Long-term metabolic effects of different doses of niacin-bound chromium on Sprague-Dawley rats.

We simultaneously assessed benefits and risks of niacin-bound chromium (NBC) intake at varying doses over a prolonged period of time (>1.2 years) in male and female Sprague-Dawley (SD) rats. We performed the study in two phases. First, we followed 60 male and 60 female SD rats, each gender divided into six groups. Through day 150 (phase 1A), all SD rats received a high sucrose diet (30% w/w) with or without different concentrations of NBC. The male/female groups were: 1] control without NBC n = 10, 2] low NBC (2.8 ppm, n = 10), 3] medium NBC (8.7 ppm, n = 20), 4] high NBC (28.0 ppm, n = 20). Based on dosing, we refer to the three treatment groups as 1X, 3X, and 10X. During days 151-312 (phase 1B), NBC was removed from diets of one half of the 3X and 10X groups. These are referred to as 3X satellite and 10X satellite. In phase 2 (days 313-460), males from groups 1X, 3X, 10X, 3X satellite, and 10X satellite received the same 3X dose of NBC (8.7 ppm). The last two groups also ingested different doses of a formulation of natural products in addition to NBC. We examined blood pressure, the renin-angiotensin system (RAS), nitric oxide (NO), and insulin systems and inflammatory parameters. Results in male and female SD rats were comparable. NBC lowered systolic blood pressure (SBP) in a dose-dependent fashion; however, after 200 days, the SBP of the low dose group (1X) began to rise and returned to baseline control. After raising the dose of NBC to 3X, the SBP in the 1X group decreased significantly once more. When half the test rats (3X and 10X) were deprived of NBC, SBP rose gradually to control levels after 2 to 3 months. However, the SBP decreased significantly once more when each satellite group returned to the 3X dose. Special testing suggests that NBC at adequate dosing increases insulin sensitivity, lowers HbA1C, decreases activity of the RAS, at least in part, through ACE inhibition, enhances NO activity, and is without signs of toxicity. The addition of a formula composed of antioxidants and immune modulators to the chromium regimen caused even faster and more profound changes in SBP than with NBC alone. We conclude that NBC at adequate dosing is effective in male and female SD rats on certain metabolic parameters over a prolonged period, effects that disappear over months after NBC is removed. When dosing is returned, the effectiveness of NBC returns. Low doses of NBC may lose their effect over time. No signs of toxicity were observed.

Effects of a novel formulation of essential oils on glucose-insulin metabolism in diabetic and hypertensive rats: a pilot study.

BACKGROUND: Insulin resistance and its most severe form type 2 diabetes mellitus are rapidly increasing throughout the world. It is generally recognized that natural products with a long history of safety can increase insulin sensitivity. AIMS: The present investigation examined the ability of various combinations of essential oils such as fenugreek, cinnamon, cumin, oregano, etc. to enhance insulin sensitivity. As a first approximation, we examined the effects of these natural products on Zucker fatty rats (ZFRs), a model of obesity and insulin resistance, and spontaneously hypertensive rats (SHRs), a model of genetic hypertension. MATERIAL AND METHODS: Water or essential oils were given orally via droplets, and insulin sensitivity was estimated by systolic blood pressure (SBP) changes and circulating glucose and/or insulin concentrations. RESULTS: We have found that the ability to alter SBP in rat models is the most sensitive early index of insulin sensitivity. The combined essential oils lowered circulating glucose levels and SBP in both ZFRs and SHRs, suggesting that these natural products are enhancing insulin sensitivity. The second series of studies examined two additional combinations of essential oils along with the original formula. The major differences were in the types and proportions of individual oils contributing to a given formula. CONCLUSIONS: Although all the three formulae decreased SBP in ZFRs, one of the formulae was more effective than the others in lowering circulating glucose in the glucose tolerance testing. Accordingly, some essential oils may be added to the long list of natural products that can affect insulin sensitivity.

Effects of a water-soluble extract of maitake mushroom on circulating glucose/insulin concentrations in KK mice.

AIM: We examined benefits of a water-soluble extract of maitake mushroom designated as Fraction X (FXM) on the glucose/insulin metabolism of insulin-resistant KK mice, and compared the results of FXM with those of a sulphonylurea, Glipizide. DESIGN: In several acute studies, insulin-resistant KK mice were gavaged with a single dose of varying concentrations of FXM, or a single dose of one concentration of the oral hypoglycaemic drug, Glipizide. In the one chronic study, KK mice were gavaged with FXM, Glipizide, or an equal volume of isotonic saline (baseline control) twice daily. Retro-orbital blood was drawn on the morning of the 4th and 7th days before the early gavage. Blood glucose was measured by routine laboratory procedures, and serum insulin was estimated by a radioimmunoassay (RIA) assay developed specifically for rodents. RESULTS: At a dose of FXM (140 mg/mouse), a statistically significant lowering of circulating glucose concentrations was again seen at 8-12 h and 16-18 h after oral gavage. The lowering approximated 25% of the original concentration. Oral gavage of Glipizide resulted in statistically significantly lower values of circulating glucose (25-37% lower compared with baseline) at 8-24 h post dosing. In the chronic study, the circulating concentrations of glucose and insulin of mice taking 140 mg FXM per day were decreased significantly at days 4 and 7. CONCLUSIONS: FXM, a natural extract obtained from maitake mushroom, favourably influences glucose/insulin metabolism in insulin-resistant KK mice. The lowering of both circulating glucose and insulin concentrations suggests that FXM works primarily by enhancing peripheral insulin sensitivity.

Effects of oral glucosamine and chondroitin sulfate alone and in combination on the metabolism of SHR and SD rats.

Glucosamine (G), often combined with chondroitin sulfate (CS), is a popular natural supplement used widely to treat osteoarthritis. However, use of glucosamine has been linked to development of insulin resistance. To assess the association between glucosamine and insulin resistance more closely, we challenged two rat strains highly sensitive to sugar-induced insulin resistance-Sprague-Dawley (SD) and Spontaneously Hypertensive (SHR) rats. Since elevations of systolic blood pressure (SBP) have been found to be an early and highly sensitive sign of insulin resistance in these two rat strains, we used this parameter as our primary endpoint. Four groups of both rat strains received either no agent (control), G, CS, or a combination of both for 9 weeks. The intake of each agent was calculated to be approximately 3-7 times comparable to human dose. Throughout the study, SBP of both strains consuming the two ingredients alone and in combination were not elevated. Rather, they were significantly lower than control, contrary to what is found in glucose-induced insulin resistance in rats. Over the study period, body weights of the four groups of SD and SHR did not vary significantly. Furthermore, no consistent trends in circulating glucose concentrations were found among the four different groups in the two strains after oral challenge with glucose. Finally, no significant histological differences were found in hearts, kidneys, and livers among the various groups of SHR and SD. From the above result, we conclude that glucosamine and chondroitin sulfate given alone or together do not produce insulin resistance or other related perturbations in two rat strains highly sensitive to sugar-induced insulin resistance.

Long-term effects of chromium, grape seed extract, and zinc on various metabolic parameters of rats.

Progressive insulin resistance may contribute to both enhanced glycosylation of proteins and nucleic acids and augmented free radical damage commonly associated with aging. Accordingly, ingestion of chromium and antioxidants which improve insulin sensitivity and/or lessen free radical formation could theoretically ameliorate these basic disorders and lessen signs and symptoms of chronic age-related disorders. However, this supposition is based primarily upon acute rather than chronic data. Therefore, we divided 104 F344/BN rats into 2 groups: a control group receiving a basic diet and a test group receiving the same diet with added chromium polynicotinate (5 ppm), zinc monomethionine (18 ppm elemental zinc), and a grape seed extract high in flavonoids (250 ppm). Initial mean systolic blood pressures (SBP) of both control and test groups were 122 mm Hg. Over the first 7 months, the SBP of the control animals steadily increased to 140 mm Hg and remained at this level for the next 7-8 months. In contrast, the SBP of the test animals initially decreased over the first 4 months to as low as 110-114 mm Hg. The SBP then increased over the following months, essentially reaching the starting value of 120 mm Hg. This was still significantly lower than control (p < 0.001). In 12 control and 12 test rats, hepatic TBARS formation, an estimate of lipid peroxidation/free radical formation, was significantly lower after 1 year ingesting the test diet (p < 0.04); and HbA1C was also statistically significantly lower in the test group (5.4 vs. 4.8%, p < 0.003). Circulating levels of cholesterol, HDL, and triglycerides were similar between the two groups. Body, kidney, and liver weights were not different after 1 year ingesting the different diets; but epididymal fat pad weight was less in the group receiving supplements. We conclude that after prolonged supplementation a combination of agents known to sensitize insulin response and act as antioxidants (chromium polynicotinate, grape seed extract, and zinc monomethionine) can markedly lower SBP in normotensive rats, lessen oxidative damage to fats as suggested by decreased TBARS formation, and lower HbA1C without showing signs of toxicity.

Influence of a combination of herbs on appetite suppression and weight loss in rats.

AIM: We evaluated the ability of a Chinese herbal formulation previously associated with weight loss to influence appetite and weight loss in a carefully controlled laboratory study performed on rats. As a secondary gain, results with this herbal formulation were compared with those from a commonly available phenylpropanolamine (PPA) compound. DESIGN: Eight rats were placed in each arm of a three-arm study, a total of 24 rats. All rats were gavaged with a 2-ml fluid volume containing no addition (control) or the two test substances (combined herbs or PPA) for the first 4 days of the week over 6 consecutive weeks; no gavages were given over weekends. Rats in the two-test groups were given a relatively low dose of the test substance for 3 weeks, followed by a higher dose over the next 3-week periods. Food and water intake were measured for 24-h periods over the ensuing week days. The average daily values for food and water intake for an individual rat were calculated on the basis of collected data over each 3-week period. The mean values for each rat obtained over the low- and high-dose periods comprised results from averaging at least 10 measurements. RESULTS: Average daily food intake was decreased only with the herbal formulation, not the PPA compound at the low and high doses. Both the PPA compound and the herbal formulation lowered water intake significantly at the low and high doses. Rats ingesting the herbal formulation at the lower dose had statistically significant lower daily body weight changes over the 3 weeks than those ingesting the PPA compound. At the higher dose, body weight changes for both agents were significantly less than the control, but not significantly different from each other. No evidence of toxicity was seen in the blood chemistries or after histopathological examination. CONCLUSIONS: Data collected on rats suggest that the herbal formulation examined might be a useful and safe combination to overcome the overweight state and obesity.

Hepatoprotective ability of a novel botanical formulation on mild liver injury in rats produced by acute acetaminophen and/or alcohol ingestion.

Medicinal herbs have been used for centuries in an attempt to overcome hepatic dysfunctions emanating from ingestion of hepatotoxic substances. However, the vast majority of information concerning their use is anecdotal. Well-performed animal studies would lend credence to the concept that some medicinal herbs may prevent or, at least ameliorate, hepatic dysfunction arising from drug-induced toxicity. The present investigation examined the potential for a combination of medicinal herbs to favorably influence the course of mild/moderate acute hepatic injury induced in rats by the oral intake of acetaminophen and/or ethyl alcohol. We performed four separate studies using elevations of liver enzymes [aspartate aminotransferase (AST) and alanine aminotransferase (ALT)] as our primary biomarkers of hepatotoxicity. In the first study, the ability of orally administered acetaminophen at different doses to produce acute hepatotoxicity was examined. In the second and third studies, the ability of a combination of medicinal herbs (a novel botanical formulation) was assessed to ameliorate the acetaminophen-induced hepatotoxicity. In the last series of studies, we used acute alcohol ingestion to cause liver perturbations and examined the ability of medicinal herbs to overcome hepatotoxicity. We also evaluated the ability of the medicinal herb combination to overcome acetaminophen-induced hepatotoxicity in rats simultaneously challenged with ethyl alcohol ingestion. Hepatotoxicity, estimated by increased levels of AST and ALT, was produced by a 2.0 mg/Kg oral dose of acetaminophen but not by lesser doses. Treatment with a combination of medicinal herbs (a novel botanical formulation) significantly ameliorated acetaminophen-induced toxic response. The combination of medicinal herbs also decreased the hepatic toxicity produced by acute ethyl alcohol ingestion. We conclude that oral ingestion of a novel botanical formulation (a combination of medicinal herbs) is effective in lessening drug-induced hepatotoxicity produced by acetaminophen and/or ethyl alcohol in an animal model.

Antifungal activities of origanum oil against Candida albicans.

The antimicrobial properties of volatile aromatic oils from medicinal as well as other edible plants has been recognized since antiquity. Origanum oil, which is used as a food flavoring agent, possesses a broad spectrum of in vitro antimicrobial activities attributed to the high content of phenolic derivatives such as carvacrol and thymol. In the present study, antifungal properties of origanum oil were examined both in vitro and in vivo. Using Candida albicans in broth cultures and a micro dilution method, comparative efficacy of origanum oil, carvacrol, nystatin and amphotericin B were examined in vitro. Origanum oil at 0.25 mg/ml was found to completely inhibit the growth of C. albicans in culture. Growth inhibitions of 75% and >50% were observed at 0.125 mg/ml and 0.0625 mg/ml level, respectively. In addition, both the germination and the mycelial growth of C. albicans were found to be inhibited by origanum oil and carvacrol in a dose-dependent manner. Furthermore, the therapeutic efficacy of origanum oil was examined in an experimental murine systemic candidiasis model. Groups of mice (n = 6) infected with C. albicans (5 x LD50) were fed varying amounts of origanum oil in a final vol. of 0.1 ml of olive oil (vehicle). The daily administration of 8.6 mg of origanum oil in 100 microl of olive oil/kg body weight for 30 days resulted in 80% survivability, with no renal burden of C. albicans as opposed to the group of mice fed olive oil alone, who died within 10 days. Similar results were obtained with carvacrol. However, mice fed origanum oil exhibited cosmetically better clinical appearance compared to those cured with carvacrol. The results from our study encourage examination of the efficacy of origanum oil in other forms of systemic and superficial fungal infections and exploration of its broad spectrum effect against other pathogenic manifestations including malignancy.

Effects of niacin-bound chromium and grape seed proanthocyanidin extract on the lipid profile of hypercholesterolemic subjects: a pilot study.

Hypercholesterolemia, a significant cardiovascular risk factor, is prevalent in the American population. Many drugs lower circulating cholesterol levels, but they are not infrequently associated with severe side effects. Accordingly, natural means to lower cholesterol levels safely would be welcomed. We examined 40 hypercholesterolemic subjects (total cholesterol 210-300 mg/dL) in a randomized, double-blind, placebo-controlled study. The four groups of ten subjects received either placebo bid, chromium polynicotinate (Cr) 200 microg bid, grape seed extract (GSE) 100 mg bid, or a combination of Cr and GSE at the same dosage bid. Over two months, the average percent change +/- SEM in the total cholesterol from baseline among groups was: placebo -3.5% +/- 4, GSE -2.5% +/- 2, Cr -10% +/- 5, and combination -16.5% +/- 3. The decrease in the last group was significantly different from placebo (p < 0.01). The major decrease in cholesterol concentration was in the LDL levels: placebo -3.0% +/- 4, GSE -1.0% +/- 2.0, Cr -14% +/- 4.0, and the combination -20% +/- 6.0. Again, the combination of Cr and GSE significantly decreased LDL when compared to placebo (p<0.01). HDL levels essentially did not change among the groups. Also, there was no significant difference in the triglyceride concentrations among the groups; and no statistically significant differences were seen in the levels of autoantibodies to oxidized LDL (Ox-LDL). However, the trend was for the two groups receiving GSE to have greater decreases in the latter parameter, i.e., -30.7% and -44.0% in the GSE and combined groups in contrast to -17.3% and -10.4% in the placebo and chromium groups. We determined the number of subjects in each group who decreased autoantibodies to oxidized LDL greater than 50% over eight weeks and found these ratios among groups: placebo = 2/9, Cr = 1/10, GSE = 6/10, and combined = 3/8. Thus, 50% of subjects (9/18) receiving GSE had a greater than 50% decrease in autoantibodies compared to 16% (3/19) in the two groups not receiving GSE. No significant changes occurred in the levels of circulating homocysteine and blood pressure among the four groups. We conclude that a combination of Cr and GSE can decrease total cholesterol and LDL levels significantly. Furthermore, there was a trend to decrease the circulating autoantibodies to oxidized LDL in the two groups receiving GSE.