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Prospective Study for Korean Red Ginseng Extract as an Immune Modulator following a Curative Surgery in Patients with Advanced Colon Cancer
Abstract
In this paper, we present evidence that the Korean red ginseng extract shows the immunomodulatory activities during postoperative chemotherapy after curative surgery in patients with advanced colon cancer. We measured the circulating interleukin-2 (IL-2), interleukin-8 (IL-8)and interleukin-10 (IL-10) as a immune modulator to evaluate the effect of Korean red ginseng. The mean preoperative value of IL-2 was similar in the non-RG group and the RG group (5.72 pg/ml versus 6.87 pg/ml, p>0.05). The mean value of IL-2 was compared with IL-2 from healthy control group, there was no significant difference (14.89 pg/ml versus 14.22 pg/ml, p>0.05). The mean preoperative value of IL-8 was higher in the non-RG group comparing with the RG group (30.92 pg/ml versus 36.25 pg/ml, p < 0.05). At postoperative 3 month, the mean values of IL-8 from non-RG and RG group down to 24.56 pg/ml and 21.46 pg/ml respectively. The IL-8 of RG group at 3 month showed no difference with that of HC group(21.46 pg/ml versus 16.31 pg/ml, p>0.05). The preoperative mean value of IL-10 of non-RG, RG and HC group was 11.56 pg/ml, 10.8 pg/ml, and 3.68 pg/ml respectively. At postoperative 3 month, the mean values of IL-10 from non-RG and RG group down to 8.45 pg/ml and 5.04 pg/ml respectively. In spite of decreasing IL-10 levels of both cancer Patients group with time, there was still significant difference with that of HC group (non-RG versus HC group, p=0.00, RC versus HC group, p=0.04). The results of this study suggest that the red ginseng extract may have some immunomodulatory properties associated with IL-2, IL-8 and IL-10 activity in patients with advanced colorectal cancer during postoperative chemotherapy. We think to need the further studies and a larger sample size to fully evaluate the antitumor effect of ginseng and need to establish this mechanism of action as well as identify the active components associated with antitumor activity and immunomodulation in patients with advanced colorectal cancer.
... Twenty-eight trials originated from Korea , and two trials were conducted in Thailand [26] and the United Kingdom [27]. Sixteen studies [28,[32][33][34][35][36][37][38][39][40][41][44][45][46][47]53] were published in Korean, and 14 trials [26,27,[29][30][31]42,43,[48][49][50][51][52]54,55] were written in English. ...
... The key data from studies in healthy persons are summarised in Table 1 [26][27][28][29][30][31][32][33][34], and the data regarding other various conditions are summarised in Table 2 . The included RCTs used ginseng powder either in raw (4 studies) [35,38,53,55] or in capsules (22 studies) [26][27][28][29]31,32,34,36,37,[39][40][41][43][44][45][46][47][48][50][51][52]54] and extract preparation (2 studies) [33,42], while two studies [30,49] did not report the preparation type of ginseng. They addressed a wide range of conditions: generally healthy (i.e., studies in healthy individuals) [26][27][28][29][30][31][32][33][34], erectile dysfunction [35][36][37][38][39][40], gastric cancer [41,43], colon cancer [42], gastrointestinal carcinoma [44], chronic gastritis [45], diabetes mellitus [46,47], androgenic alopecia [48], coronary artery [49], dry mouth [50], glaucoma [51], obesity [52], metabolic syndrome [53], dyspepsia and indigestion [54] and Alzheimer's disease [55]. ...
... The included RCTs used ginseng powder either in raw (4 studies) [35,38,53,55] or in capsules (22 studies) [26][27][28][29]31,32,34,36,37,[39][40][41][43][44][45][46][47][48][50][51][52]54] and extract preparation (2 studies) [33,42], while two studies [30,49] did not report the preparation type of ginseng. They addressed a wide range of conditions: generally healthy (i.e., studies in healthy individuals) [26][27][28][29][30][31][32][33][34], erectile dysfunction [35][36][37][38][39][40], gastric cancer [41,43], colon cancer [42], gastrointestinal carcinoma [44], chronic gastritis [45], diabetes mellitus [46,47], androgenic alopecia [48], coronary artery [49], dry mouth [50], glaucoma [51], obesity [52], metabolic syndrome [53], dyspepsia and indigestion [54] and Alzheimer's disease [55]. ...
This systematic review was performed to summarise randomised clinical trials (RCTs) assessing the efficacy and safety of ginseng in the Korean literature.
The study involved systematic searches conducted in eight Korean Medical databases. The methodological quality of all of the included studies was assessed using the Cochrane Risk of Bias tool. We included all RCTs on any type of ginseng compared to placebo, active treatment or no treatment in healthy individuals or patients regardless of conditions.
In total, 1415 potentially relevant studies were identified, and 30 randomised clinical trials were included. Nine RCTs assessed the effects of ginseng on exercise capacity, cognitive performance, somatic symptoms, quality of life, and sleeping in healthy persons. Six RCTs tested ginseng compared with placebo for erectile dysfunction, while another four studies evaluated the effects of ginseng against no treatment for gastric and colon cancer. Two RCTs compared the effect of red ginseng on diabetes mellitus with no treatment or placebo, and the other nine RCTs assessed the effects of ginseng compared with placebo or no treatment on various conditions. The methodological caveats of the included trials make their contribution to the current clinical evidence of ginseng somewhat limited. However, the 20 newly added trials (66.7% of the 30 trials) may provide useful information for future trials. Ginseng appears to be generally safe, and no serious adverse effects have been reported.
The clinical effects of ginseng have been tested in a wide range of conditions in Korea. Although the quality of RCTs published in the Korean literature was generally poor, this review is useful for researchers to access studies that were originally published in languages that they would otherwise be unable to read and due to the paucity of evidence on this subject.
... Ginsenosides are reported to have various antitumor effects, including inhibition of angiogenesis as well as tumor invasion and metastasis. 50 Ginseng also appears to induce apoptosis through both the intrinsic and extrinsic pathways, inhibit NF-kB, and inhibit matrix metalloproteinase. 51 In a rat model of colon carcinogenesis, P. ginseng powder supplemented orally has been found to have a number of effects. ...
... This includes enhanced recovery of interleukin-2 (IL-2), as well as normalization of IL-8 and IL-10. 50 Specific to COX inhibition, Korean red ginseng (P. ginseng C.A. Meyer), or KRG, has been shown to impact COX activity in a mouse model of colon cancer and colitis. ...
Botanical medicines may prevent or hamper colon carcinogenesis through a variety of mechanisms, such as induction of apoptosis or cell cycle regulation. As evidenced by primary and secondary prevention studies using aspirin, inflammation and COX-2 expression are important drivers of colon carcinogenesis, promoting both the initiation and progression of colon cancer. Some botanical medicines may exert a protective effect by quelling such inflammation. This article reviews pertinent clinical or preclinical evidence for the preventive effects of garlic, curcumin, berberine, Boswellia, ginseng, ginger, resveratrol, and rosmarinic acid, in reference to colorectal cancer. While the data for medicinal plants and their constituents remain largely preclinical, there are several areas of interest that warrant additional study.
... The ginseng group received 3 g of Korean Red ginseng (Korea Ginseng Corporation, Seoul, Republic of Korea) daily as a pill. The dosage of 3 g/day was decided based on the safety dose from previous reports (13,14). Peripheral blood sampling was performed thrice during the study period: before the initiation of adjuvant chemotherapy, during chemotherapy, and after the end of chemotherapy ( Figure 2). ...
... The target sample size was calculated to have 80% power with a type I error rate of 0.05 and a dropout rate of 10%. Incremental differences between the two groups were based on a previous study, reporting 1.5 fold higher levels of antiinflammatory cytokines in the ginseng group in colorectal cancer (13). All analyses were conducted in the per-protocol population. ...
Background/aim:
We aimed to clarify the clinical effect of Korean Red ginseng administered with adjuvant chemotherapy on the immune function of patients with bile duct or pancreatic cancer.
Patients and methods:
This was a prospective, randomized controlled trial conducted at a single tertiary center. Twenty-six consecutive patients who underwent curative resection for bile duct or pancreatic cancer followed by 5-fluorouracil/leucovorin or gemcitabine chemotherapy were included. They were randomized 1:1 to the ginseng and control groups. Immune and inflammatory markers were assayed in peripheral blood samples during and after chemotherapy.
Results:
Intergroup differences in immune-related parameters before and during chemotherapy were not significant. After chemotherapy, the percentage of CD4+ T lymphocytes was significantly higher in the ginseng group than in the control group (42.01% vs. 33.69%, p=0.048). The ratio of CD4+/CD8+ T lymphocytes was also higher in the ginseng group (2.03 vs. 1.28, p=0.027). Neutropenia and liver dysfunction prevalence did not differ between the groups.
Conclusion:
The ginseng group, which received Korean Red ginseng daily during adjuvant chemotherapy, showed higher levels of CD4+ T lymphocytes and CD4+/CD8+ T lymphocyte ratio after chemotherapy.
... PG and its major pharmacologically active ingredients, ginsenosides, have various pharmacological properties, such as regulating central nervous system, immunomodulation, anti-inflammation, anticancer, antidiabetes, antioxidative, antifatigue [2][3][4][5]. PG is an immune modulator and exhibits effects on maintaining immune homeostasis and enhancing resistance to illness or microbial attacks [6]. It has been proved that PG extract and components have immuneregulatory properties through modulation of macrophages, which are the most versatile cells of human immune system to form the first line of defense against pathogens [7][8][9]. ...
Panax ginseng (PG) is a widely used functional food and herbal with immunoregulation activity. Currently, immunoregulation studies of PG mainly focused on the specific actions of individual constituents. However, the integral immunoregulation mechanisms of PG need further research. In this study, an integrated metabolomics and network pharmacology approach were used to investigate it. High-content screening was used to evaluate macrophage phagocytosis activity of PG. Untargeted metabolomics profiling of murine macrophage cells with UHPLC-Q-TOF-MS and a multivariate data method were performed to discover the potential biomarkers and metabolic pathways. Then, a macrophage phenotype related “ingredients-targets-metabolites” network of PG was constructed using network pharmacology for further research. As a result, PG can significantly enhance macrophage phagocytosis of GFP- E. coli . A total of twenty potential biomarkers and ten main pathways for which levels changed markedly upon treatment were identified, including glycerophospholipid metabolism, glutathione metabolism, choline metabolism, and taurine metabolism. Twenty compounds of PG associated with metabolomic changes were selected by the network pharmacology analysis, including ginsenoside Re, ginsenoside Rg1, frutinone A, and kaempferol. The network pharmacology results also showed that PG can polarize macrophages to both M1 and M2 phenotype but may be prone to M2 phenotype. In conclusion, our results indicated that PG may be prone to polarize macrophages to M2 phenotype by mainly regulating the glutathione and choline metabolism, which was related to twenty compounds of PG.
... This study was conducted to investigate the immunomodulatory effect of HCE comprising C. officinalis S. et Z., E. japonica Lindley, and olive leaves. RGE, which have found application in antioxidant and anti-inflammatory properties [31,32]. ...
Objective: To investigate the effects of a herb complex extract (HCE) prepared from Cornus officinalis Sieb. Et Zucc., Eriobotrya japonica Lindley, and olive leaves on immune response of mouse spleen NK cells in vitro and in vivo analysis. Methods: The activity of natural killer (NK) cells was measured in splenocytes and YAC-1 cells. Mice were immunosuppressed using cyclophosphamide (5 mg/kg body weight). Three different doses of HCE (200, 400, and 800 mg/kg body weight) and red ginseng extract (800 mg/kg body weight) which was used as standard immunomodulatory herb were administered orally for 4 weeks. The body weight, dietary, water intake, organs (liver, thymus, and spleen) weight, completed blood count, and cytokines (tumor necrosis factor alpha, interferon gamma, and interleukin-2) production was measured. Results: At the maximum concentration of HCE, the activity of NK cells was increased by 48.5%. HCE increased liver, spleen, and thymus weights without altering numbers of white blood cells, lymphocytes, and neutrophils in a cyclophosphamide-induced immunosuppression rat model. However, HCE recovered the inhibited cytokine expression; HCE (800 mg/kg) increased cytokines levels. The results indicate the immune enhancement potential of this HCE. Conclusion: The HCE enhances immunity by increasing NK cell activity, regulating cytokine levels, and maintaining spleen weight. Therefore, it may be used as
a potential immunity enhancer.
... Ginseng extract was evaluated during chemotherapy in 47 colon cancer patients after surgical treatment. IL-2, IL-8, and IL-10 associated immnunomodulatory effect was observed (Boo, Park, Kim, & Suh, 2007). Standardized ginseng extract (Ginsana G115) showed immune regulatory action in a double-blind sixty healthy adults clinical study (Scaglione et al., 1990). ...
Background: Mechanistic studies suggest that ginseng, as dietary supplement, plays a key role in disease prevention by modulating the immune function of human body. The root of Panax ginseng and Panax quinquefolius (Family: Araliaceae) are commonly known as ‘ginseng’. Ginseng roots are well known for their high content of saponins, ginsenosides, phenolic compounds, including carbohydrates and carotenoids. In recent years, there is a growing interest in the role of ginseng as a nutraceutical or functional food with increasing market value. Extracts and bioactive compounds isolated from ginseng are studied for their various health promoting activities such as antioxidant, antitumor, antihyperglycemic, skin protecting, anti-osteoporotic anticancer, anti-infective and respiratory problems. Scope and approach: The present review reports structural and functional diversity of ginseng, key bioactive compounds, their immunity boosting potential and studies related to cell mediated and humoral immunity of ginseng. Immunity-boosting power of ginseng against cancer, autoimmune diseases and viral and bacterial infections has been compiled. The vaccine adjuvant role, safety profile and drug interactions ginseng and derived products are also discussed. Nano-ginseng as immune modulators has been a unit of article. The clinical trials carried out and patent portfolio of ginseng against immune disorders is the important section of this article. Patent search was performed by using The Patent Lens search engine and results included under heading “Ginseng based Patents for immunomodulation”. Key isolated compounds have been mentioned along with their structures to give a quick overview of the chemical constituents. Key findings and conclusions: After critically reviewing the immune potential of ginseng both in vitro and in vivo and even describing the clinical data in humans we reached at conclusion that ginseng can be considered as good candidates for the development of novel functional foods that has natural potential to modulate immunity against various diseases. Future work will have to focus on the identification of the relevant compounds from ginseng, the thorough preclinical characterization and selection of the candidate bioactives, and the rational design of immunotherapy studies involving objective as well as subjective parameters for measuring clinical efficacy. We believe that this review will be a valuable resource for more studies on ginseng as a dietary supplement in relevance to immune-modulation.
... Safety of 3 g KRG intake in a day was already proved in a previous randomized controlled trial on the effect of improving blood circulation [18]. In addition, another prospective randomized trial investigating the immune effect of KRG in patients with colon cancer who had a curative resection and chemotherapy used daily 3 g of KRG [19]. Based on these previous results, the initial prospective study chose to use 3 g of KRG as a daily dose. ...
Purpose
This study investigated how adding Korean red ginseng extract (KRG) to folinic acid, fluorouracil and oxaliplatin (FOLFOX) chemotherapy affected the rate of splenomegaly in colon cancer.
Methods
This retrospective study analyzed 42 patients who were randomly assigned to receive a FOLFOX regimen with or without KRG. Spleen volume change was assessed by computed tomography scans measured before surgery (presurgery volume) and 3 weeks after cessation of the 12th cycle of FOLFOX (postchemotherapy volume).
Results
All patients showed increased spleen volume. No difference was observed in median presurgery and postchemotherapy volume between the KRG and control groups. However, a ratio defined as postchemotherapy volume divided by presurgery volume was significantly lower in the KRG group than the control group (median, 1.38 [range, 1.0–2.8] in KRG group vs. median, 1.89 [range, 1.1–3.0] in control group, P = 0.028). When splenomegaly was defined as a >61% increase in spleen volume, the rate of splenomegaly was significantly lower in the KRG group than the control group (28.6% vs. 61.9%, P = 0.03). KRG consumption was inversely associated with developing splenomegaly in multivariate analysis.
Conclusion
Adding KRG during FOLFOX chemotherapy for colon cancer might protect against oxaliplatin-induced splenomegaly. The protective effect of Korean red ginseng should be investigated with further research.
... These results confirm that red ginseng has protective effects against acute respiratory diseases [40]. When type 1 human immunodeficiency virus-infected patients (AIDS patients) either took medication and red ginseng together or took red ginseng alone Red ginseng extract Random (no placebo) 25 healthy individuals and 50 stomach cancer patients 3 g/3 months -IL-2 and decrease rate of IL-10 were higher in the red ginseng group than in the control group [37] Red ginseng extract Random (no placebo) 47 colorectal cancer patients 3 g/3 months -IL-2, IL-8, and IL-10 activity was regulated in the red ginseng group than in the control group [38] Red ginseng powder ...
Ginseng has been traditionally used for several millennia in Asian countries, including Korea, China, and Japan, not only as a nourishing and tonifying agent but also as a therapeutic agent for a variety of diseases. In recent years, the various effects of red ginseng including immunity improvement, fatigue relief, memory improvement, blood circulation improvement, antioxidation, mitigation of menopausal women's symptoms, and anticancer an effect have been reported in clinical as well as basic research. Around the world, there is a trend of the rising consumption of health functional foods on the level of disease prevention along with increased interest in maintaining health because of population aging and the awareness of lifestyle diseases and chronic diseases. Red ginseng occupies an important position as a health functional food. But till now, international ginseng monographs including those of the World Health Organization have been based on data on white ginseng and have mentioned red ginseng only partly. Therefore, the red ginseng monograph is needed for component of red ginseng, functionality certified as a health functional food in the Korea Food and Drug Administration, major efficacy, action mechanism, and safety. The present red ginseng monograph will contribute to providing accurate information on red ginseng to agencies, businesses, and consumers both in South Korea and abroad.
... , 항 산 화 (Cho et al., 2006;Keum et al., 2000), 항 암 (Kim et al., 2004;Suh et al., 2007;Surh et al., 2001), 신 경 세 포 보 호 (Kampen et al., 2003;Lopez et al., 2007), 간 기 능 개 선 (Kang et al, 2007;Kwon and Jang, 2004), 항 스 트 레 스 (Kim et al., 2003a;2003b) Corbit et al., 2005;Lou et al., 2005;Wan et al., 2006a;2006b). Lee et al., 2007). ...
An advanced extraction method by ultrasonic extraction with applied solid phase extraction (SPE) has been developed for the determination of simultaneous eight major ginsenosides, namely ginsenosides Rg1, Re, Rf, Rb1, Rg2, Rc, Rb2, and Rd in the root of Panax ginseng. Four extraction methods including n-BuOH reflux extraction (Method A), 70% EtOH reflux extraction (Method B), 50% MeOH reflux extraction with SPE (Method C), and 50% MeOH ultrasonication with SPE clean-up process (Method D) were investigated for the determination of eight major ginsenosides. Total contents of ginsenosides were highest by extraction of Method C as . However, Method D was evaluated as relatively simpler and more efficient method due to short extraction time, small solvent consumption and less expensive, compared to conservative reflux method. Ginsenosides were also satisfactorily separated with good resolution and the accuracy range was between 1.05 and 4.06% as relative standard deviation (RSD) by Method D. SPE condition and HPLC condition were further optimized for determination of eight major ginsenosides by the ultrasonic extraction method. Conclusively, ultrasonic extraction of 2 g sample of ginseng using ultrasonic bath and 1 loading for SPE was evaluated as proper condition for extraction of ginseng.
... It has been used as a medicine to treat various diseases in the Orient for several thousand. The major active components of ginseng are ginsenosides, having bioactive and pharmacological activities, including anti-cancer activities [1], anti-inflammatory [2], antiaging activities [3]. However, these naturally occurring ginsenosides are observed to be poorly absorbed along the human intestinal tracts [4]. ...
Ginsenoside Rb1is the main component in ginsenosides. It is a protopanaxadiol-type ginsenoside that has a dammarane-type triterpenoid as an aglycone. In this study, ginsenoside Rb1 was transformed into gypenoside XVII, ginsenoside Rd, ginsenoside F2 and compound K by glycosidase from Leuconostoc mesenteroides DC102. The optimum time for the conversion was about 72 h at a constant pH of 6.0 to 8.0 and the optimum temperature was about 30℃. Under optimal conditions, ginsenoside Rb1 was decomposed and converted into compound K by 72 h post-reaction (99%). The enzymatic reaction was analyzed by highperformance liquid chromatography, suggesting the transformation pathway: ginsenoside Rb1→ gypenoside XVII and ginsenoside Rd→ginsenoside F2→compound K.
... These results are comparable to our study. Suh et al. [32] reported that KRG had immunemodulatory properties associated with IL-2, IL-8, and IL-10 in adult colon cancer patients after surgery. They reported IL-2 was increased and IL-10 was decreased after KRG administration. ...
Ginseng has been used as an herbal medicine, widely used in Asian countries, for long time. Recently, beneficial effects for immune functions of Korean red ginseng (KRG) have been reported in adults. This study was performed to investigate the effects of ginseng on immune functions in children after cessation of chemotherapy or stem cell transplantation for advanced cancer. Thirty patients, who were diagnosed and treated for leukemia and solid cancer at the department of pediatrics and adolescence of the Yeungnam University Hospital from June 2004 to June 2009, were enrolled for the study. The study group consisted of 19 patients who received KRG extract (60 mg/kg/d) for 1 yr and 11 patients who did not receive KRG extract were the control group. Blood samples were collected every 6 mo. Immune assays included circulating lymphocyte subpopulation, serum cytokines (IL- 2, IL-10, IL-12, TNF-alpha, and IFN-gamma), and total concentrations of serum IgG, IgA, and IgM subclasses. Age at diagnosis ranged from 2 mo to 15 yr (median 5 yr). Nine patients received stem cell transplantation. The cytokines of the KRG treated group were decreasing more rapidly than that of the control group. Lymphocyte subpopulations (T cell, B cell, NK cell, T4, T8, and T4/ T8 ratio) and serum immunoglobulin subclasses (IgG, IgA, and IgM) did not show significant differences between the study and the control groups. This study suggests that KRG extract might have a stabilizing effect on the inflammatory cytokines in children with cancer after chemotherapy.
This study aimed to elucidate the effects of amifostine (ethyol) (AM), a synthetic radioprotector, and red ginseng (RG), a natural radioprotective agent, against the toxic effect of ionizing radiation (IR) on kidney tissues through changes in biochemical and histopathological parameters in addition to contributions to the use of amifostine and RG in clinical studies. Five groups were established: Group I (control, receiving only saline by gavage), Group II (IR only), and Group III (IR+AM, 200 mg/kg intraperitoneally (i.p.). Group IV (IR + RG, 200 mg/kg orally once a day for 4 weeks), and Group V (IR+RG+AM, 200 mg/kg orally once/day for 4 weeks before IR and 200 mg/kg AM administered (i.p.) 30 min before IR). All groups, except for the control group, were subject to 6-Gy whole-body IR in a single fraction. 24 h after irradiation, all animals were sacrificed under anesthesia. IR enhanced MDA, 8-OHdG, and caspase-3 expression while decreasing renal tissue GSH levels (p < .05). Significant numbers of necrotic tubules together with diffuse vacuolization in proximal and distal tubule epithelial cells were also observed. The examination also revealed substantial brush boundary loss in proximal tubules as well as relatively unusual glomerular structures. While GSH levels significantly increased in the AM, RG, and AM+RG groups, a decrease in KHDS, MDA, 8-OHdG, and caspase-3 expression was observed, compared to the group subject to IR only (p < .05). Therefore, reactive oxygen species-scavenging antioxidants may represent a promising treatment for avoiding kidney damage in patients receiving radiation.
Background
Most clinical studies of immune responses activated by Korean Red Ginseng (KRG) have been conducted exclusively in patients. However, there is still a lack of clinical research on immune-boosting benefits of KRG for healthy persons. This study aims to confirm how KRG boosts the immune system of healthy subjects.
Methods
A total of 100 healthy adult subjects were randomly divided into two groups that took either a 2 g KRG tablet or a placebo per day for 8 weeks. The primary efficacy evaluation variables included changes in T cells, B cells, and white blood cells (WBCs) before and after eight weeks of KRG ingestion. Cytokines (TNF-α, INF-γ, IL-2 and IL-4), WBC differential count, and incidence of colds were measured in the secondary efficacy evaluation variables. Safety evaluation variables were used to identify changes in laboratory test results that incorporated adverse reactions, vital signs, hematological tests, blood chemistry tests, and urinalysis.
Results
Compared to the placebo group, the KRG intake group showed a significant increase in the number of T cells (CD3) and its subtypes (CD4 and CD8), B cells, and the WBC count before and after eight weeks of the intake. There were no clinically significant adverse reactions or other notable results in the safety evaluation factors observed.
Conclusion
This study has proven through its eight-week intake test and subsequent analysis that KRG boosts the immune system through an increase in T cells, B cells, and WBCs, and that it is safe according to the study's safety evaluation.
Traditional medicinal practices have used natural products such as adaptogens to treat inflammatory, autoimmune, neurodegenerative, bacterial, and viral diseases since the early days of civilization. Panax ginseng Myer is a common herb used in East Asian countries for millennia, especially in Korea, China, and Japan. Numerous studies indicate that ginseng can modulate the immune system and thereby prevent diseases. Although the human immune system comprises many different types of cells, multiple studies suggest that each type of immune cell can be controlled or stimulated by ginseng or its derivatives. Provisional lists of ginseng’s potential for use against viruses, bacteria, and other microorganisms suggest it may prove to be a valuable pharmaceutical resource, particularly if higher-quality evidence can be found. Here, we reviewed the role of ginseng as an immune-modulating agent in attempt to provide a valuable starting point for future studies on the herb and the human immune system.
The effects of aqueous extracts of red ginseng on the damage of DNA and erythrocyte by herbicides were evaluated using comet assay and hemolysis assay. Notably, the oxidative DNA damage and erytbrocyte hemolysis by 2,4-D (2,4-dichlorophenoxyacetic acid) and 2,4,5-T (2,4,5-trichlorophenoxyacetic acid) were significantly suppressed by red ginseng treatment. Moreover, red ginseng could suppress significantly paraquat-induced oxidative DNA damage and hemolysis. These suppressive effects of red ginseng on the herbicide-induced damages might be due to the antioxidant components.
The pharmacological activities of Panax ginseng, Panax quinquefolium, and Panax notoginseng as herbal medicinal resources were reviewed to evaluate their biofunctional effects. P. ginseng contains relatively many kinds of ginsenoside that possess pharmacological activity compared with P. quinquefolium and P. notoginseng. However, the ratio of panaxatriol and panaxadiol of ginsenoside in P. notoginseng is higher than those of P. ginseng and P. quinquefolium. The free sugar content of P. ginseng is similar to P. quinquefolium but is different from P. notoginseng. The total free amino acid content is highest in P. ginseng and lowest in P. notoginseng. P. ginseng has the highest antioxidative effects and P. ginseng and P. quinquefoilum possess more potent cytotoxicities on A549 and SK-OV-3 cell lines than P. notoginseng. Particularly, red ginseng of P. ginseng shows the highest antidiabetic effects, suggesting that it possesses activity to enhance insulin secretion as well as to prevent a destruction of pancreatic islet cells.
This study was conducted to evaluate the effects of natural bioactive products such as Manda enzyme (T1), Yangmyeongwon (T2), effective microorganisms (T3), and Kelpak (T4) on the growth and ginsenoside contents of Panax ginseng cultured in an aeroponic system using a two-layer vertical type of nutrient bath under natural light conditions. The growth of ginseng plants showed specific characteristics according to the positions in which they were cultured due to the difference of light transmittance and temperature in the upper and lower layers during aeroponic culture in a two-layer vertical type of system. The growth of the aerial part of the leaves and stems of ginseng plants cultured in the lower layer (4,000 to 6,000 lx, 23℃ to 26℃) of the nutrient bath was observed to be superior to that of the ginseng plants cultured in the upper layer (12,000 to 15,000 lx, 25℃ to 28℃). The leaf area was significantly larger in the treatment of T2 and T4 (46.70 cm(2)) than with other treatments. Conversely, the values of the root weight and root diameter were higher in ginseng plants cultured in the upper layer of the nutrient bath. The root weight was significantly heavier in the treatment of T4 (6.46 g) and T3 (6.26 g) than with other treatments. The total ginsenoside content in the leaves and roots was highest in the ginseng plants cultured by the treatment of T1, at 16.20%, while the total ginsenoside content obtained by other treatments decreased in the order of T4, T5 (control), T2, and T3, at 13.21%, 12.30%, 14.84%, and 14.86%, respectively. The total ginsenoside content of the ginseng leaves was found to be significantly higher in the treatment of T1 in the lower layer of the nutrient bath, at 15.30%, while the content of the ginseng roots in the treatments of T3 and T4, at 1.27% and 1.23%, respectively, was significantly higher than in other treatments in the upper layer of the nutrient bath.
In this study, rare ginsenoside Rf was transformed into 20(S)-protopanaxatriol (PPT(S)) by glycosidase from Aspergillus niger. By investing the reaction conditions, the optimal conditions were obtained, as follows: pH 5.0, temperature 55 degrees C, and substrate concentration 1.25 mmol/l. Under optimal conditions, PPT(S) (1.13 micromol) prepared from 1.25 mumol Rf showed a higher yield (90.4%). The enzymatic reaction was analyzed by reversed-phase HPLC, suggesting the transformation pathway: Rf-->Rh1(S)-->PPT(S).
The effects of Panax ginseng extracts on DNA damage, expression of cytochrome P450 (CYP) 1A1 and reproductive toxicity were evaluated in the testis of rats exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxinthe (TCDD). Fifty rats were divided into five groups according to treatment with 2,3,7,8-TCDD and P. ginseng extracts. Single cell gel electrophoresis assays were performed to evaluate DNA damage that occurred in the lymphocytes of rats. Histological changes in the seminiferous tubules of the testis were determined using Johnsen's scoring system and Real Time-PCR was performed to evaluate the mRNA expression of CYP1A1. Significant pathological effects were observed in the 2,3,7,8-TCDD treated rats including a reduced seminiferous tubular diameter, an increased number of damaged tubules (maturation arrest, eosinophilic degeneration and spermatid giant cells) and increased Johnsen's score. DNA damage and the expression of CYP1A1 mRNA were significantly increased in rat testes. There were no significant differences between the control and animals treated with P. ginseng extracts. However, a significantly decreased level of DNA damage, decreased CYP1A1 expression and reduced pathological effects were observed in the 2,3,7,8-TCDD with P. ginseng extracts treated groups when compared with the TCDD treated group. In summary, our study demonstrates that 2,3,7,8-TCDD induces the pathological and genotoxical damage in rat testes, while P. ginseng extract treatment exhibits a therapeutic capacity to reduce these effects via reduction of CYP1A1 mRNA.
Patients with cancer often show impaired immune functions; however, the basis of this suppression is still not understood. In several experimental systems, human T-cells with receptors for Fc of immunoglobulin G may function as suppressors, and those with receptors for Fc of immunoglobulin M may function as helpers. Peripheral blood as well as tumor tissue infiltrates were examined for proportions and numbers of Ty, T/i, or la- positive T-cells. Forty-five untreated patients with solid tumors and 24 patients with lymphomas were studied. An increase in the percentage of peripheral blood Ty cells (p < 0.001) and a decrease in T/i cells (p < 0.0005) were recorded in all tumor patients when compared with 30 normal controls. Percentages and absolute numbers of peripheral blood la-positive T-cells were decreased (p < 0.001 and < 0.00001) in solid-tumor patients; by contrast, the proportion of peripheral blood la- positive T-cells was elevated (p < 0.005) in lymphoma sub jects. Studies of cancer tissues from 46 untreated patients using immunofluorescence and mouse hybridoma antibody specific for T-cells showed that tumor lymphocytic infiltrates were composed mainly of T-cells. Double staining with fluores- cein-conjugated specific anti-Ty and anti-human la reagents detected relatively high proportions of Ty and la-positive T- cells within solid-tumor lymphoid infiltrates. A comparison of peripheral blood and tumor lymphocyte T-cell profiles revealed that, in some patients, low proportions of la-positive T-cells in blood were paralleled by a high percentage of such cells in tumor lymphoid infiltrates.
Interleukin-2 (IL-2) is recognized as a T cell growth factor. We have previously reported that human carcinoma cell lines are inhibited in growth by exogenous IL-2, which binds to the IL-2 receptor β (IL-2Rβ) chain ubiquitously expressed on the surface of tumor cells. A possibility was considered that IL-2R/β on carcinomas responsible for negative signaling was different from that expressed on hematopoietic cells. To investigate this possibility, mRNA for the IL-2Rβ chain was amplified and compared in carcinoma and lymphoid cells. Using RT-PCR with pairs of sense-antisense oligonucleotide primers specific for the various regions of extracellular, transmembrane and intracellular domains of the IL-2Rβ chain, we amplified mRNA obtained from three human carcinoma cell lines and human lymphoid cells as controls. The identity of the amplicons was confirmed by Southern analysis with the 32P-labeled cDNA probe coding for the entire span of the IL-2Rβ chain. In addition, genomic DNA obtained from the tumor cell lines was sequenced to examine the possibility that a mutation is present in the gene coding for the intracellular IL-2R/β chain domain. No mutations or deletions were detected. The message for all three domains of the β chain was identical in tumor cells and in normal lymphoid cells used as controls. Also, by Western blot and northern analyses no differences between IL-2Rβ chain in tumors vs that expressed in lymphoid cells were demonstrable. The IL-2Rγ chain, which participates in IL-2/IL-2R signaling pathway, was expressed in tumor cells. Expression of JAK1 transcripts in these cells was comparable to that in lymphocytes. However, RT-PCR analysis identified differences in expression of JAK3 splice variants (B and M) in tumor cells. These differences may be responsible for altered downstream signaling by IL-2. Overall, our data indicate that the same IL-2/IL-2R pathway is operative in human carcinomas and in normal epithelial or lymphoid cells.
Colorectal cancer development is associated with a shift in host immunity with suppression of the cell-mediated immune system (CMI) and a predominance of humoral immunity (HI). Tumour progression is also associated with increased rates of cell proliferation and apoptosis. The aim of this study was to investigate whether these factors correlate and have an influence upon prognosis. Long-term follow-up was performed on 40 patients with colorectal cancer who had levels of tumour necrosis factor (TNF)-alpha, interferon (IFN)-gamma and interleukin (IL)-10 measured from stimulated blood cultures before surgery. Their archived tumour specimens were analysed to determine a Ki-67-derived proliferation index (PI) and a M30-derived apoptosis index (AI). Tumour necrosis factor-alpha levels negatively correlated to tumour proliferation (rho=-0.697, P=0.01). Interleukin-10 levels had a positive correlation with tumour proliferation (rho=0.452, P=0.05) and apoptosis (rho=0.587, P=0.01). Patient survival correlates to tumour pathological stage (P=0.0038) and vascular invasion (P=0.0014). An AI< or =0.6% and TNF-alpha levels > or =8148 pg ml(-1) correlate to improved survival (P=0.032, P=0.021). Tumour proliferation and apoptosis correlate to progressive suppression of the CMI-associated cytokine TNF-alpha and to and higher levels of IL-10. Survival is dependent upon the histological stage of the tumour, vascular invasion, rates of apoptosis and proliferation and systemic immunity which are all interconnected.
The aim of this study was to evaluate prospectively the impact of the red ginseng extract on circulating interleukin (IL) 2 and 10 in advanced gastric cancer during chemotherapy after operative treatment. Analysis of circulating IL-2 and 10 was performed in 50 patients with advanced gastric adenocarcinoma who underwent a curative surgery or with an unresectable gastric adenocarcinoma by using ELISA and monoclonal antibodies at preoperative day 1, postoperative months 1, and 3. Twenty-five patients as the control group, twenty-six patients as the non-ginseng (NG) group, and twenty-four patients as the ginseng (G) group were eligible in this study. All plasma IL-2 of the NG and G groups was significantly lower an that of the control group on preoperative 1 day. These values of the G group were more increase than these of the NG group during the postoperative chemotherapy. The mean value of serum IL-10 of the control group (0.608pg/ml) was significantly lower than that of the advanced gastric cancer patients including the NG (12.015 pg/ml) and G group (9.409 pg/ml) (p?0.001). These values of the G group were reduced progressively during the postoperative chemotherapy. The mesh value of the G group were only close to that of the control group on postoperative months 3 (p=0.003). The number of patients who were enrolled in this study was relatively small to fully evaluate the immunologic effects of the red ginseng extract on circulating IL-2 and 10. Despite this limitation, these results suggest that the post-operative intake of the red ginseng extract have potential to improve earlier anti-cancer immunity with recovering IL-2 and reducing IL-10 from the depressed IL-2 and elevated IL-10 by gastric cancer during the postoperative chemotherapy. This study will be based on the future study to evaluate the anti-immunity of the red ginseng extract.
Ginsenosides (oligoglycosides) extracted from the root of Panax Ginseng, C. A. Meyer, are found to induce the reverse transformation of Morris hepatoma cells (MH1C1) in vitro.After 24 subcultures of growth medium containing ginsenoside, MH1C1 cells were morphologically changed. These cells were relatively large and polygonal in shape with abundant fine granular cytoplasm and clear intercellular space, and resembled normal hepatocyte-like cells.These cells reversely transformed, by ginsenosides, showed much less ability to grow in a 0.33% soft agar suspension culture in comparison to control MH1C1 cells, but the doubling time of these cells was 30 hr which is similar to that of original Morris hepatoma cells.In these reversely transformed cells, a remarkable increase in uptake of l-3H-ornithine in an arginine deficient medium, an increase of activity of succinate-cytochrome c reductase and a decrease in 5′-nucleotidase activity were observed.
Red ginseng extract A and B are the active components of Panax ginseng. Red ginseng is a classical traditional Chinese medicine. Among Chinese herbs, red ginseng has been considered as one of the tonics. Many studies indicated that red ginseng could enhance immune function of the human body. The effects of red ginseng extracts on transplantable tumors, proliferation of lymphocyte, two-stage model and rat liver lipid peroxidation were studied. In a two-stage model, red ginseng extracts had a significant cancer chemoprevention. At 50-400 mg/kg, they could inhibit DMBA/Croton oil-induced skin papilloma in mice, decrease the incidence of papilloma, prolong the latent period of tumor occurrence and reduce tumor number per mouse in a dose-dependent manner. Red ginseng extract B could effectively inhibit the Fe2+/cysteine-induced lipid peroxidation of rat liver microsome, suggesting that red ginseng extract B has a stronger antioxidative effect than that of extract A. The results indicated that red ginseng extracts (50 approximately 400 mg/kg) could significantly inhibit the growth of transplantable mouse sarcoma S180 and melanoma B16. Red ginseng extracts A (0.5 mg/ml) and B (0.1 and 0.25 mg/ml) might effectively promote the transformation of T lymphocyte, but there was no influence on lymphocyte proliferation stimulated by concanavalin A. This suggests that red ginseng extracts have potent tumor therapeutic activity and improve the cell immune system.
The cytotoxic ability of interleukin 2 (IL2)-induced T cells and the effect on their cytotoxicity of serum suppressive factors obtained from cancer patients were examined. Peripheral blood mononuclear cells (PBL) of healthy adults were IL2-cultured for 72 h either together with a gastric carcinoma cell line MKN-28 or with phytohemagglutinin, then IL2-cultured for another 11 days. Cytotoxicity of the MKN-28 precultured lymphocytes against MKN-28 was particularly increased. Presence during preculture or during cytotoxicity assay of sera from gastric cancer patients having the same histological type as MKN-28 suppressed the cytotoxicity. However, the serum suppressive effect on cytotoxicity of the IL2-cultured lymphocytes was far milder than that on PBL cytotoxicity.
The present study was designed to investigate the mechanisms responsible for suppressed T-cell immunity in gastric cancer patients. The peripheral blood T-cell functions in gastric cancer patients were evaluated by measuring responses to PHA and IL-2, and T-cell subpopulations were assessed by flow cytometry. Both the PHA and IL-2 responses decreased in patients with gastric cancer, although the proportions of CD3+ and CD25+ cells were the same for gastric cancer patients and healthy volunteers. The PHA response, but not that of IL-2, was lower in patients with liver metastasis or peritoneal dissemination than in patients without these conditions. Single regression analysis showed that with lymph node involvement in the disease the IL-2 response was more strongly suppressed than PHA response. The serum level of IAP did not correlate with the response to either PHA or IL-2. The proportion of CD4+ cells was not affected by any factor related to gastric cancer, although CD4+/CD8+ and CD8+11b-/CD8+11b+ ratios did decrease in patients with distant lymph node involvement. These changes may be due to a comparative increase in suppressor cells. These results suggest that gastric cancer patients exhibit impaired IL-2 mediated T-cell function and that the number of suppressor cells may increase with progressive lymph node involvement. These two serial effects may be indeed responsible for the impaired blood T-cell function in patients with gastric cancer.
The cell-mediated immune function of 83 patients with gastric carcinoma was assessed preoperatively and the results were compared to that of 52 patients with benign lesions. The data were subjected to an analysis in order to evaluate their prognostic significance. The abilities to induce allogeneic cytotoxicity and to produce interleukin 2 (IL2) in patients with stage IV carcinoma were significantly depressed, as compared to those in patients with benign lesions, whereas natural killer (NK) cell activity was not significantly impaired. There was no significant correlation among these immune functions. When the patients were stratified into two groups, those who had high (greater than the mean value in patients with benign lesions) and low (less than the same value) values of these immune reactivities, the survival of patients with high NK activity (greater than or equal to 43%) was significantly better, as compared to that of patients with low cytotoxicity (less than 43%). However, there was no correlation between the survival and allogeneic cytotoxicity in these patients. The high ability to produce IL2 (greater than or equal to 1.3 U/ml) correlated with the better survival in the patients, but not in the group of patients who underwent curative resection.
An antitumor-active substance was obtained from the residue of the ethyl acetate extract of red ginseng, a traditional Chinese medicine, by chromatography on a silica gel column. From the proton and carbon-13 nuclear magnetic resonance spectra, it was identified as heptadeca-1-ene-4,6-diyne-3,9,10-triol (panaxytriol). The panaxytriol contents of red ginseng and white ginseng, determined by gas chromatography after solvent extraction and formation of trimethylsilyl derivatives, were 0.38 and 0.25 mg/g, respectively. Panaxytriol showed a growth-inhibitory activity against several tumor cell lines.
Panax ginseng occupies an important place among the tonic remedies of Oriental medicine. Pharmacological investigations show that crude ginsenosides can increase non-specific resistance of an organism to various untoward influences. The effects of purified derived derivatives have only recently become better studied in immunological and cell growth studies in animals and in man. This has now provided some evidence to suggest that ginseng is a drug that contains many derivatives with different pharmacological properties, which could be useful in clinical medicine.
The effect of prolactin (PRL) treatment on estrogen production by rat granulosa cells was investigated in vitro. Immature, hypophysectomized, DES-treated rats were injected for 2 days with FSH to induce aromatase enzymes and receptors for PRL and LH. After FSH priming, the granulosa cells were cultured for 4 days in serum-free medium containing 10(-7) M androstenedione and purified FSH, LH and/or PRL. A dose-related inhibition of estrogen production from control cells was observed following PRL treatment in which 1 micrograms/ml of PRL inhibited estrogen formation by > 90%. In these same cultures, PRL caused a dose-related increase in progesterone and 20 alpha-dihydroprogesterone secretion. Treatment with purified FSH or LH stimulated estrogen synthesis by 3-10-fold. Concomitant treatment with PRL suppressed the FSH- and LH-induced increases in estrogen production in a dose-dependent manner; 1 micrograms/ml PRL suppressed estrogen production by > 80% during days 2-4 of culture. In these same cultures, PRL did not alter the stimulatory effects of FSH and LH on progesterone and 20 alpha-dihydroprogesterone production. These experiments demonstrate that PRL acts directly on rat granulosa cells in vitro to suppress basal and gonadotropin-induced increases in estrogen production.
We studied the effect of ginsenoside-Rb2 extracted from Panax ginseng on angiogenesis and metastasis produced by B16-BL6 melanoma cells in syngeneic mice. Intravenous administration of ginsenoside-Rb2 on day 1, 3 or 7 after tumor inoculation achieved a remarkable reduction in the number of vessels oriented toward the tumor mass, but did not cause a significant inhibition of tumor growth. The anti-angiogenic effect was dose-dependent ranging from 10 to 500 micrograms/mouse. In contrast, intra-tumoral or oral administration of ginsenoside-Rb2 caused a marked inhibition of both neovascularization and tumor growth. Ginsenoside-Rb2 did not affect the growth of rat lung endothelial (RLE) cells, B16-BL6 melanoma cells or various types of murine normal cells in vitro. The invasion of RLE cells into the reconstituted basement membrane (Matrigel), which is considered to be an essential event in tumor neovascularization, was inhibited by ginsenoside-Rb2 in a concentration-dependent fashion, while ginsenoside-Rb2 did not inhibit the haptotactic migration of endothelial cells to fibronectin-substrate. Multiple administrations of ginsenoside-Rb2 after the intravenous inoculation of B16-BL6 melanoma cells resulted in a significant inhibition of lung metastasis as compared with the untreated control. These results suggest that the inhibition of tumor-associated angiogenesis by ginsenoside-Rb2 may partly contribute to the inhibition of lung tumor metastasis.
This study presents the risk of various cancers in relation to ginseng intake based on the data from a case-control study conducted in the Korea Cancer Center Hospital. Ginseng intakers had a decreased risk [odds ratio = 0.50, 95% confidence interval (CI) = 0.44-0.58] for cancer compared with nonintakers. On the type of ginseng, the odds ratios for cancer were 0.37 (95% CI = 0.29-0.46) for fresh ginseng extract intakers, 0.57 (95% CI = 0.48-0.68) for white ginseng extract intakers, 0.30 (95% CI = 0.22-0.41) for white ginseng powder intakers, and 0.20 (95% CI = 0.08-0.50) for red ginseng intakers. Intakers of fresh ginseng slice, fresh ginseng juice, and white ginseng tea, however, showed no decreasing risk. There was a decrease in risk with the rising frequency and duration of ginseng intake, showing a dose-response relationship. On the site of cancer, the odds ratios were 0.47 for cancer of the lip, oral cavity, and pharynx; 0.20 for esophageal cancer; 0.36 for stomach cancer; 0.42 for colorectal cancer; 0.48 for liver cancer; 0.22 for pancreatic cancer; 0.18 for laryngeal cancer; 0.55 for lung cancer; and 0.15 for ovarian cancer. In cancers of the female breast, uterine cervix, urinary bladder, and thyroid gland, however, there was no association with ginseng intake. In cancers of the lung, lip, oral cavity and pharynx, and liver, smokers with ginseng intake showed decreased odds ratios compared with smokers without ginseng intake. These findings support the view that ginseng intakers had a decreased risk for most cancers compared with nonintakers.(ABSTRACT TRUNCATED AT 250 WORDS)
We examined the inhibitory effect of two saponin preparations from Red ginseng, 20(R)- and 20(S)-ginsenoside-Rg3, in comparison with that of ginsenoside-Rb2, on lung metastasis produced by two highly metastatic tumor cells, B16-BL6 melanoma and colon 26-M3.1 carcinoma, in syngeneic mice. In an in vitro analysis, both saponin preparations showed a significant inhibition of adhesion to fibronectin (FN) and laminin (LM) by B16-BL6 melanoma. Similarly, they significantly inhibited the invasion of B16-BL6 cells into the reconstituted basement membrane (Matrigel)/FN in a dose-dependent manner. In an experimental metastasis model using B16-BL6 melanoma, consecutive intravenous (i.v.) administrations of 100 micrograms/mouse of 20(R)- or 20(S)-ginsenoside-Rg3 1, 2, 3 and 4 d after tumor inoculation led to a significant decrease in lung metastasis. The inhibitory effect of i.v. administration of both ginseng saponins on the tumor metastasis of B16-BL6 melanoma was also recognized in a low dose of 10 micrograms/mouse. The oral administration (p.o.) of both saponins (100-1000 micrograms/mouse) induced a significant decrease in lung metastasis of B16-BL6 melanoma. Moreover, both ginseng saponins were effective in inhibiting of lung metastasis produced by colon 26-M3.1 carcinoma. When 20(R)- or 20(S)-ginsenoside-Rg3 was orally administered consecutively after tumor inoculation in a spontaneous metastasis model using B16-BL6 melanoma, both of them significantly inhibited lung metastasis. In the experiment involving neovasculization by tumor cells in vivo, both mice groups given each saponin preparation after tumor inoculation exhibited a significant decrease in the number of blood vessels oriented toward the tumor mass, with no repression of tumor size. These findings suggest that both ginseng saponins, 20(R)- and 20(S)-ginsenoside-Rg3, possess an ability to inhibit the lung metastasis of tumor cells, and the mechanism of their antimetastatic effect is related to inhibition of the adhesion and invasion of tumor cells, and also to anti-angiogenesis activity.
Interleukin-8 (IL-8) is a member of the chemokine family of pro-inflammatory chemotactic cytokines and is secreted by some human colorectal carcinoma cell lines. We have used in situ hybridisation and immunohistochemistry to determine whether IL-8 mRNA and protein, respectively, are produced by human colorectal carcinoma cells in vivo. IL-8 mRNA was detected within the cytoplasm of tumour cells in all nine samples tested, including that of a tumour which had metastasised to a lymph node. Non-involved colonic mucosa within the same tissue blocks showed much weaker labelling. IL-8 protein was detected in 74% (23/31) of tumour samples and was mainly localised to the tumour cell cytoplasm. In 30% of cases, staining was heterogeneous, with between 1 and 30% of cells being positive. In some tumour cells, IL-8 showed a perinuclear distribution resembling that found by in situ hybridisation. Some infiltrating leucocytes, endothelial cells and fibroblast-like cells within the tumour sections were also positive for IL-8 mRNA and protein. The possibilities that colorectal tumours produce IL-8 to aid invasion and/or metastasis or as a tumour growth factor are discussed.
In the present study an acidic polysaccharide ginsan, with a molecular weight of 150,000, devoid of lectin properties, was purified from Panax ginseng C.A. Meyer (Araliaceae). Ginsan induced the proliferation of T cells and B cells. Spleen cells became cytotoxic to a wide range of tumor cells without major histocompatibility complex-restriction after 4 or 5 days culture in vitro with ginsan. For the generation of these ginsan-activated killer (AK) cells adherent macrophages and CD4+ cells were needed as accessory cells. The generation of ginsan-AK cells was blocked in the presence of anti-IL-2, anti-IFN gamma, anti-IL-1 or anti-TNF alpha antibodies, showing the importance of these cytokines in the process. The surface phenotypes of the 4 day-cultured ginsan-AK cells was Thy1+, AsGM1+, CD8+, which is distinct from rIL-2 induced lymphokine activated killer (LAK) cells that were CD8. The ginsan also activated macrophages to produce reactive nitrogen intermediates and become tumoricidal. It also exhibited significant in vivo antitumor activity against B16 melanoma cells lines, and in the benzo(a)pyrene-induced autochthonous lung tumor model, at much lower doses than the maximum tolerate doses. Indeed, no mice died, which injected with ginsan at 1g/kg body weight intraperitoneally. In conclusion, 'ginsan' could potentially be an ideal nontoxic antineoplastic immunostimulator by activating multiple effector arms of the immune system.
The effects of concomitant use of bombesin and ginsenoside Rg3 on the incidence of peritoneal metastasis of intestinal adenocarcinomas induced by azoxymethane were investigated in male inbred Wistar rats. From the start of the experiment, rats were given weekly s.c. injections of azoxymethane (7.4 mg/kg body weight) for 10 weeks and s.c. injection of bombesin (40 microg/kg body weight) every other day, and from week 20, s.c. injections of ginsenoside Rg3 (2.5 or 5.0 mg/kg body weight) every other day until the end of the experiment in week 45. Bombesin significantly increased the incidence of intestinal tumors and cancer metastasis to the peritoneum in week 45. It also significantly increased the labeling index of intestinal cancers. Although administration of a higher dose of ginsenoside Rg3 with bombesin had little or no effect on the enhancement of intestinal carcinogenesis by bombesin, the location, histologic type, depth of involvement, infiltrating growth pattern, labeling and apoptotic indices and tumor vascularity of intestinal cancers, it significantly decreased the incidence of cancer metastasis. These findings indicate that ginsenoside Rg3 inhibits cancer metastasis through activities that do not affect the growth or vascularity of intestinal cancers.
We have examined the possibility that a component of Panax ginseng, ginsenoside-Rg1 (G-Rg1), acts by binding to the glucocorticoid receptor (GR). G-Rg1 competed for [3H]dexamethasone (Dex) binding to GR with a specific affinity of 1-10 microM and activated a glucocorticoid responsive element-containing luciferase reporter gene. The dose-dependence patterns of G-Rg1 and Dex for these two effects were nearly identical, although two to three orders of magnitude higher concentration of G-Rg1 than that of Dex was required for the same magnitude of response. At the cellular level, the growth of FT02B cells was suppressed by G-Rg1 as well as by Dex, each of whose effects were abolished by RU486. These results demonstrate that G-Rg1 is a functional ligand of GR.
We previously reported that an acidic polysaccharide from Panax ginseng named ginsan inhibits the incidence of benzo[a]pyrene-induced autochthonous lung tumors in mice. To elucidate the mechanism of antineoplastic activity, ginsan was tested for its ability to generate LAK cells and to produce cytokines. Spleen cells became cytotoxic to a wide range of tumor cells after 5 days of culture with ginsan in a non-major histocompatibility restricted manner and the activity of ginsan was 12 times higher than that of lentinan. The generation of killer cells by rIL-2 was neutralized only in the presence of anti-IL-2, whereas by ginsan it was neutralized in the presence of anti-IL-2 as well as anti-IFN gamma, or anti-IL-1 alpha. It was confirmed that ginsan induces the expression of mRNA for IL-2, IFN gamma, IL-1 alpha, and GM-CSF. Depletion of AsGM1+ cells from spleen cells reduced the generation of LAK by rIL-2. In contrast, depletion of AsGM1+ as well as Thy1+ cells, CD4+ cells, or DC8+ cells reduced the generation of LAK cells by ginsan. The serologic phenotype of rIL-2 induced LAK cells was CD8- cells, whereas the ginsan induced LAK cells, were CD8+ cells. Ginsan synergized with rIL-2 to generate LAK cells (2.0-15 fold) and the most dramatic synergy was seen at rIL-2 concentrations below 3 U/ml. Ginsan alone inhibited pulmonary metastasis of B16-F10 melanoma cells and enhanced the inhibition of lung colonies by rIL-2. These findings demonstrate that ginsan generates LAK cells from both NK and T cells through endogeneously produced multiple cytokines. This property may contribute to its effectiveness in the immunoprevention and immunotherapy of cancer.
Our previous study demonstrated that the in vivo anti-metastatic effect induced by oral administration of ginseng protopanaxadiol saponins was mediated by their metabolic component M1, and that the growth, invasion and migration of tumor cells were inhibited by M1 but not by ginsenosides. Here we investigated the inhibitory mechanism of M1 on the growth of tumor cells. M1 inhibited the proliferation of B16-BL6 mouse melanoma cells in a time- and dose-dependent manner, with accompanying morphological changes at the concentration of 20 microM. In addition, at 40 microM M1 induced apoptotic cell death within 24 h. Fluorescence microscopy revealed that dansyl M1 entered the cytosol and quickly reached the nuclei (approximately 15 min). Western blot analysis revealed that M1 rapidly up-regulated the expression of p27Kip1, but down-regulated the expression of c-Myc and cyclin D1 in a time-dependent manner. Thus, the regulation of apoptosis-related proteins by M1 is responsible for the induction of apoptotic cell death, and this probably leads to the anti-metastatic activity in vivo.
A number of studies have reported that increased consumption of natural products reduced the risk of cancer. Our previous case-control studies have shown a significant reduction in the risk of cancer development among those who regularly consumed ginseng. We conducted a prospective cohort study to evaluate the preventive effect of ginseng against cancer on a population residing in a ginseng cultivation area on the basis of the result of case-control studies.
This study was conducted in Kangwha-eup from August 1987 to December 1992. We studied 4634 people over 40 years old who completed a questionnaire on ginseng intake. In an attempt to obtain detailed information about ginseng intake, we asked them to specify their age at initial intake, their frequency and duration of ginseng intake, the kind of ginseng, etc. Multiple logistic regression was used to estimate relative risks (RR) when controlling simultaneously for covariates.
Ginseng consumers had a decreased risk (RR = 0.40, 95% confidence interval [CI] : 0.28-0.56) compared with non-consumers. On the type of ginseng, the RR was 0.31 (95% CI: 0.13-0.74) for fresh ginseng extract consumers and 0.34 (95% CI: 0.20-0.53) for consumers of multiple combinations. There was no cancer death among 24 red ginseng consumers. There was a decreased risk with a rise in the frequency of ginseng intake, showing a dose-response relationship. The RR of ginseng consumers were 0.33 (95% CI: 0.18-0.57) in gastric cancer and 0.30 (95% CI : 0.14-0.65) in lung cancer. Among ginseng preparations, fresh ginseng extract consumers were significantly associated with a decreased risk of gastric cancer (RR = 0.33, 95% CI: 0.12-0.88).
These results strongly suggest that Panax ginseng C.A. Meyer has non-organ specific preventive effect against cancer, providing support for the previous case-control studies.
In this paper, we present evidence that the red ginseng powder from Panax ginseng C.A. Meyer inhibits the recurrence of AJCC stage III gastric cancer and shows immunomodulatory activities during postoperative chemotherapy, after a curative resection with D2 lymph node dissection. Flow cytometric analyses for peripheral T-lymphocyte subsets showed that the red ginseng powder restored CD4 levels to the initial preoperative values during postoperative chemotherapy. Depression of CD3 during postoperative chemotherapy was also inhibited by the red ginseng powder ingestion. This study demonstrated a five-year disease free survival and overall survival rate that was significantly higher in patients taking the red ginseng powder during postoperative chemotherapy versus control (68.2% versus 33.3%, 76.4% versus 38.5%, respectively, p < 0.05). In spite of the limitation of a small number of patients (n = 42), these findings suggest that red ginseng powder may help to improve postoperative survival in these patients. Additionally, red ginseng powder may have some immunomodulatory properties associated with CD3 and CD4 activity in patients with advanced gastric cancer during postoperative chemotherapy.
The correlation between colorectal cancer rates of proliferation and apoptosis and systemic cytokine levels; plus their influence upon survival
- C Evans
- I Morrison
- A G Heriot
- J B Bartlett
- C Finlayson
- A Dalgleish
- G
- D Kumar