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What do herbalists suggest to diabetic patients in order to improve glycemic control? Evaluation of scientific evidence and potential risks.

In the course of 12 continuing education seminars given in different regions of Italy in 2001, we distributed a questionnaire to all the attending herbalists asking information about the herbal remedy and dietary supplement they mainly recommended to subjects who required a "natural" treatment to control glycemia. We distributed 720 questionnaires and we received 685 completed ones. We have compiled a short review on the efficacy and safety of the 10 most frequently advised products for each category. The 10 more frequently suggested herbal remedies were gymnema, psyllium, fenugreek, bilberry, garlic, Chinese ginseng, dandelion, burdock, prickly pear cactus, and bitter melon. The 10 most frequently recommended dietary supplements were biotin, vanadium, chromium, vitamin B6, vitamin C, vitamin E, zinc, selenium, alpha-lipoic acid, and fructooligosaccharides. The majority of the products recommended by Italian herbalists may be efficacious in reducing glycemia. If a diabetic patient is already assuming products that even slightly reduce glycemia, we risk to underestimate the level of glucose intolerance, while if the patient stops the complementary treatment after initiating pharmaceutical therapy, in the subsequent visit we may underestimate the effect of our prescription. Therefore, if doctors are to have a role in gate-keeping or advising patients about complementary and alternative medicine, they need to be familiar with this type of medicine. If they choose otherwise, then the provision of complementary and alternative medicine will continue to be patchy and largely outside the conventional care framework, perhaps through a growing network of parallel care providers involving a large number of non-medically qualified practitioners, who patients will continue to access directly.

Blood Glucose↗

Ginsenosides Rb1 and Rg1 effects on survival and neurite growth of MPP+-affected mesencephalic dopaminergic cells.

Ginsenosides Rb1 and Rg1 are the main active ingredients of Panax ginseng C.A. Meyer (Araliaceae). They appear to exert protection against ischaemia and anoxic damage in animal models, suggesting an antioxidative and cytoprotective role. In our study, primary cultures from embryonic mouse mesencephalon are applied to examine the effects of these two ginsenosides on neuritic growth of dopaminergic cells and their survival affected by 1-methyl-4-phenylpyridinium-iodide (MPP(+)). Ginsenoside Rb1 (at 10 microM) enhanced the survival of dopaminergic neurons by 19% compared to untreated control. MPP(+) (at 1 microM) significantly reduced the number of dopaminergic neurons and severely affected neuronal processes. Both ginsenosides counteracted these degenerations and significantly protected lengths and numbers of neurites of TH(+) cells. Both compounds however could not prevent the cell loss caused by MPP(+). Our study thus indicates partial neurotrophic and neuroprotective actions of ginsenosides Rb1 and Rg1 in dopaminergic cell culture.

1-Methyl-4-phenylpyridinium↗

Effect of Hochu-ekki-to on asymptomatic MRSA bacteriuria.

Hochu-ekki-to, a multiple herbal drug which consists of 10 medicinal plants (Astragali radix, Atractylodis lanceae rhizoma, Ginseng radix, Angelicae radix, Bupleuri radix, Zizyphi fructus, Aurantii nobilis pericarpium, Glycyrrhizae radix, Cimicifugae rhizoma, and Zingiberis rhizoma), was administered to 38 patients with asymptomatic methicillin-resistant Staphylococcus aureus (MRSA) bacteriuria, and the effect was evaluated. The patients received Hochu-ekki-to at a daily dose of 7.5 g for at least 24 weeks. As a prognostic nutritional index (PNI), albumin and lymphocytes in the peripheral blood were measured, in addition to urine culture. The results were compared with those in 12 untreated control patients with asymptomatic MRSA bacteriuria. Four of the 38 patients treated with Hochu-ekki-to received antibacterial drugs during the treatment period, and were excluded from the study. Among the 34 eligible patients treated with Hochu-ekki-to, urinary MRSA was eradicated in 12 patients, and the bacterial counts in urine culture decreased to 10(2) CFU/ml or less in 10 patients. In patients treated with Hochu-ekki-to, urinary bacteria were decreased from 10 weeks after treatment compared with the findings in control patients (P < 0.05). PNI improved in all patients compared with the baseline before treatment. It was considered that the biodefense function was recovered via nutritional improvement by the administration of Hochu-ekki-to, and, as a result, MRSA bacteriuria improved. Further investigation would be needed in future.

Adult↗

Elucidation of the mechanisms underlying the angiogenic effects of ginsenoside Rg(1) in vivo and in vitro.

The major active constituents of ginseng are ginsenosides, and Rg(1) is a predominant compound of the total extract. Recent studies have demonstrated that Rg(1) can promote angiogenesis in vivo and in vitro. In this study, we used a DNA microarray technology to elucidate the mechanisms of action of Rg(1). We report that Rg(1) induces the proliferation of HUVECs, monitored using [(3)H]-thymidine incorporation and Trypan blue exclusion assays. Furthermore, Rg(1) (150-600 nM) also showed an enhanced tube forming inducing effect on the HUVEC. Rg(1) was also demonstrated to promote angiogenesis in an in vivo Matrigel plug assay, and increase endothelial sprouting in the ex vivo rat aorta ring assay. Differential gene expression profile of HUVEC following treatment with Rg(1) revealed the expression of genes related to cell adhesion, migration and cytoskeleton, including RhoA, RhoB, IQGAP1, CALM2, Vav2 and LAMA4. Our results suggest that Rg(1) can promote angiogenesis in multiple models, and this effect is partly due to the modulation of genes that are involved in the cytoskeletal dynamics, cell-cell adhesion and migration.

Cell Adhesion↗

Functional foods, herbs and nutraceuticals: towards biochemical mechanisms of healthy aging.

Aging is associated with mitochondrial dysfunctions, which trigger membrane leakage, release of reactive species from oxygen and nitrogen and subsequent induction of peroxidative reactions that result in biomolecules' damaging and releasing of metals with amplification of free radicals discharge. Free radicals induce neuronal cell death increasing tissue loss, which could be associated with memory detriment. These pathological events are involved in cardiovascular, neurodegenerative and carcinogenic processes. Dietary bioactive compounds from different functional foods, herbs and nutraceuticals (ginseng, ginkgo, nuts, grains, tomato, soy phytoestrogens, curcumin, melatonin, polyphenols, antioxidant vitamins, carnitine, carnosine, ubiquinone, etc.) can ameliorate or even prevent diseases. Protection from chronic diseases of aging involves antioxidant activities, mitochondrial stabilizing functions, metal chelating activities, inhibition of apoptosis of vital cells, and induction of cancer cell apoptosis. Functional foods and nutraceuticals constitute a great promise to improve health and prevent aging-related chronic diseases.

Aging↗

Conversion of major ginsenoside Rb1 to ginsenoside F2 by Caulobacter leidyia.

Ginsenoside Rb1 is the most predominant ginsenoside in Panax species (ginseng) and the hydrolysis of this ginsenoside produces pharmaceutically active compounds. Caulobacter leidyia GP45, one of the isolates having strong beta-glucosidase-producing activity, converted ginsenoside Rb(1) to the active metabolites by 91%. The structures of the resultant metabolites were identified by NMR. Ginsenoside Rb1 had been consecutively converted to ginsenoside Rd (1), F2(2) and compound K (3) via the hydrolyses of 20-C beta-(1-->6)-glucoside, 3-C beta-(1-->2)-glucoside, and 3-C beta-glucose of ginsenoside Rb1.

Biotransformation↗

Neuroprotective effect of a chuk-me-sun-dan on neurons from ischemic damage and neuronal cell toxicity.

Chukmesundan (CMSD), composed of the following 8 medicinal herbs including Panex ginseng C.A. MEYER, Atractylodes macrocephala KOID, Poria cocos WOLF, Pinellia ternata BREIT, Brassica alba BOISS, Aconitum carmichaeli DEBX, Cynanchum atratum BGE and Cuscuta chinensis LAM. CMSD is being used in Korea for the treatment of various symptoms accompanying hypertension and cerebrovascular disorders. This study was carried out to examine the effects of CMSD on cultured primary neuron cell, cell cytotoxicity and lipid peroxidation in Abeta-treated cells. Cell death was enhanced by addition of Abeta. Pretreatment of CMSD attenuated in cell killing induced by Abeta. The protective effect of the CMSD water extracts on Abeta-induced neuronal death was also observed by lactate dehydrogenase assay using cultured astrocyte cells. Abeta-induced cell death was protected by the water extract of CMSD in a dose-dependent manner, and 25-50 microg/ml was the most effective concentration. CMSD has been also shown to protect primary cultured neurons from N-methyl-D: -aspartate receptor-mediated glutamate toxicity. It was in vivo evidenced that CMSD protects neurons against ischemia-induced cell death. Moreover, oral administration of CMSD into mice prevented ischemia-induced learning disability and rescued hippocampal CA1 neurons from lethal ischemic damage. The neuroprotective action of exogenous CMSD was also confirmed by counting synapses in the hippocampal CA1 region. The presence of CMSD in neuron cultures rescued the neurons from nitrogen oxide (NO)-induced death. From these, it was suggested that CMSD may exert its neuroprotective effect by reducing the NO-mediated formation of free radicals or antagonizing their toxicity.

Amyloid beta-Peptides↗

Enhancement of the release of inflammatory mediators by substance P in rat basophilic leukemia RBL-2H3 cells.

Substance P (SP), a neurotransmitter, may play an important role in neurogenic inflammation. Ginseng has been used extensively in traditional medicine; however, few studies were focused on their anti-allergic effect. Therefore, the effect and mechanism of ginsenoside Rb1 on the SP enhancement of allergic mediators were explored. In this study, SP and dinitrophenyl-bovine serum albumin (DNP-BSA) were used to activate rat basophilic leukemia (RBL)-2H3 cells. The cultured supernatants were assayed for histamine, leukotriene C(4)(LTC(4)) and interleulin-4 (IL-4) production. The mitogen-activated protein kinases (MAPKs) signaling pathway was determined by Western blotting analysis. We found that IgE/DNP-BSA, SP, ginsenoside Rb1, or MAPK specific inhibitors had no effect on cell viability and cytotoxicity. SP (30 microM) alone, did not induce histamine and LTC(4) release, but it enhanced allergen-induced histamine and LTC(4) release. In addition, SP significantly induced and enhanced allergen-activated IL-4. Ginsenoside Rb1 dose-dependently inhibited these effects. SP enhanced the allergen-activated ERK pathway in RBL-2H3 cells, and Rb1 effectively inhibited the ERK pathway activation. Although MAPK specific inhibitors suppressed LTC(4) and IL-4, only U0126 inhibited the SP enhanced histamine release. These results demonstrate that Rb1 dose-dependently inhibited SP enhanced allergen-induced mediator release and its mechanism was through the inhibition of the ERK pathway.

Animals↗

Prevention of liver cancer.

Hepatocellular carcinoma (HCC) is among the most prevalent and deadly cancers worldwide. Prominent risk factors for HCC include viral hepatitis infection; dietary exposure to hepatotoxic contaminants such as aflatoxins; alcoholism; smoking; and male gender. This review highlights ongoing efforts in HCC prevention. Strategies include vaccination against, and treatment of, viral hepatitis infection. In addition to interferon alpha, an acyclic retinoid (all-trans-3,7,11, 15-tetramethyl-2,4,6,10,14-hexadecapentanoic acid), glycyrrhizin and ginseng are currently under clinical investigation for HCC prevention in Japanese hepatitis C patients. Several recent clinical studies in a Chinese region of pervasive aflatoxin contamination also support the approach of favorably altering aflatoxin metabolism and excretion using the chemopreventive agents oltipraz or chlorophyllin. Agents exhibiting chemopreventive efficacy in preclinical HCC models include vitamins A, D, and E, herbal extracts, a 5alpha-reductase inhibitor, green tea, and D-limonene. Efforts to elucidate the molecular lesions and processes underlying HCC development have identified several putative molecular targets for preventive interventions. These include genes and gene products controlling viral replication, carcinogen metabolism, signal transduction, cell-cycle arrest, apoptosis, proliferation, and oxidative stress.

Animals↗

Ginsenosides protect pulmonary vascular endothelium against free radical-induced injury.

We studied the actions of saponin (ginsenosides) from Panax ginseng on free radical-induced pulmonary endothelial injury which is manifest as reversal of the normal vasodilator response to acetylcholine in perfused, vasoconstricted lungs. 50 or 200 micrograms/ml ginsenosides prevented this injury response and also reduced the pulmonary edema which follows free radical injury but did not alter the normal ACh-induced vasodilation in intact lungs. In control perfused lungs preconstricted with U46619, the ginsenoside mixture or purified ginsenosides Rb1 and Rg1 caused vasodilatation. This effect was eliminated by 100 microM nitro-L-arginine, an inhibitor of nitric oxide synthase. In cultured bovine aortic endothelial cells, ginsenosides (10 micrograms/ml) stimulated the conversion of [14C]-L-arginine to [14C]-L-citrulline. These data indicate that GS may cause vasorelaxation and prevent manifestations of oxygen free radical injury by promoting release of nitric oxide.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

Determination of acidic saponins in crude drugs by high-performance liquid chromatography on octadecylsilyl porous glass.

High-performance liquid chromatographic (HPLC) analysis on octadecylsilyl porous glass was investigated for acidic saponins in ginseng, bupleurum root and senega. The acidic saponins, malonyl-ginsenosides, malonyl-saikosaponins and senegins, as well as neutral saponins in the crude drugs were separated rapidly by HPLC on this column with aqueous acetonitrile containing KH2PO4 as the mobile phase at room temperature.

Carbohydrate Sequence↗

Ginsenosides activate DNA polymerase delta from bovine placenta.

The activation of a DNA polymerase delta (pol delta) purified from bovine placenta by ginsenosides from Panax Ginseng C. A. Meyer has been studied. Preincubation of the enzyme with ginsenosides increased the polymerase activity 2.2-fold in a dose-dependent manner. There was a reproducible decrease in Km, in addition to a substantial increase in Vmax, in response to increasing concentrations of ginsenosides. Ginsenosides also activated the proofreading ability of 3'- to 5'-exonuclease activity associated with DNA pol delta. The coordinated activation of both polymerase and exonuclease activities of DNA pol delta by ginsenosides is consistent with the view that its polymerase and its exonuclease activities residue on the same protein molecule. UV/Vis difference spectroscopic studies suggested that the activation of DNA pol delta by ginsenosides might be due to the conformational change induced by ginsenosides binding.

Animals↗

Ginsenoside Rg1 modulates ingestive behavior and thermal response induced by interleukin-1 beta in rats.

Effects of ginsenoside Rg1 (Rg1), a major component of panax ginseng, on changes in ingestive behavior and rectal temperature induced by interleukin-1 beta (IL-1 beta) were investigated in rats. Intraperitoneal (ip) injection of IL-1 beta suppressed food and water intake and elevated rectal temperature. The suppressive effect of IL-1 beta on water intake was converted to an increase when 4.0 mM Rg1 was continuously infused into the third cerebroventricle (ICV) at a rate of 0.966 microliters/h. The elevation of rectal temperature induced by IL-1 beta was attenuated by ICV infusion of Rg1. The feeding suppression caused by IL-1 beta was unaffected by ICV infusion of Rg1. These results suggest that sustained ICV infusion of Rg1 may modulate the effects of IL-1 beta on ingestive behaviors, i.e., increase in water intake and sustained decrease in food intake, resulting in a lowering of body temperature.

Animals↗

Influence of a double blind pharmacological trial on two domains of well-being in subjects with age associated memory impairment.

This random double-blind trial compares psychological well-being and perceived quality of life in 60 subjects (18 M, 42 F), mean age 61 years, with age-associated memory impairment (AAMI), who were administered a standardised ginseng-containing vitamin complex or placebo for 9 months. We evaluated psychological well-being, in terms of affective status and memory functioning using the Symptom Rating Test [SRT] (depression, anxiety, somatisation, inadequacy) and Randt Memory Test [RMT] (memory index [MI]), respectively, and the quality of life, using the Life Satisfaction in the Elderly Scale [LSES]. At final evaluation, SRT did not differ in the drug and placebo groups, whereas MI and LSES were significantly higher in the drug-treated group. Moreover, the negative correlation between the affective (SRT) and cognitive (MI) component of psychological well-being waned in the drug-treated but not placebo group. In the drug-treated group, a positive correlation emerged between the cognitive index and social contacts, mood and self-concept factors of the LSES. In both groups, the initial negative correlations between quality of life (LSES) and affection (SRT) persisted at the end of the study. Drug-treated AAMI subjects differ from controls in part by improved scores on objective cognitive tests but even more so by modifications of the correlations among indexes of psychological well-being and quality of life.

Clinical Trial↗

The Japanese herbal medicine 'saiko-keishi-to' activates GABAA receptors of rat sensory neurons in culture.

The mechanism underlying the anticonvulsant action of 'Saiko-Keishi-To' (SK), the Japanese herbal medicine, was examined using whole-cell patch-clamp recording from cultured rat dorsal root ganglion cells. Neurons were held at -60 mV and perfused with an internal solution containing a high concentration of Cl-. Under these circumstances, SK produced an inward current which reversed at +8 mV, and was identical to the gamma-aminobutyric acid (GABA)-induced chloride current (IC). The SK-induced current was completely blocked by bicuculline. SK depressed a high voltage-activated calcium current (HVA-ICa), but this depression could not be antagonized by either phaclofen or saclofen. Of nine crude herbal drugs constituting SK, only Bupleuri radix, Ginseng radix, Zingiberis rhizoma and Paeoniae radix produced the inward currents blocked by bicuculline. These results suggest that SK, and four of its crude herbal drugs, activate the ICl mediated by the GABAA receptor. In addition, SK depresses a HVA-ICa through some mechanism other than an activation of GABAB receptors.

Animals↗

Ginsenoside Rg1 inhibits the brain cAMP phosphodiesterase activity in young and aged rats.

1. The in vitro effect of ginsenoside Rg1 from Panax ginseng on the low- and high-KM cyclic AMP phosphodiesterase (cAMP PDE) activity in the frontal cortex, striatum, hypothalamus and hippocampus of young (4-5-month old) and aged (22-month old) rats has been studied. 2. Administered in increasing concentrations (from 5 x 10(-5) M up to 5 x 10(-4) M), ginsenoside Rg1 exerted a pronounced inhibitory effect on the low- and high-KM enzyme activity in all brain structures studied in rats of both age groups. 3. Ginsenoside Rg1 exhibited inhibitory potency similar to that of theophylline. 4. The present results provide evidence for the CNS effects of ginsenoside Rg1 through inhibition of the intracellular level of cAMP.

3',5'-Cyclic-AMP Phosphodiesterases↗

New experimental model for the evaluation of adaptogenic products.

A new animal model for evaluating improvement in physical work performance and endurance in an adverse environment is described. In this model, rats in restraint were exposed to 5 degrees C at 480 mmHg atmospheric pressure. Results were compared to an animal forced to swim in water at 23 degrees C. In both the models, colonic temperature (Tr) of the rats was continually monitored during exposure to adverse environment and during recovery at 32 degrees C and normal atmospheric pressure. The time and pattern for Tr fall to 23 degrees C and its recovery to 37 degrees C were used as measures of endurance. The cold-hypoxia-restraint model was found to provide more precise results compared with the cold-swimming model. Panax ginseng root and Ginkgo biloba leaf extracts were compared for their positive endurance-promoting properties using both models.

Adaptation, Physiological↗

Immunological aspects of Chinese medicinal plants as antiageing drugs.

The development of a predominantly geriatric community worldwide has become an inevitable fact. Antiageing agents could be, in a certain sense, attentive to the well-being of the aged. There are quite a lot of medicinal plants and prescriptions recorded in Chinese medical literatures aimed at the well-being of the aged as well as the prevention of diseases and prolongation of life-span. By means of modern scientific research, a strategy towards antiageing drugs is presented in this paper. One of the effective routes is to select the candidates based on their ethnopharmacological usages, followed by immunological investigation in connection with other antiageing experimentation. A list of Chinese medicinal plants used as or related to the antiageing agents are presented. Specifically, five Chinese traditional drugs, Herba Epimedii, Fructus Lycii, Radix Polygoni multiflori, Radix Cynanchi auriculati and Ganoderma along with a composite prescription 'American Ginseng Royal Jelly' are selected as representatives. The prospect of research and development of antiageing drugs based on natural origin is also discussed.

Aging↗