbal formula comprising Lonicera japonica Thunberg, Artemisia capillaris Thunberg, and Cordyceps militaris (Linn.) Link, in the treatment of cervical cancer. Through the pharmacokinetic assessment of absorption-distribution-metabolism-excretion characteristics, we found 18 active compounds that might interact with 106 cervical cancer-related targets responsible for the pharmacological effects. FDY003 targets were significantly associated with gene ontology terms related to the regulation of cellular behaviors, including cell proliferation, cell cycle processes, cell migration, cell apoptosis, cell death, and angiogenesis. The therapeutic targets of the herbal drug were further enriched in various oncogenic pathways that are implicated in the tumorigenesis and progression of cervical cancer, including the phosphatidylinositol 3-kinase, mitogen-activated protein kinase, focal adhesion, human papillomavirus infection, and tumor necrosis factor signaling pathways. Our study provides a systematic approach to explore the anticancer properties of herbal medicines against cervical cancer.
... Similarly, C. militaris (L.) Fr. induces apoptosis via mitochondrial dysfunction and caspase activation in human breast cancer cell lines as well . Furthermore, pure compounds isolated from the extracts of C. militaris (L.) Fr. have been reported to be antiproliferative against PC-3, colon 205, and HepG2 cells (Rao et al., 2010). Furthermore, it was reported that C. militaris (L.) Fr. inhibit cancer growth through regulation of p85/Akt-dependent or GSK3β-related caspase-3-dependent apoptosis on a xenograft mouse model bearing murine T cell lymphoma (RMA) cell-derived cancers . ...
Article
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In recent decades, interest in the Cordyceps genus has amplified due to its immunostimulatory potential. Cordyceps species, its extracts, and bioactive constituents have been related with cytokine production such as interleukin (IL)-1β, IL-2, IL-6, IL-8, IL-10, IL-12, and tumor necrosis factor (TNF)-α, phagocytosis stimulation of immune cells, nitric oxide production by increasing inducible nitric oxide synthase activity, and stimulation of inflammatory response via mitogen-activated protein kinase pathway. Other pharmacological activities like antioxidant, anti-cancer, antihyperlipidemic, anti-diabetic, anti-fatigue, anti-aging, hypocholesterolemic, hypotensive, vasorelaxation, anti-depressant, aphrodisiac, and kidney protection, has been reported in pre-clinical studies. These biological activities are correlated with the bioactive compounds present in Cordyceps including nucleosides, sterols, flavonoids, cyclic peptides, phenolic, bioxanthracenes, polyketides, and alkaloids, being the cyclic peptides compounds the most studied. An organized review of the existing literature was executed by surveying several databanks like PubMed, Scopus, etc. using keywords like Cordyceps , cordycepin, immune system, immunostimulation, immunomodulatory, pharmacology, anti-cancer, anti-viral, clinical trials, ethnomedicine, pharmacology, phytochemical analysis, and different species names. This review collects and analyzes state-of-the-art about the properties of Cordyceps species along with ethnopharmacological properties, application in food, chemical compounds, extraction of bioactive compounds, and various pharmacological properties with a special focus on the stimulatory properties of immunity.
... Cordyceps militaris belongs to the family of Cordycipitaceae contains a bioactive compound called CMP18. (Rao et al., 2010) C.militaris extract elevated the levels of IL-18 transcription by enhancing the activity of the P1 promoter region in mice liver and brain, thereby stimulating the INF-γ secretion in leukemic mouse monocyte cell line (C. S. Kim et al., 2008). ...
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Mushrooms have been an invaluable ingredient in terms of food and medicine to humanity since time immemorial. Mushrooms have been shown to be possessing properties such as anti-tumor, antiproliferative, antioxidant, immunomodulatory, anti-diabetic. Traditional Czech republic medicine involved using Piptoporus betulinus in curing colorectal cancer; similarly, fruiting bodies of Inonotus obliquus were employed in Folk medicine in eastern Europe since the 16th century. The oriental practice of utilizing mushrooms has witnessed an overwhelming attentiveness from the global research fraternity in exploring its wonder substances. Cancer is one of the key problems faced by researchers in finding an efficient medicine without inducing severe health complications. Mushrooms contain a plethora of bioactive compounds involved in tumor inhibition, such as hispolon, lentinan, gannoderic acid, illudin-s, and many more. The current article briefly describes various edible mushrooms with anti-tumorigenic compounds and their effect on the cancer cells of various means.
... 21 Ergosterol (compound 11) inhibits NO production, nuclear factor-κB transcriptional activity, and IL1 α/β expression in macrophage RAW 264.7 cells. [22][23][24] Lucidenic acid A (compound 14) inhibits topical anti-inflammatory activity-induced inflammation in mice. 25 Also, in an unexpected outcome of this work, it turned out that the bioactivity of ergosta-7,22-dien-3-one (compound 1), the main ligand of our top hits list, had already been experimentally determined by our research group. ...
Article
An extensive database of sterols and triterpenoids isolated from Ganoderma mushrooms was evaluated by in silico structure-based virtual screening to determine their respective ligand affinities for the glucocorticoid or mineralocorticoid receptor (GCR or MNR). The main ligands for GCR in our database were ergosta-7,22-dien-3-one (compound 1) and ganodermaside B (compound 2), while the best ligands for MNR were 2β,3α,9α-trihydroxyergosta-7,22-diene (compound 8) and 5α-ergosta-7,22-dien-3β-ol (compound 3). The binding free energy (BFE) values calculated for such metabolites were similar to those of the natural ligands for each receptor (i.e., dexamethasone for GCR and aldosterone for MNR). Moreover, the differences between mean BFE values calculated for both receptors suggest that ergosta-7,22-dien-3-one (compound 1), ganodermaside B (compound 2), fungisterol (compound 5), ganoderic acid Ma (compound 9), and cerevisterol (compound 10) might be used as specific ligands for GCR, with a significantly lower affinity for MNR. Finally, it is worth noting that even though this work is exclusively theoretical, the reported bioactivities (either pro- or anti-inflammatory) for those metabolites that were previously studied are consistent with our findings, suggesting that the well-known immunomodulatory effect of Ganoderma triterpenoids and sterols might be attributed, at least partially, to their ability to act as specific GCR ligands.
... [10] Constituents isolated from C. militaris suppressed the inflammatory mediator's production and human cancer cell proliferation, and one of them inhibited the proliferation of HepG2 cells. [11] C. militaris aqueous extract was reported to exert the cytotoxic effect on MCF-7 and HepG2 cells through the caspase-dependent mitochondrial pathway. [12] The vascular endothelial growth factor (VEGF) family plays a crucial role in angiogenesis. ...
... Therefore, anti-inflammatory agents are claimed to be effective in the acute treatment of these burns. The water extract and constituents isolated from C. militaris were reported to be anti-inflammatory in the murine macrophage and lipopolysaccharide (LPS)/ interferon (IFN)-γ stimulated macrophage cells 30,31 . The major active ingredient of C. militaris, cordycepin has been well documented to alleviate inflammation and oxidative stress both in vitro and in vivo 32 . ...
Article
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Purpose: To investigate the efficacy of cordycepin, an adenosine analogue, on prevention of esophageal damage and stricture formation due to esophageal caustic burns in rat model comparing with prednisolone. Methods: Caustic esophageal burn was introduced by 37.5% of NaOH to distal esophagus. Thirty-two Wistar albino rats were divided in four groups: sham rats undergone laparotomy, treated with 0.9% NaCl; control rats injured with NaOH without cordycepin treatment; cordycepin group injured with NaOH, treated with 20 mg/kg cordycepin; prednisolone group injured with NaOH, treated with 1 mg/kg prednisolone for 28 days. Efficacy was assessed by histopathological and immunohistochemical analysis of esophageal tissues. Results: Cordycepin treatment significantly decreased inflammation, granulation tissue and fibrous tissue formation and prevented formation of esophageal strictures shown by histopathological damage score and stenosis indexes compared to control group (p < 0.01). These effects are relatively more substantial than prednisolone, probably based on attenuation of elevation of proinflammatory cytokines hypoxia-inducible factor 1-alpha (HIF-1?), tumor necrosis factor alpha (TNF-?), proliferative and fibrotic factor fibroblast growth factor 2 (FGF2) and angiogenic factor vascular endothelial growth factor A (VEGFA) (p < 0.05). Conclusions: The findings suggest that cordycepin has a complex multifactorial healing process in alkali-burned tissue, more successful than prednisolone in preventing the formation of esophageal strictures and may be used as a therapeutic agent in the acute phase of esophageal alkali-burn.
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Overwhelming consensus among medical authorities and scholarly bodies on the high susceptibility to chronic ailments such as coronary diseases, cancers, and diabetes and the failure to make any leap forward progress in controlling casualties or even to completely understand their pathology is a frightening reality. To comprehend alterations, additions, and management of diet is a preferable approach not only to prevent the occurrence of cardiovascular diseases but also to precise and enhance treatment measures. Proper application of potential drugs is possible only by establishing a systemic correlation and compilation of the knowledge obtained on the possible bioactive drugs. In this perspective gathering knowledge on the health-promoting potential of mushrooms which are considered as one of the promising sources of potential products that provide cardioprotection is indispensable. While there are several mushrooms traditionally utilized around the world for the treatment of cardiovascular diseases (CVD), they are also being cautiously evaluated experimentally for the available evidences of ethnopharmacology. Some therapeutic mushrooms have preclinical studies to demonstrate that uptake of these organic dietary supplements and their constituents as a therapeutic alternative or supplement is conceivable, and further evaluations are carried out to help in lessening the prevalence and mortality of CVD by incorporating them either as a population medicine or as a clinical medicine. A few examinations have demonstrated the effect of mushrooms and their bioactive compounds on metabolic markers such as low-density lipoprotein, high-density lipoprotein, total cholesterol, fasting triacylglycerol, and homocysteine levels and on conditions such as hypertension, body hemostasis, oxidative stress, and inflammation which are associated with cardiovascular ailments. The focus of this chapter will primarily be on mushrooms used traditionally for the treatment of CVD.
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Ethnopharmacological relevance Cordyceps militaris have proven to be effective in treating inflammation, prostate cancer and oxidative in cell line models. Experimental treatments on animal subjects have demonstrated evidence of increased sex hormones and gonadal volumes, and phytosterols, especially β-sitosterol, in terms of decreasing hypertrophied prostate glands. Aim of the study Evaluating the effects of how ingesting Cordyceps militaris fruiting bodies can alleviate BPH disease as well as improve sexual function in elderly male volunteers who were the main subjects of this study. Materials and Methods We conducted an open clinical trial, consisting of 62 patients in conjunction with administering the standard medical treatment. The maximum flow (Q-max), post void residual volume (PVR), the prostate volume, International Prostate Symptom Score questionnaire (IPSS), International Index of Erectile Function questionnaire (IIEF) and blood test for prostate specific antigen (PSA), blood urea nitrogen (BUN), creatinine (Cr), testosterone (T), estradiol (E2) and luteinizing hormone (LH) were recorded before and after administering the treatment. We used a Pair-t test for the analysis. Results The study showed an increase in the maximum flow (p =0.025*), and a decrease in prostate volume (p =0.016*). The IPSS and IIEF Questionnaire results were (p =0.0001***) and (p=0.005**) respectively, and was therefore duly significant in terms of demonstrating visible clinical results. Conclusions Cordyceps militaris fruiting bodies had the tendency in increasing the urinary flow, decreasing the size of the prostatic gland and alleviating micturition symptoms as well as having positive effect on sexual functions.
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Background: Cordyceps has long been used to treat cancer. However, its pharmacologically active components as well as the molecular mechanisms underlying its effects are still unclear. Purpose: To investigate the effect of MHP-1, a newly isolated polysaccharide from Mortierella hepialid (the asexual structure of C. sinensis), on breast cancer metastasis. Study design: The effect of MHP-1 on breast cancer cell migration, epithelial-mesenchymal transition (EMT) and TGF-β signaling were investigated in vitro and in vivo. The effect of MHP-1 against topotecan-resistant MCF-7 cells that developed an EMT-like phenotype was also examined. Methods: The in vitro effect of MHP-1 on breast cancer cell proliferation and migration was evaluated by CCK8 and transwell assay. Morphological changes were observed and EMT markers were detected by western blot. The production of MMPs was measured by quantitative PCR and ELISA assay. To further investigate the mechanism that MHP-1 inhibited breast cancer EMT, western blot, ELISA, luciferase reporter gene assay, siRNA, quantitative PCR, immunohistochemistry, and xenograft tumor model were performed. Results: MHP-1 inhibited breast cancer cell migration but did not cause any cytotoxicity. MHP-1 significantly surpressed breast cancer EMT, and slightly decreased MMP-9 secretion. TGF-β signaling was selectively inhibited after MHP-1 treatment, and other EMT-related pathways, like Wnt and Notch, were not affected. MHP-1 reduced the secretion of TGF-β1, but rarely affected other EMT-induced cytokines. Dual luciferase assay and Smad2/3 phosphorylation analysis indicated that MHP-1 suppressed TGF-β signaling. We further showed that MHP-1 restored sensitivity in topotecan (TPT)-resistant MCF-7 cells that developed an EMT-like phenotype. Similarly, the effect of TPT on resistant MCF-7 cells was also increased either by ALK5 (TGFβRI) siRNA or by a small molecular inhibitor of ALK5, SB-431542. MHP-1 inhibited breast cancer metastasis in the MDA-MB-231 xenograft model, and the immunohistochemical staining showed dramatically decreased expression of ALK5 and vimentin, and increased expression of E-cadherin. Conclusion: MHP-1 significantly inhibited breast cancer metastasis and restored drug sensitivity in TPT-resistant cells via down-regulation of TGF-β signaling and EMT program. The combination of non-toxic agents like MHP-1 and current anti-cancer drugs should be considered in the future treatment of cancer.
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Cordyceps generally known as caterpillar fungus infects various insects in nature. These fungi have unique mechanism to infect the host insects and are generally hostile to unique ecological niches. The well-recognized caterpillar fungus is usually found at high altitudes on the Himalayan plateau and is used as a traditional medicinal mushroom producing a number of active substances used in medicine and naturopathy. Cordycepin is one of them having nutraceutical potential and helps in maintaining good health. Polysaccharides having health promoting activity are also reported under in vivo and in vitro conditions. High demand of these bioactive compounds requires a suitable strategy to meet out the demands. In addition, anticancer, antidiabetic, anti-hyperlipidaemia, antifungal, immunomodulatory, antioxidant, antiaging, antiviral, hepato-protective, hypo-sexuality, cardiovascular diseases and anti-inflammatory activities are also reported. In this review, we have compiled the information on potential of cordycepin and other polysaccharides of Cordyceps and discuss about optimization of culture conditions for enhanced recovery of these bioactive compounds.
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Aquaculture industry is one of the major food-producing sectors in the world that provide nutritional food security for mankind. Fish and crustacean farmers are facing various challenges in treating the rapid spread of infectious diseases in recent times. Numerous strategies, including antibiotics, disinfectants, and other antimicrobial agents, have been applied to protect the cultivable aquatic animals from infectious diseases. These applications lead to the development of antimicrobial resistance, toxicity, and the accumulation of antibiotic residues in cells and organelles of the cultivable edible organisms and the environment. The use of naturally derived compounds, polysaccharides, and functional metabolites has gained immense attention among aquaculturists. Mushrooms and their nutraceutical components have been widely used in various sectors, including food, pharmaceutical, poultry, and aquaculture industries, for their non-toxic and eco-friendly properties. To date, there are several reports available on edible and medicinal mushrooms as a dietary ingredient for fish and decapod crustacean culture. The mushroom products such as mycelia, stalk, dry powder, polysaccharides, and extracts have been utilized in aquaculture as growth promoters and immunostimulants, improving the digestive enzyme activity, antimicrobials, and improving the health status of cultivable aquatic animals. This present review elucidates the effectiveness of mushrooms and mushroom-derived compounds as prebiotics in aquaculture. The challenges and future perspectives of mushroom-derived bioactive molecules have been discussed in this review.
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Cordyceps militaris is an entomopathogenic ascomycete with similar pharmacological importance to that of the wild caterpillar fungus Ophiocordyceps sinensis. C. militaris has attracted significant research and commercial interest due to its content in bioactive compounds beneficial to human health and the relative ease of cultivation under laboratory conditions. However, room for improvement exists in the commercial-scale cultivation of C. militaris and concerns issues principally related to appropriate strain selection, genetic degeneration of cultures, and substrate optimization. In particular, culture degeneration—usually expressed by abnormal fruit body formation and reduced sporulation—results in important economic losses and is holding back investors and potential growers (mainly in Western countries) from further developing this highly promising sector. In the present review, the main factors that influence the generation of biomass and metabolites (with emphasis on cordycepin biosynthesis) by C. militaris are presented and evaluated in conjunction with the use of a wide range of supplements or additives towards the enhancement of fungal productivity in large-scale cultivation processes. Moreover, physiological and genetic factors that increase or reduce the manifestation of strain degeneration in C. militaris are outlined. Finally, methodologies for developing protocols to be used in C. militaris functional biology studies are discussed.
Article
Ethnopharmacological relevance: Cordyceps militaris is an ingredient of traditional Chinese medicine and have been widely used for inflammatory diseases and cancer. Cordycepin is one of the major bioactive components of Cordyceps militaris, and has been known to have anti-inflammatory and anti-oxidant effects. Aim of this study: In the present study, we examined whether WIB-801C, a standardized and cordycepin-enriched extract of caterpillar fungus (Cordyceps militaris), would attenuate blood-spinal cord barrier (BSCB) disruption by inhibiting matrix metalloprotease (MMP)-9 activity, leading to improvement of functional outcomes after spinal cord injury (SCI). Materials and methods: Male Sparague-Dawley rats were subjected to contusive SCI using a New York University (NYU) impactor, and WIB-801C (50mg/kg) was administered at 2h and 8h after injury orally and further treated once a day for indicated time points. BSCB disruption, MMP-9 activity, blood infiltration, inflammation, neuronal apoptosis, axonal loss, demyelination, and neurological deficit were evaluated. Results: We found that WIB-801C significantly attenuated BSCB disruption by inhibiting MMP-9 expression and activation after injury. The infiltration of neutrophils at 1 d and macrophage at 5 d after SCI was also ameliorated by WIB-801C as compared with vehicle control. In addition, the expression of inflammatory cytokines and mediators such as Tnf-?, IL-1?, IL-6, Cox-2, and inos as well as chemokines such as Gro-? and Mip-2? was significantly inhibited by WIB-801C. Furthermore, WIB-801C inhibits p38MAPK activation and proNGF production in microglia after injury. These events eventually led to the inhibition of apoptotic cell death of neurons and oligodendrocytes, improved functional recovery and attenuated demyelination and axon loss after SCI. Conclusion: Our results suggest that WIB-801C can be used as a therapeutic agent after SCI by attenuating BSCB disruption followed inflammation.
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According to the “amyloid cascade hypothesis”, amyloid-beta (Aβ) protein occupied one of the risk factors of Alzheimer’s disease (AD). Cordyceps militaris (CM) has been reported to exert anti-inflammatory, anti-oxidant, and neuroprotective activities; however, its activity against cognitive dysfunction has not been studied yet. In this study, the CM ethanol extract was administered with a dose of 100 or 200 mg/kg for 2 weeks, and behavioral assessments were performed for learning and memory function in Aβ1–42-induced AD mice models. Supplementation with CM extract enhanced new route consciousness and novel object recognition, and in the Morris water maze test, CM-administered groups showed less time to reach to the hidden platform compared with the control group. Moreover, the CM extract inhibited nitric oxide production and lipid peroxidation in the brain, liver, and kidney. The present study indicated that CM could have the protective role from cognitive impairment and progression of AD.
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Herbal medicines have drawn considerable attention with regard to their potential applications in breast cancer (BC) treatment, a frequently diagnosed malignant disease, considering their anticancer efficacy with relatively less adverse effects. However, their mechanisms of systemic action have not been understood comprehensively. Based on network pharmacology approaches, we attempted to unveil the mechanisms of FDY003, an herbal drug comprised of Lonicera japonica Thunberg, Artemisia capillaris Thunberg, and Cordyceps militaris, against BC at a systemic level. We found that FDY003 exhibited pharmacological effects on human BC cells. Subsequently, detailed data regarding the biochemical components contained in FDY003 were obtained from comprehensive herbal medicine-related databases, including TCMSP and CancerHSP. By evaluating their pharmacokinetic properties, 18 chemical compounds in FDY003 were shown to be potentially active constituents interacting with 140 BC-associated therapeutic targets to produce the pharmacological activity. Gene ontology enrichment analysis using g:Profiler indicated that the FDY003 targets were involved in the modulation of cellular processes, involving the cell proliferation, cell cycle process, and cell apoptosis. Based on a KEGG pathway enrichment analysis, we further revealed that a variety of oncogenic pathways that play key roles in the pathology of BC were significantly enriched with the therapeutic targets of FDY003; these included PI3K-Akt, MAPK, focal adhesion, FoxO, TNF, and estrogen signaling pathways. Here, we present a network-perspective of the molecular mechanisms via which herbal drugs treat BC.
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The ubiquitous transcription factor, NF-κB, has been reported to inhibit apoptosis and induce drug resistance in cancer cells. Cordyceps militaris extract (CME) is involved in the regulation of the NF-κB signaling pathway. However, the detailed role of CME in the suppression of the NF-κB signaling pathway is unclear. We found that CME dose-dependently inhibited tumor necrosis factor-α (TNF-α)-induced NF-κB activation in TK-10 human renal cell carcinoma. CME prevented NF-κB from translocating to the nucleus, which resulted in the downregulation of GADD45B, upregulation of MKK7, and phosphorylation of JNK (p-JNK). The increased activation of Bax led to pronounced CME-induced apoptosis, which occurred through caspase-3. Furthermore, the siRNA-mediated knockdown of GADD45B inhibited MKK7 expression, whereas the siRNA-mediated inhibition of MKK7 downregulated p-JNK and the JNK inhibitor, SP600125, inhibited Bax expression. Thus, these results indicated that CME inhibited the activation of GADD45B via the inhibition of NF-κB activation, which upregulated the MKK7-JNK signaling pathway to induce apoptosis in TK-10 cells. Thus, this study reveals a novel anticancer function of CME.
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A new nucleoside, a new natural product nucleoside, and two new pyrrole alkaloids derivatives with eight known compounds were isolated from the fruiting body of Cordyceps militaris. The structures of the new compounds were elucidated through extensive analysis of spectroscopic data including 1D and 2D NMR, HRESIMS, IR and UV. All the isolated compounds were detected for their bioactivities against LPS-induced NO production in RAW 264.7 cells. Unfortunately, all the isolates have shown no obvious activity.
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A comparison of the anti-tumor activity of CMPS-II and CBPS-II polysaccharides, respectively is obtained from the fermented mycelium and cultivated fruiting bodies of Cordyceps militaris. This in vitro anti-tumor activity is investigated using an MTT assay, immunofluorescence staining, a Western Blot assay, a qRT-PCR assay, and Annexin V-FITC/PI double staining. The experimental results indicate that the inhibition rate of CMPS-II on H1299 tumor cells is higher than that of CBPS-II. With a concentration of 500 μ g/mL, the inhibition rate of CMPS-II and CBPS-II were 54.55% and 34.80%, respectively. Both CMPS-II and CBPS-II can increase the protein and mRNA expression level of cell apoptosis factors Caspase-3, Caspase-9, and p53, while reducing the protein and mRNA expression levels of proliferating cell nuclear antigen (PCNA), to induce tumor cells apoptosis. The induction effect of CMPS-II was stronger than CBPS-II. These results suggest that CMPS-II is superior to CBPS-II regarding the inhibition of H1299 lung cancer cells. Furthermore, CMPS-II is a potentially useful substitution for CBPS-II in the treatment of lung cancer and provides new insights into the mechanism of its anti-tumor activity.
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Cordyceps militaris is a unique and precious medical fungus in Chinese Cordyceps, which has been widely used as the traditional medicines or as biocontrol agents against pests in China for centuries. Polysaccharides are one of bioactive constituents in Cordyceps militaris with a variety of biological activities, including immunomodulation, antioxidant, anti-tumor, and anti-aging activities, among others. However, natural Cordyceps militaris are very rare and expensive, most of literatures indicated that the polysaccharides were mostly extracted from artificially cultivated fungal fruiting bodies (intracellular polysaccharides) or mycelia fermentation broths (extracellular polysaccharides). Moreover, separation and purification of polysaccharides was a very complicated and cumbersome process. Nevertheless, a large number of polysaccharides were purified and its characterization was elucidated by structure and biological activities. However, the relationship between structure and activity of polysaccharides has not been well established. Therefore, this review detailed the recent advance in several aspects (i.e., extraction, isolation, structure, and bioactivities) of the polysaccharides from fruiting body of Cordyceps militaris. This information could provide theoretical basis for the research on related polysaccharides, and also have important reference value in the field of functional foods and medicine in the future.
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In this study, we investigated the protective efficacy of extracellular polysaccharide from Cordyceps militaris (CEP-I) in liver and kidney and their regulating effect on gut microbiota against Pb-induced toxicity in vivo. The results indicated that CEP-I could reduce the Pb2+ content and organ index of liver and kidney in mice. Besides, biochemical analysis showed that CEP-I could improve the activity of glutathione peroxidase (GSH-Px), malondialdehyde (MDA) and superoxide dismutase (SOD) in serum and organs, restore the physiological indexes of total protein (TP), albumin (ALB), blood urea nitrogen (BUN) and creatinine (CRE) in serum and decrease the enzyme activity of lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) in the liver and kidney of mice poisoned by Pb2+. This indicated that CEP-I has a protective effect on organs against damage in mice. In addition, CEP-I could regulate the expression of key proteins in the Nrf2 signaling pathway, including NF-E2-related factor 2 (Nrf2), Kelch-like ECH-associated protein-1 (Keap1), Heme oxygenase (HO-1) and NAD(P)H: quinone oxidoreductase 1 (NQO1). Furthermore, the intestinal flora analysis results indicated that CEP-I also has the capacity to regulate the intestinal flora imbalance caused by Pb2+ in poisoned mice. In conclusion, we hope that this study can provide theoretical basis for the treatment of tissue damage induced by Pb2+.
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In this study, the purified polysaccharide (DCP-I) was extracted from Cordyceps militaris domesticated with Pb2+. After that, the structural feature and mechanism of lead resistance of DCP-I were investigated using novel approaches. The results showed that the average molecular weight of DCP-I was 1.206 × 103 kDa and mainly consist of Rhamnose, Galactose, Glucose, Galacturonic acid and Glucuronic acid in a molar ratio of 0.130:47.687:40.784:1.795:0.48. Besides, the main chain of DCP-I was composed by →6)-Galp-(1→, →4)-Glcp-(1→ and →1,4)-Glcp-(6→, while the side chain was →1)-Rhaf-(2→ and D-Glcp-(1→, and the DCP-I contained Alacturonic acid and Glucuronic acid. In addition, the result of Congo red test showed that DCP-I did not exist triple-helical structures. SEM, EDX and XPS analyses results showed that the functional groups of DCP-I related to C, H and O (-OH, -COOH and -C=O) could combined with Pb2+effectively. The adsorption processes were described by the Pseudo-second-order kinetic model (R2 = 0.9978) and Langmuir isotherm (R2 = 0.9979) for Pb2+ indicating that adsorption process of DCP-I to Pb2+ was a kind of single molecular layer chemical adsorption.
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Across the globe cancer is emerging as an overriding source of death raising enduring consequences all through the life period of patients. Chemotherapeutic drugs adopted for cancer therapy have grievous after-effects, and growth of resistance is a major downside for these agents. For decades natural products and medicine have been intimately connected through the usage of conventional medicines. Mushrooms own substantial antiquity of use in conventional medicine with no or minimal side effects. Mushrooms are considered as superfoods due to the presence of bioactive compounds and origin of medical drug and nutraceutical development for enhancing longevity of people. Recently there is an elevated interest found in people for the secondary metabolites of higher fungi in order to explore novel medical substance or lead compounds for cancer treatment. A number of novel fungal metabolites have been extracted from higher fungi which are likely to provide drugs with chemopreventive property. The researches involved the drug discovery from medicinal fungi mainly implicating multifaceted approach. Most of the isolated compounds have exhibited prominent in vitro cytotoxic effects in cancer cell lines from human tissue, and specifically selected compounds were used for in vivo experiments. This chapter cautiously deals with the review of low-molecular-weight compounds obtained from higher fungi with anticancer potential identified so far. In the near future, among these novel compounds many are presumed to enter human clinical trials.
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Bioactive compounds derived from mushrooms have been shown to present promising potential as cosmeceutical or nutricosmetic ingredients. Scientific data reviewed herein showed that extracts prepared from medicinal and edible mushrooms and their individual metabolites presented anti-inflammatory, antioxidant, photoprotective, antimicrobial, anti-tyrosinase, anti-elastase and anti-collagenase activities. These metabolites can be utilised as ingredients to suppress the severity of inflammatory skin diseases, offer photoprotection to the skin and correct hyperpigmentation. However, studies regarding the molecular mechanism behind the mentioned bioactivities are still lacking. Challenges associated with the use of mushroom extracts and their associated metabolites as cosmeceutical and nutricosmetic ingredients include several steps from the fruiting bodies to the final product: extraction optimization, estimation of the efficacy and safety claims, the use of micro and nanocarriers to allow for controlled release and the pros and cons associated with the use of extracts vs individual compounds. This systematic review highlights that mushrooms contain diverse biomolecules that can be sustainably used in the development of nutricosmetic and cosmeceutical formulations. Reports regarding stability, compatibility, and safety assessment, but also toxicological studies are still needed to be considered. Furthermore, some of the constraints and limitations hindering the development of this type of ingredients still require long-term studies to achieve major breakthroughs.
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It has been found that 4-isopropyl-2,6-bis(1-phenylethyl)phenol (KTH-13), a novel compound isolated from Cordyceps bassiana, is able to suppress tumor cell proliferation by inducing apoptosis. To mass produce this compound, we established a total synthesis method. Using those conditions, we further synthesized various analogs with structural similarity to KTH-13. In this study, we aimed to test their anti-cancer activity by measuring anti-proliferative and pro-apoptotic activities. Of 8 compounds tested, 4-methyl-2,6-bis(1-phenylethyl)phenol (KTH-13-Me) exhibited the strongest anti-proliferative activity toward MDA-MB 231 cells. KTH-13-Me also similarly suppressed the survival of various cancer cell lines, including C6 glioma, HCT-15, and LoVo cells. Administration of KTH-13-Me induced several apoptotic signs in C6 glioma cells, such as morphological changes, induction of apoptotic bodies, and nuclear fragmentation and chromatin condensation. Concordantly, early-apoptotic cells were also identified by staining with FITC-Annexin V/PI. Moreover, KTH-13-Me highly enhanced the activation of caspase-3 and caspase-9, and decreased the protein level of Bcl-2. In addition, the phosphorylation levels of Src and STAT3 were diminished in KTH-13-Me-treated C6 cells. Therefore, these results suggest that KTH-13-Me can be developed as a novel anti-cancer drug capable of blocking proliferation, inducing apoptosis, and blocking cell survival signaling in cancer cells.
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Chronic inflammation is a risk factor for several gastrointestinal malignancies, including colorectal cancer. Recent epidemiological studies and clinical trials demonstrate that long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) markedly reduced the relative risk of colorectal cancer. Chronic inflammation associated with development of cancer is partly driven by the chemokine system. Chemokines are chemoattractant cytokines that recruit leukocytes from the circulatory system to local inflammatory sites. In this review, we highlight recent breakthroughs in our understanding of the role of chemokines in inflammatory bowel disease and colorectal cancer from animal models and human studies. These findings provide a rationale for the development of new anti-inflammatory therapeutic approaches for prevention and/or treatment of inflammatory bowel disease and colorectal cancer.
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An interleukin-18 binding protein (IL-18BP) was purified from urine by chromatography on IL-18 beads, sequenced, cloned, and expressed in COS7 cells. IL-18BP abolished IL-18 induction of interferon-gamma (IFNgamma), IL-8, and activation of NF-kappaB in vitro. Administration of IL-18BP to mice abrogated circulating IFNgamma following LPS. Thus, IL-18BP functions as an inhibitor of the early Th1 cytokine response. IL-18BP is constitutively expressed in the spleen, belongs to the immunoglobulin superfamily, and has limited homology to the IL-1 type II receptor. Its gene was localized on human chromosome 11q13, and no exon coding for a transmembrane domain was found in an 8.3 kb genomic sequence. Several Poxviruses encode putative proteins highly homologous to IL-18BP, suggesting that viral products may attenuate IL-18 and interfere with the cytotoxic T cell response.
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The anti-inflammatory activities of five flavonoids, namely 5,7-dimethoxyflavanone (1), 5,7-dimethoxy-3',4'-methylenedioxyflavanone (2), isobonducellin (3), 2'-hydroxy-2,3,4',6'-tetramethoxychalcone (4) and bonducellin (5), all of them isolated from Caesalpinia pulcherrima L. was studied in lipopolysaccharide (LPS) and interferon (IFN)-gamma activated murine peritoneal macrophages. These five compounds significantly and dose-dependently inhibited the inflammatory mediators; nitric oxide (NO), and cytokines [tumor necrosis factor (TNF)-alpha and interleukin (IL)-12]. According to their inhibitory results, the order of anti-inflammatory potency was compounds 3>5>4>2>1. Furthermore, peritoneal macrophages were pre-activated with LPS/IFN-gamma for 24h, and determined the inhibitory effects of the above-mentioned isolates on the production of NO after a further 24h. The present study supports the use of Caesalpinia pulcherrima for the treatment of inflammatory diseases in traditional medicine. This is the first study on compounds 1-5 about their anti-inflammatory activities.
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Cordyceps militaris, a caterpillar-grown traditional medicinal mushroom, produces an important bioactive compound, cordycepin (3'-deoxyadenosine). Cordycepin is reported to possess many pharmacological activities including immunological stimulating, anti-cancer, anti-virus and anti-infection activities. The molecular mechanisms of cordycepin on pharmacological and biochemical actions of macrophages in inflammation have not been clearly elucidated yet. In the present study, we tested the role of cordycepin on the anti-inflammation cascades in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells. In LPS-activated macrophage, nitric oxide (NO) production was inhibited by butanol fraction of C. militaris and the major component of C. militaris butanol faction was identified as cordycepin by high performance liquid chromatography. To investigate the mechanism by which cordycepin inhibits NO production and inducible nitric oxide synthase (iNOS) expression, we examined the activation of Akt and MAP kinases in LPS-activated macrophage. Cordycepin markedly inhibited the phosphorylation of Akt and p38 in dose-dependent manners in LPS-activated macrophage. Moreover, cordycepin suppressed tumor necrosis factor (TNF-alpha) expression, IkappaB alpha phosphorylation, and translocation of nuclear factor-kappaB (NF-kappaB). The expressions of cycloxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) were significantly decreased in RAW 264.7 cell by cordycepin. Taken together, these results suggest that cordycepin inhibits the production of NO production by down-regulation of iNOS and COX-2 gene expression via the suppression of NF-kappaB activation, Akt and p38 phosphorylation. Thus, cordycepin may provide a potential therapeutic approach for inflammation-associated disorders.
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The extracts of chloroform (1) and methanol (2) from Antrodia camphorata (AC), and chloroform (3) and n-butanol (4) fractions of methanol extract from Cordyceps sinensis (CS), and hexane (5), ethyl acetate (6), and methanol (7) from Cinnamomum osmophloeum bark (CO) were evaluated for their anti-inflammatory as well as tumor-cell growth inhibitory activities in vitro. All the tested extracts dose dependently inhibited the enhanced production of inflammatory mediators such as nitric oxide (NO) through reducing inducible NO synthase expression, and cytokines (tumor necrosis factor (TNF)-alpha and interleukin (IL)-12 in LPS/IFN-gamma activated murine peritoneal macrophages. In addition, extracts 1 from AC, and 5 and 6 from CO significantly arrest the mitogen-stimulated spleen cells in G0/G1 stage. On the other hand, all these extracts were also evaluated for their tumor-cell proliferation activities in different type of cancer cell lines such as Jurkat, HepG2, PC 3, Colon 205, and MCF 7 as well as normal PBMCs. Compared to untreated controls, the extracts 1, 2, and 4-7 were most active and inhibited Jurkat cells with IC50 value of 22, 40, 18, 4, 5, and 45 microg/ml, respectively. In addition, the extracts 5, 6, and 7 from CO showed potent growth inhibition of HepG2 and PC 3 with IC50 values of 35, 80, 55 microg/ml; and 42, 125, and 50 microg/ml, respectively. Similarly, the extracts 1 and 5 inhibited the growth of Colon 205 and MCF 7 cells with IC50 values of 65, 33; and 95 and 30 microg/ml, respectively. Interestingly, none of the tested extract has shown cytotoxicity towards normal PBMCs up to the concentration range studies (0-150 microg/ml). Taken together, these data suggest that the anti-inflammatory and anti-cancer properties of AC, CS, and CO might result from the growth inhibition of NO, TNF-alpha and IL-12, and tumor cells proliferation, respectively.
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The hot corrosion properties of heat-resistant steels were investigated in an oxidation atmosphere including artificial ash and sulfur dioxide. The heat-resistant steels of T22, T92, T122, T347HFG, Super304H and HR3C were evaluated at 620, 670 and 720 degrees C for 400 hours. The relationship between the corrosion rate and the temperature followed a bell-shaped curve with a peak rate at around 670 degrees C. The corrosion rates showed a decreasing tendency as the chrome contents of these steels increased from 2.15 wt.% to 24.5 wt.%, and austenitic steels had a lower corrosion rate than ferritic steels. Sulfidation by SO(2) as well as molten salt corrosion also had an effect on the total corrosion rate, especially showing an increase in the corrosion rate in ferritic steels. Regardless of the chrome content in the steels and irrespective of the test temperature, the corrosion scale was composed of an outer oxide and an artificial ash mixed layer, a middle oxide layer andinner sulfide, and amixed oxide layer. As the chrome content increased, the proportion of chrome oxide in the corrosion scale increased. Before spoiling of the corrosion scale, voids and cracks were initiated in the sulfide and the mixed oxide layer or at the interface with the substrate.
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Cordyceps militaris is a traditional herbal ingredient frequently used for tonic and medicinal purposes in eastern Asia. The hot water extract of its cultivated fruiting bodies demonstrated a potent cytotoxic effect against the proliferation of the human premyelocytic leukemia cell HL-60, with an IC50, of 0.8mg/ml for a 12-h treatment. It induced the characteristic apoptotic symptoms in the HL-60 cells, including DNA fragmentation and chromatin condensation, occurring within 12-16 h of treatment at a dose of I mg/ml. The activation of caspase-3 and the specific proteolytic cleavage of poly (ADP-ribose) polymerase were detected during the course of apoptosis induction. These results indicate that the hot water extract of Cordyceps militaris fruiting bodies inhibited cancer cell proliferation by inducing cell apoptosis through the activation of caspase-3, and that the Cordyceps militaris extract may therefore have therapeutic potential against human leukemia.
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An interleukin-18 binding protein (IL-18BP) was purified from urine by chromatography on IL-18 beads, sequenced, cloned, and expressed in COS7 cells. IL-18BP abolished IL-18 induction of interferon-γ (IFNγ), IL-8, and activation of NF-κB in vitro. Administration of IL-18BP to mice abrogated circulating IFNγ following LPS. Thus, IL-18BP functions as an inhibitor of the early Th1 cytokine response. IL-18BP is constitutively expressed in the spleen, belongs to the immunoglobulin superfamily, and has limited homology to the IL-1 type II receptor. Its gene was localized on human chromosome 11q13, and no exon coding for a transmembrane domain was found in an 8.3 kb genomic sequence. Several Poxviruses encode putative proteins highly homologous to IL-18BP, suggesting that viral products may attenuate IL-18 and interfere with the cytotoxic T cell response.
Article
Ergosterol peroxide, the steroidal derivative with cytotoxic activity, has been isolated for the first time from the mycelium of edible and medicinal mushroom Hericiumerinaceum (lion’s mane mushroom) together with erinacine A. The new densitometric method was applied for the quantitative determination of ergosterol peroxide in n-hexane extracts of H. erinaceum, Laetiporus sulfureus (chicken mushroom), and Morchella esculenta (common morel) mycelia, as well as in Boletus edulis (king bolete), Suillus bovinus (Jersey cow mushroom), and B. badius (bay bolete) fruiting bodies. The ergosterol peroxide content reached 15.98 ± 0.78, 10.07 ± 0.75, 13.37 ± 0.56, 29.32 ± 1.43, 17.27 ± 0.84, and 12.60 ± 0.59 mg per 100 g, respectively. What is significant was that ergosterol peroxide was identified for the first time, to the best of our knowledge, in edible mushrooms mentioned above.
Article
Three non-Ganoderma medicinal mushrooms are currently popular in Taiwan, including Brazilian mushroom (Agaricus blazei), chang-chih (Antrodia camphorata) and northern caterpillar fungus (Cordyceps militaris). The moisture contents of three dry mycelia ranged widely from 6.65 to 14.91%. All mycelia were high in carbohydrate content with chang-chih being the highest. The protein contents ranged from 9.49 to 29.1%. Soluble sugars found were arabitol, glucose and trehalose, and the contents exceeded 10%. Total free amino acid contents ranged from 7.01 to 11.1 mg g−1 dry weight. Contents of monosodium glutamate-like components were relatively low and similar in Brazilian mushroom and chang-chih, but high in northern Cordyceps. Contents of bitter components were significantly high in Brazilian mushroom and northern Cordyceps. Contents of flavour 5′-nucleotides were similarly high in chang-chih and northern Cordyceps, and low in Brazilian mushroom. The three mushroom mycelia had different proximate compositions. However, northern Cordyceps and chang-chih might exhibit similar umami and sweet tastes.
Article
Matrix metalloproteinase-9 (MMP-9), which degrades the extracellular matrix (ECM), plays an important role in breast cancer cell invasion. NF-kappaB and AP-1 are known to induce MMP-9 expression. We investigated whether cordycepin, an NF-kappaB or AP-1 inhibitor, can modulate MMP-9 expression and cell invasion in MCF-7 cells. Toxicity of cordycepin was determined by 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. MMP-9 expression was determined by real-time PCR, Zymography, and Western blot analysis. AP-1 activation was assayed by electrophoretic mobility shift assay (EMSA). MAPK signaling was evaluated by Western blotting with specific p-ERK, and ERK, p-p38, p38, p-JNK, JNK antibodies. Cordycepin suppressed AP-1 activation, but not NF-kappaB activation in 12-O-tetradecanoylpho-bol-13-acetate (TPA)-treated MCF-7 cells. Cordycepin inhibits TPA-induced MMP-9 expression and cell invasion by suppressing AP-1 activation. Also, cordycepin suppressed the MAPK signaling pathway. Cordycepin is a potent inhibitor of TPA-induced MMP-9 expression and blocks strongly the ability of AP-1 activation via MAPK signaling pathway in MCF-7 cells.
Article
Inflammation is a complex and necessary component of an organism's response to biological, chemical or physical stimuli. In the acute phase, cells of the immune system migrate to the site of injury in a carefully orchestrated sequence of events that is mediated by cytokines and acute phase proteins. Depending upon the degree of injury, this acute phase may be sufficient to resolve the damage and initiate healing. Persistent inflammation as a result of prolonged exposure to stimulus or an inappropriate reaction to self molecules can lead to the chronic phase, in which tissue damage and fibrosis can occur. Chronic inflammation is reported to contribute to numerous diseases including allergy, arthritis, asthma, atherosclerosis, autoimmune diseases, diabetes, and cancer, and to conditions of aging. Hematology and clinical chemistry data from standard toxicology studies can provide an initial indication of the presence and sometimes location of inflammation in the absence of specific data on the immune tissues. These data may suggest more specific immune function assays are necessary to determine the existence or mechanism(s) of -immunomodulation. Although changes in hematology dynamics, acute phase proteins, complement factors and cytokines are common to virtually all inflammatory conditions and can be measured by a variety of techniques, individual biomarkers have yet to be strongly associated with specific pathologic events. The specific profile in a given inflammatory condition is dependent upon species, mechanisms, severity, chronicity, and capacity of the immune system to respond and adapt.
Article
Cordycepin (3'-deoxyadenosine) has many anti-cancer properties. However, neither its molecular mechanism nor its molecular targets are well understood. In the present study, we investigated novel molecular mechanisms for the anti-tumor effects of cordycepin in human colon cancer HCT116 cells. After treatment of cells with cordycepin, dose-dependent cell growth inhibition was observed at an IC(50) value of 200muM. Cordycepin treatment resulted in G2/M-phase cell-cycle arrest, which was associated with increased p21WAF1 levels and reduced amounts of cyclin B1, Cdc2, and Cdc25c in a p53-independent pathway. Moreover, cordycepin treatment induced activation of JNK (c-Jun N-terminal kinases). Pretreatment with SP600125, a JNK-specific inhibitor, abrogated cordycepin-mediated p21WAF1 expression, cell growth inhibition, and reduced cell-cycle proteins. Furthermore, JNK1 inhibition by small interfering RNA (siRNA) produced similar results: suppression of cordycepin-induced p21WAF1 expression, decreased cell growth, and reduced cell-cycle proteins. Together, these results suggest a critical role for JNK1 activation in cordycepin-induced inhibition of cell growth and G2/M-phase arrest in human colon cancer cells.
Article
In order to elucidate immunoregulatory mechanisms of Cordyceps militaris, a methanol extract of Cordyceps militaris grown on germinated soybeans was prepared and its immunoregulatory effect in the human lung epithelial cells was investigated by examining its ability to induce IL-8 expression. Cordyceps militaris grown on germinated soybeans was extracted with 80% methanol (GSC4M) and used for stimulation of a human lung epithelial cell-line, A549. An enzyme-linked immunosorbent assay and reverse transcription-polymerase chain reaction were performed to examine the production of IL-8 protein and its mRNA, respectively. For the analysis of transcription factors regulating IL-8 transcriptional activation, the nuclear fraction was extracted from GSC4M-treated A549 cells and subjected to electrophoretic mobility shift assay. GSC4M induced IL-8 protein secretion and its mRNA expression from A549 cells in a dose- and time-dependent manner. GSC4M-induced IL-8 expression was inhibited by an inhibitor for lipid rafts formation but not by that for clathrin-coated pits. In addition, signaling pathways for GSC4M-induced IL-8 expression were mediated through ERK and JNK but hardly through p38 kinase. Furthermore, GSC4M augmented the DNA-binding activity of the transcription factors AP-1, NF-IL6, and NF-kappaB, all of which are involved in the transcriptional activation of the IL-8 gene. Cordyceps militaris grown on germinated soybeans stimulates lung epithelial cells to produce IL-8 through lipid rafts formation and signaling pathways via ERK and JNK.
Article
A regulated low level of nitric oxide (NO) production in the body is essential for maintaining homeostasis (neuroprotection, vasorelaxation, etc.), though certain pathophysiological conditions associated with inflammation involve de novo synthesis of inducible NO synthase (iNOS) in immune cells, including macrophages. A large body of evidence indicates that many inflammatory diseases, such as colitis and gastritis, as well as many types of cancer, occur through sustained and elevated activation of this particular enzyme. The biochemical process of iNOS protein expression is tightly regulated and complex, in which the endotoxin lipopolysaccharide selectively binds to toll-like receptor 4 and thereby activates its adaptor protein MyD88, which in turn targets downstream proteins such as IRAK and TRAF6. This leads to functional activation of key protein kinases, including IkB kinases and mitogen-activated protein kinases (MAPKs), such as p38 MAPK, JNK1/2, and ERK1/2, all of which are involved in activating key transcription factors, including nuclear factor-kappaB and activator protein-1. In addition, the production of proinflammatory cytokines such as interferon-gamma and interleukin-12 potentiates iNOS induction in autocrine fashions. Meanwhile, an LPS-stimulated p38 MAPK pathway plays a pivotal role in the stabilization of iNOS mRNA, which has the AU-rich element in its 3'-untranslated region, for rapid NO production. Thus, suppression and/or inhibition of the above-mentioned signaling molecules may have a great potential for the prevention and treatment of inflammation-associated carcinogenesis. In fact, there have been numerous reports of phytochemicals found capable of targeting NO production by unique mechanisms, including polyphenols, terpenoids, and others. This review article briefly highlights the molecular mechanisms underlying endotoxin-induced iNOS expression in macrophages, and also focuses on promising natural agents that may be useful for anti-inflammation and anticarcinogenesis strategies.
Article
Anisomeles indica (L.) Kuntze. (Labiatae), popularly known as 'yu-chen-tsao', has been traditionally used as anti-inflammatory agent. Investigate the chemical constituents from the whole plants of Anisomeles indica, and evaluate their in vitro anti-inflammatory activities. The combined MeOH extract was successively partitioned with CHCl(3) and n-butanol, then submitted to several column chromatographic, and HPLC purification procedures which led to the isolation of one cembrane-type diterpenoid (3), two benzenoids (4 and 5), five flavonoids (1, 2, 6, 7 and 14), and six phenyl propanoids (8-13). The compounds 1-14 were examined for their inhibitory effects on inflammatory mediator's enhanced production from LPS/IFN-gamma-stimulated macrophages. Among these, ovatodiolide (3) exhibited potent inhibition on NO, TNF-alpha and IL-12 enhanced production at a concentration of 5 microM, followed by pedalitin (1), scutellarein 7-O-beta-d-glucuronide methyl ester (6), and acteoside (12) at 40 microM (P<0.05). Furthermore, 2 microM of 3, and 20 microM of 1 and 6 significantly (P<0.05) arrested the cell cycle of Con A-stimulated spleen cells at the G0/G1 stage. This is the first report on the presence of compounds 1 and 4-13 in this plant and of the potent anti-inflammatory activity of 1, 3, 6 and 12 in vitro. These compounds may account for the use of Anisomeles indica in folk medicine to treat inflammation.
Article
A large number of cytokines are active in the joints of patients with rheumatoid arthritis (RA). It is now clear that these cytokines play a fundamental role in the processes that cause inflammation, articular destruction, and the comorbidities associated with RA. Following the success of TNF-alpha blockade as a treatment for RA, other cytokines now offer alternative targets for therapeutic intervention or might be useful as predictive biomarkers of disease. In this Review, we discuss the biologic contribution and therapeutic potential of the major cytokine families to RA pathology, focusing on molecules contained within the TNF-alpha, IL-1, IL-6, IL-23, and IL-2 families.
Article
Cordyceps militaris, one of traditional herbal ingredient in oriental medicine, has been known to promote anticancer and immunomodulatory activities in vitro and in vivo. However, the biological mechanism of anticancer activity has been unknown. To investigate the effect of Cordyceps militaris extract on expression of interferon gamma (IFN-gamma) through interlukin-18 (IL-18) induction and its biological mechanism in vitro and in vivo. Mice were administrated orally with solution extracted from Cordyceps militaris. The transcription level of IL-18 and IFN-gamma production were measured by reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry. RAW 264.7 cells were transiently transfected with pCATp1 and pCATp2 for IL-18 promoter functional analysis. Cordyceps militaris extracts treatment significantly induced level of IL-18 transcription in mouse brain and liver and enhanced IL-18 transcription level and activated the IFN-gamma production in RAW 264.7 cells. Furthermore, Cordyceps militaris extract led to increase the activity of pCATp1 construct containing the 5' franking region of IL-18 promoter in RAW 264.7 cells. Cordyceps militaris extract induced IL-18 mRNA level via enhancing of P1 promoter region result in activation of IFN-gamma production, indicating its potential as an immune activator or anticancer drug.
Article
This article has no abstract; the first 100 words appear below. THE growth of solid neoplasms is always accompanied by neovascularization. This new capillary growth is even more vigorous and continuous than a similar outgrowth of capillary sprouts observed in fresh wounds or in inflammation.¹ Many workers have described the association between growing solid malignant tumors and new vessel growth.²³⁴⁵⁶ However, it has not been appreciated until the past few years that the population of tumor cells and the population of capillary endothelial cells within a neoplasm may constitute a highly integrated ecosystem. In this ecosystem the mitotic index of the two cell populations may depend upon each other. Tumor cells . . . Supported by a grant (5 RO1 CA08185–06) from the National Cancer Institute, a grant from the American Cancer Society, National Chapter (IC-28), and gifts from the Merck Company and the Alza Corporation. Source Information From the Department of Surgery, Children's Hospital Medical Center and Harvard Medical School, Boston, Massachusetts 02115.
Article
The effect of fractions from a water extract of Polyporus on bladder tumor promotion was examined using 5% sodium saccharin (SS) in a short-term test with concanavalin A (Con A) in Wistar rats. Rats were given N-butyl-N-(4-hydroxybutyl) nitrosamine (BHBN) in drinking water for one week, and then promoter alone or test samples (given orally) plus promoter was administered for 3 weeks. Treatment with the BuOH fraction isolated from the water extract showed a strong inhibitory effect against the promoter. It was found that the inhibitory effect of the BuOH fraction is due to the effect of ergosterol contained in the fraction. Treatment with ergosterol showed a strong inhibitory effect against 5% SS, 0.01% BHBN, 3% DL-tryptophan (Trp) or 2% butylated hydroxyanisole (BHA); ID50 was 1.4 microg/kg/d, 2.9 microg/kg/d, 11.6 microg/kg/d, and 11.7 microg/kg/d against SS, BHBN, Trp and BHA, respectively. We also examined the effect of steroids and related compounds. Squalene and vitamin D2 showed strong inhibitory effect against 5% SS-induced bladder tumor promotion. These results strongly suggest that ergosterol could provide significant protection against the promotion of bladder tumor induced by many types of promoters in the environment.
Article
Four kaempferol glycosides were isolated from the leaves of Cinnamomum osmophloeum Kaneh, a Taiwan endemic tree. These compounds namely, kaempferitrin (1), kaempferol 3-O-beta-D-glucopyranosyl-(1-->4)-alpha-L-rhamnopyranosyl-7-O-alpha-L-rhamnopyranoside (2), kaempferol 3-O-beta-D-apiofuranosyl-(1-->2)-alpha-L-arabinofuranosyl-7-O-alpha-L-rhamnopyranoside (3), and kaempferol 3-O-beta-D-apiofuranosy-(1-->4)-alpha-L-rhamnopyranosyl-7-O-alpha-L-rhamnopyranoside (4). The structure of compound 2 was determined by spectroscopic analyses and acid hydrolysis. The isolates 1-4 were evaluated as inhibitors of some macrophage functions involved in the inflammatory process. These four compounds inhibited lipopolysaccharide (LPS) and interferon (IFN)-gamma-induced nitric oxide (NO), and cytokines [tumor necrosis factor (TNF)-alpha and interleukin (IL)-12] in a dose-dependent manner. The concentration of 50% inhibition (IC(50)) of NO by compounds 1, 3, 4 were 40, 15, 20microM, respectively. In parallel, these concentrations were approximately in a similar manner to that observed for TNF-alpha and IL-12 production. However, compound 2 inhibited NO and cytokines production by 30% at 100microM concentration. On the other hand, compounds 3 and 4 showed no inhibitory effect on the production of NO from macrophages, when inducible NO synthase was already expressed by the stimulation with LPS and IFN-gamma. Taken together, our results provide evidence that isolates of C. osmophloeum possess an anti-inflammatory potential which constitutes a previously unrecognized biological activity.
Article
Cordyceps militaris is a traditional herbal ingredient, which has been used for patients suffering from cancer in Oriental medicine. In the present study, we investigated the biochemical mechanisms of anti-proliferative effects by aqueous extract of C. militaris (AECM) in human leukemia U937 cells. It was found that AECM could inhibit cell growth of U937 cells in a dose-dependent manner, which was associated with morphological change and apoptotic cell death such as formation of apoptotic bodies and DNA fragmentation. We observed the down-regulation of anti-apoptotic Bcl-2 expression and proteolytic activation of caspase-3 in AECM-treated U937 cells. However, AECM did not affect the pro-apoptotic Bax expression and activity of caspase-9. Furthermore, Western blotting and RT-PCR revealed that AECM treatment caused a dose-dependent inhibition of cyclooxygenase-2 and prostaglandin E2 accumulation. Taken together, these results indicated that the anti-proliferative effects of AECM were associated with the induction of apoptotic cell death through regulation of several major growth regulatory gene products such as Bcl-2 family expression and caspase protease activity, and AECM may have therapeutic potential in human leukemia treatment.
Article
Four compounds, including one benzenoid, 4-O-methylgallic acid (1), together with three arylnaphthalide lignans, namely phyllamyricin C (2), justicidin B (3) and diphyllin (4) were isolated from the whole plants of Phyllanthus polyphyllus L. (Euphorbiaceae). This was the first isolation report of compounds 1-4 from this plant species. The in vitro inhibitory effects of these compounds were evaluated on the production of nitric oxide (NO) and cytokines (tumor necrosis factor (TNF)-alpha and interleukin (IL)-12), from LPS/IFN-gamma activated murine peritoneal macrophages. The results indicated that the 50% inhibition concentration (IC(50)) values of NO production from activated peritoneal macrophages by compounds 1-4 were 100, 25, 12.5 and 50 microM, respectively. In parallel, these dilutions were approximately inhibited in a similar manner to that observed for cytokines (TNF-alpha, and IL-12) production. On the other hand, at 100 microM concentration compounds 3 and 4 showed 50% inhibition of NO production from peritoneal macrophages that had been pre-activated with LPS/IFN-gamma for 24h, whereas compounds 1 and 2 inhibited only about 20 and 10%, respectively. These results support the use of this plant for the treatment of inflammatory diseases in oriental traditional medicine.
Article
Cordyceps militaris is a traditional herbal ingredient frequently used for tonic and medicinal purposes in eastern Asia. The hot water extract of its cultivated fruiting bodies demonstrated a potent cytotoxic effect against the proliferation of the human premyelocytic leukemia cell HL-60, with an IC50 of 0.8 mg/ml for a 12-h treatment. It induced the characteristic apoptotic symptoms in the HL-60 cells, including DNA fragmentation and chromatin condensation, occurring within 12-16 h of treatment at a dose of 1 mg/ml. The activation of caspase-3 and the specific proteolytic cleavage of poly (ADP-ribose) polymerase were detected during the course of apoptosis induction. These results indicate that the hot water extract of Cordyceps militaris fruiting bodies inhibited cancer cell proliferation by inducing cell apoptosis through the activation of caspase-3, and that the Cordyceps militaris extract may therefore have therapeutic potential against human leukemia.
Article
The Chinese herb DongChong-XiaCao originating from Cordyceps sinensis is widely used as a traditional medicine in China for treatment of a wide variety of diseases. The extracts of Cordyceps sinensis (CSE) and Cordyceps militaris (CME) are well-known for their biological effects. In the present study, the antioxidant efficiency of CME and CSE in protecting lipid, protein, and low-density lipoprotein (LDL) against oxidative damage was investigated. CME and CSE showed weakly inhibitory effect on liposome oxidation, that of CME being superior to that of CSE. As for the protein oxidation model system, the inhibitory effect of CME on protein oxidation was inferior to that of CSE. CME and CSE at 1.0 mg/mL showed 50.5 and 67.1% inhibition of LDL oxidation, respectively. The contents of bioactive ingredients cordycepin and adenosine in CME are higher than those of CSE; however, both cordycepin and adenosine showed no significant antioxidant activity as determined by the Trolox equivalent antioxidant capacity method. Polyphenolic and flavonoid contents are 60.2 and 0.598 microg/mL in CME and 31.8 and 0.616 microg/mL in CSE, respectively, which may in part be responsible for their antioxidant activities. In addition, a polysaccharide present in CME and CSE displayed antioxidant activity, which suggested that the activity might be derived partly from polysaccharides of CME and CSE. The tendency to scavenge the ABTS(*)(+) free radical and the reducing ability of CME and CSE display concentration-dependent manners, suggesting that CME and CSE may be potent hydrogen donators. On the basis of the results obtained, the protective effects of CME and CSE against oxidative damage of biomolecules are a result of their free radical scavenging abilities.
Article
The antioxidant (DPPH radical and superoxide anion scavenging activities), and cytotoxic (in tumor, Jurkat, PC-3, Colon 205, HepG2, and normal PBMCs cells) activities of 16 plant phenolic or related compounds were evaluated in vitro. Different categories compounds corresponding to 10 flavonoids, three lignans, two phenolic acids, and a catechin showed significant mean differences in antioxidant and cytotoxic activities. Particularly, the flavonols, quercetin (3) and tiliroside (11) possess significant antioxidant activity, as well as cytotoxic activity against Jurkat; and Jurkat and HepG2 cells, respectively. In contrast, the flavanone, 5,7-dimethoxy-3',4'-methylenedioxyflavanone (7), and homoisoflavonoid, isobonducellin (10) shown to have no significant antioxidant activity, but exhibited potent cytotoxic activity in Jurkat and HepG2 cells, while moderate growth inhibition against Colon205 cells. Interestingly, none of these derivatives shown to have toxicity toward normal peripheral blood mononuclear cells, over the concentration range tested (5-200 microM). Cytotoxic activities of some natural flavonoids identified in the medicinal plants were evaluated for the first time.
Article
Historically, anti-inflammatory drugs had their origins in the serendipitous discovery of certain plants and their extracts being applied for the relief of pain, fever and inflammation. When salicylates were discovered in the mid-19th century to be the active components of Willow Spp., this enabled these compounds to be synthesized and from this, acetyl-salicylic acid or Aspirin was developed. Likewise, the chemical advances of the 19th-20th centuries lead to development of the non-steroidal anti-inflammatory drugs (NSAIDs), most of which were initially organic acids, but later non-acidic compounds were discovered. There were two periods of NSAID drug discovery post-World War 2, the period up to the 1970's which was the pre-prostaglandin period and thereafter up to the latter part of the last century in which their effects on prostaglandin production formed part of the screening in the drug-discovery process. Those drugs developed up to the 1980-late 90's were largely discovered empirically following screening for anti-inflammatory, analgesic and antipyretic activities in laboratory animal models. Some were successfully developed that showed low incidence of gastro-intestinal (GI) side effects (the principal adverse reaction seen with NSAIDs) than seen with their predecessors (e.g. aspirin, indomethacin, phenylbutazone); the GI reactions being detected and screened out in animal assays. In the 1990's an important discovery was made from elegant molecular and cellular biological studies that there are two cyclo-oxygenase (COX) enzyme systems controlling the production of prostanoids [prostaglandins (PGs) and thromboxane (TxA2)]; COX-1 that produces PGs and TxA2 that regulate gastrointestinal, renal, vascular and other physiological functions, and COX-2 that regulates production of PGs involved in inflammation, pain and fever. The stage was set in the 1990's for the discovery and development of drugs to selectively control COX-2 and spare the COX-1 that is central to physiological processes whose inhibition was considered a major factor in development of adverse reactions, including those in the GI tract. At the turn of this century, there was enormous commercial development following the introduction of two new highly selective COX-2 inhibitors, known as coxibs (celecoxib and rofecoxib) which were claimed to have low GI side effects. While found to have fulfilled these aims in part, an alarming turn of events took place in the late 2004 period when rofecoxib was withdrawn worldwide because of serious cardiovascular events and other coxibs were subsequently suspected to have this adverse reaction, although to a varying degree. Major efforts are currently underway to discover why cardiovascular reactions took place with coxibs, identify safer coxibs, as well as elucidate the roles of COX-2 and COX-1 in cardiovascular diseases and stroke in the hope that there may be some basis for developing newer agents (e.g. nitric oxide-donating NSAIDs) to control these conditions. The discovery of the COX isoforms led to establishing their importance in many non-arthritic or non-pain states where there is an inflammatory component to pathogenesis, including cancer, Alzheimer's and other neurodegenerative diseases. The applications of NSAIDs and the coxibs in the prevention and treatment of these conditions as well as aspirin and other analogues in the prevention of thrombo-embolic diseases now constitute one of the major therapeutic developments of the this century. Moreover, new anti-inflammatory drugs are being discovered and developed based on their effects on signal transduction and as anti-cytokine agents and these drugs are now being heralded as the new therapies to control those diseases where cytokines and other nonprostaglandin components of chronic inflammatory and neurodegenerative diseases are manifest. To a lesser extent safer application of corticosteroids and the applications of novel drug delivery systems for use with these drugs as well as with NSAIDs also represent newer technological developments of the 21st century. What started out as drugs to control inflammation, pain and fever in the last two centuries now has exploded to reveal an enormous range and type of anti-inflammatory agents and discovery of new therapeutic targets to treat a whole range of conditions that were never hitherto envisaged.
Article
An acidic polysaccharide (APS) was isolated from the extract of Cordyceps militaris grown on germinated soybeans. Analyses of sugar composition indicated that APS consisted of d-galactose, L-arabinose, D-xylose, L-rhamnose, and D-galacturonic acid. On the basis of the result of methylation analysis, APS was considered to be mainly composed of Araf-(1-->, -->5)-Araf-(1-->, -->4)-Galp-(1--> and -->4)-GalAp-(1--> residues. When the polysaccharide was intranasally administered, it decreased virus titers in the bronchoalveolar lavage fluid and the lung of mice infected with influenza A virus and increased survival rate. Furthermore, APS increased TNF-alpha and IFN-gamma levels in mice when compared with those of untreated mice. APS enhanced nitric oxide (NO) production and induced iNOS mRNA and protein expressions in RAW 264.7 murine macrophage cells. The induction of mRNA expression of cytokines including IL-1beta, IL-6, IL-10, and TNF-alpha was also observed. These results demonstrated that APS might have beneficial therapeutic effects on influenza A virus infection at least in part by modulation of the immune function of macrophages.
Article
Phyllanthus urinaria Linnea (Euphorbiaceae), is a traditional anti-hepatitis herb used in Taiwan. In continuation of our search for potent natural anti-inflammatory agents, from the ethanolic extract of this plant, nine compounds including phyllanthin (1), phyltetralin (2), trimethyl-3,4-dehydrochebulate (3), methylgallate (4), and rhamnocitrin (5), methyl brevifolincarboxylate (6), beta-sitosterol-3-O-beta-d-glucopyranoside (7), quercitrin (8), and rutin (9) were isolated. The structures of compounds 3 and 6 were established based on NMR and mass spectral studies. The isolates 1-9 were investigated for their antioxidant, and anti-inflammatory activities in vitro. In the antioxidant assay, the isolates 3, 4 and 6 exhibited significant DPPH radical scavenging activity with an IC(50) value of 9.4, 9.8 and 8.9 microM, respectively. On the other hand, in the inflammatory mediators growth inhibitory assay from LPS/interferon (IFN)-gamma-activated peritoneal macrophages, all the isolates except 7, significantly and dose-dependently inhibited the enhanced production of NO radicals, and such modulation was closely associated with the inhibition of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6. In addition, 30 microM of isolates 3 and 6, and 50 microM of 4, significantly arrest the mitogen-stimulated spleen cells in G0/G1 stage. This is the first report on Phyllanthus urinaria isolates for their growth inhibitory activities against inflammatory mediators, in addition to spleen cell cycle arrest in G0/G1 stage. Therefore, these isolates from Phyllanthus urinaria may be useful for the treatment of cell-mediated immune diseases.
Article
Inflammation participates importantly in host defenses against infectious agents and injury, but it also contributes to the pathophysiology of many chronic diseases. Interactions of cells in the innate immune system, adaptive immune system, and inflammatory mediators orchestrate aspects of the acute and chronic inflammation that underlie diseases of many organs. A coordinated series of common effector mechanisms of inflammation contribute to tissue injury, oxidative stress, remodeling of the extracellular matrix, angiogenesis, and fibrosis in diverse target tissues. Atherosclerosis provides an example of a chronic disease that involves inflammatory mechanisms. Recruitment of blood leukocytes characterizes the initiation of this disease. Its progression involves many inflammatory mediators, modulated by cells of both innate and adaptive immunity. The complications of established atheroma, including plaque disruption and thrombosis, also intimately involve inflammation. Mastery of the inflammatory response should aid the development of novel strategies to predict disease susceptibility, target and monitor therapies, and ultimately develop new approaches to the prevention and treatment of chronic diseases associated with aging, such as atherosclerosis.
Article
The traditional Chinese medicine Cordyceps sinensis (CS) (Clavicipitaceae) improves pulmonary function and is used to treat respiratory disease. Here, we compare the efficacy and mechanisms of action of Cordyceps sinensis and Cordyceps militaris (CM) (Clavicipitaceae) in Calu-3 human airway epithelial monolayer model. The extracts of Cordyceps sinensis and Cordyceps militaris, as well as their isolated compounds, cordycepin and adenosine, stimulated ion transport in a dose-dependent manner in Calu-3 monolayers. In subsequent experiments, transport inhibitor bumetanide and carbonic anhydrase inhibitor acetazolamide were added after Cordyceps sinensis and Cordyceps militaris extracts to determine their effects on Cl- and HCO3- movement. The results suggested that Cordyceps sinensis and Cordyceps militaris extracts may affect the anion movement from the basolateral to apical compartments in the airway epithelia. Basolateral Na+-K+-2Cl- cotransporter and apical cAMP-dependent cystic fibrosis transmembrane conductance regulator Cl- channel are involved in the process. The results provide the first evidence for the pharmacological mechanism of Cordyceps sinensis and Cordyceps militaris on respiratory tract.
Icons of Medicinal Mushroom From China
  • J Ying