Life Extension Magazine®

Issue: Feb 2014

Glucose control

A fermentation product of Cordyceps sinensis increases whole-body insulin sensitivity in rats.

OBJECTIVE: CordyMax trade mark Cs-4 (Cs-4) is a standardized mycelial fermentation product of Cordyceps sinensis, a fungus that has been used for various pharmacologic, metabolic, and ergogenic purposes. The goal of this investigation was to determine the effects of oral Cs-4 administration on whole-body insulin sensitivity, skeletal muscle glucose transport, and endurance performance. DESIGN: We studied different indices of carbohydrate metabolism in rats that received Cs-4 orally at a dose of 2 g/kg of body weight daily for 30 days. RESULTS: C-peptide response observed during the oral glucose tolerance test (OGTT) after 10 days of treatment was significantly decreased in the Cs-4-treated group (Cs-4, 52,802 +/- 4,124 vs. control, 70,696 +/- 6309 pM x 120 min; p < 0.05). The integrated insulin area under the curve (53.3 +/- 4.9 ng/mL x 120 minutes) and the glucose-insulin index (6.6 +/- 0.6 units) obtained from the OGTT were significantly decreased (p < 0.01) in the Cs-4-treated group compared to their vehicle-treated counterparts (82.1 +/- 8.1 ng/mL x 120 minutes; 9.9 +/- 0.7 units) after 20 days of treatment. Neither integrated glucose area under the curve observed during either OGTT, basal- or insulin-stimulated 2-deoxyglucose transport nor skeletal muscle GLUT-4 concentrations were affected by Cs-4 treatment. In addition, swim time to exhaustion did not differ between groups in this animal model. CONCLUSION: We conclude that CordyMax Cs-4 may have potential beneficial effects by maintaining whole-body glucose disposal with a less pronounced increase in insulin secretion after a carbohydrate challenge, however, its effects on endurance performance remain questionable.

J Altern Complement Med . 2002 Jun;8(3):315-23

CordyMax Cs-4 improves steady-state bioenergy status in mouse liver.

OBJECTIVE: To evaluate effects of CordyMax Cs-4, a mycelial fermentation product of Cordyceps sinensis, on energy metabolism. DESIGN: An in vivo pharmacology study using 31P nuclear magnetic resonance (NMR) spectroscopy. SUBJECTS AND STUDY INTERVENTIONS: Adult male C57-BL/6 mice were given an aqueous extract of CordyMax, 200 or 400 mg/kg per day or placebo for 7 days. OUTCOME MEASUREMENTS: Using 31P-NMR spectroscopy to measure cellular triphosphates and inorganic phosphate, expressed as a ratio to a reference peak, and calculate tissue pH. RESULTS: Steady-state beta adenosine triphosphate (ATP) increased in the liver of mice that received CordyMax (200 or 400 mg/kg per day) for 7 days, by 12.3% +/- 0.8% and 18.4% +/- 0.9%, respectively, compared to placebo controls (both p < 0.001), suggesting a higher hepatic bioenergy status in CordyMax-treated animals. Hepatic inorganic phosphate (Pi) decreased by 24.5% +/- 0.9% and 17.6% +/- 1.7% in the two treatment groups, respectively, compared to placebo controls (p < 0.001). The ratio of beta-ATP:Pi increased by 47.7% +/- 1.6% and 41.4% +/- 2.4%, respectively, in the treatment groups (both p < 0.001 compared to placebo). After discontinuation of CordyMax for 7 days, beta-ATP and Pi returned towards baseline. CONCLUSION: CordyMax is effective in improving bioenergy status in the murine liver, suggesting a mechanism underlying the known clinical effectiveness of CordyMax in alleviating fatigue and improving physical endurance, especially in elderly subjects.

J Altern Complement Med . 2001 Jun;7(3):231-40

Effects of the mycelial extract of cultured Cordyceps sinensis on in vivo hepatic energy metabolism in the mouse.

Mice were given the extract of cultured Cordyceps sinensis (Cs) (200 mg/kg daily, p.o.) for 3 weeks. In vivo phosphorus-31 nuclear magnetic resonance (NMR) spectra of the liver were acquired at weekly intervals using a surface coil. From 1 to 3 weeks, a consistent increase in the ATP/inorganic phosphate ratio, which represents the high energy state, was observed in the Cs extract-treated mice. The intracellular pH of the Cs extract-treated mice was not significantly different from that of the control mice. No steatosis, necrosis, inflammation or fibrosis were observed in the liver specimens from Cs extract-treated mice.

Jpn J Pharmacol . 1996 Jan;70(1):85-8.

Anti-fatigue property of Cordyceps guangdongensis and the underlying mechanisms.

CONTEXT: Cordyceps guangdongensis T.H. Li, Q.Y. Lin & B. Song (Cordycipitaceae) is a nontoxic folk medicine and can be cultivated, with noticeable effects of anti-H9N2, life-prolonging and treating chronic renal failure. OBJECTIVE: The anti-fatigue effect of C. guangdongensis, possible mechanism and active constituent were investigated. MATERIALS AND METHODS: Treatment mice were treated with C. guangdongensis powder (0.455, 0.91 and 1.82 g/kg bw daily for low, middle and high doses, respectively); treatment rats were fed, respectively, with ethanol, petroleum ether, ethyl acetate, n-butanol, aqueous phase and hot water extract fractions, for 30 d. Forced swimming time to exhaustion, blood urea nitrogen (BUN) and hepatic glycogen (HG) levels of mice and blood lactic acid (BLC) levels of rats were determined. RESULTS: The swimming times to exhaustion of mice were very significantly (p < 0.01) longer in low-, middle- and high-dose groups (respectively 1.87-, 1.94- and 1.88-times), and significantly (p < 0.05) longer in the n-butanol fraction group (1.52-times), hot water extract group (1.88- times) and refined polysaccharide group (2.66-times) than in blank control; the BLC levels of rats were significantly (p < 0.05) lower in the ethyl alcohol partition group (84.8%), the n-butanol fraction group (84.0%) and the hot water extract group (84.4 %) than in blank. The BUN and HG levels were not significantly different. DISCUSSION AND CONCLUSION: Cordyceps guangdongensis can potently alleviate fatigue through reducing the accumulation of BLC; a functional constituent was the refined polysaccharide. This might become a new functional food for fatigue resistance.

Pharm Biol . 2013 May;51(5):614-20

Regulation on energy metabolism and protection on mitochondria of Panax ginseng polysaccharide.

Panax ginseng C A Meyer (PG) is one of the most popular qi-invigorating herbal medicine and has been used to promote health, vitality, and longevity in China. Although PG has been used in traditional Chinese medicine for millennia, its qi-invigorating activities still lack convincing evidence. We investigated the effects of Panax ginseng polysaccharide (PGP) on energy metabolism and mitochondrial protection. The chronic hypoxia model was set up. Lipid peroxidation product malondialdehyde (MDA) was assayed by thiobarbituric acid (TBA) colorimetry. Mice liver mitochondria were isolated by differential centrifugation. The spectrophotometric method was used to measure the swelling of mitochondria. The levels of adenosine triphosphate (ATP), adenosine diphosphate (ADP) and adenosine monophosphate (AMP) in liver cells were determined by reversed-phase high performance liquid chromatography (RP-HPLC), adenylate energy charge (AEC), total adenylate pool (TAP), ATP/ADP and ATP/AMP ratio were calculated. The creatine kinase (CK) activities in mice skeletal muscle were determined by a commercial monitoring kit. The result showed that PGP could inhibit mitochondrial injury and swelling induced by Fe(2+)-L-Cys in a concentration-dependent manner. PGP which was administered by oral gavage daily for 10 days could inhibit the formation of MDA in mice brain, increase levels of ATP, ADP, TAP and AEC, ratio of ATP/ADP and ATP/AMP in liver cells, increase CK activities in mice skeletal muscle under chronic hypoxia condition. These results indicate that PGP protect mitochondria by inhibiting mitochondrial swelling, and improving energy metabolism. PGP functions as a preventive antioxidant by increasing CK activities. Therefore, PGP had the pharmaceutical activities of antihypoxia, antioxidation and improving energy status.

Am J Chin Med . 2009;37(6):1139-52.

20(S)-ginsenoside Rg3, a neuroprotective agent, inhibits mitochondrial permeability transition pores in rat brain.

Ginseng, the root of Panax ginseng C.A. Meyer (Araliaceae), is a well-known traditional Chinese herbal medicine. Ginsenosides, which are triterpene derivatives that contain sugar moieties, are the main active ingredients of ginseng. 20(S)-Ginsenoside Rg3, a triterpene glycoside which chemically belongs to the protopanaxadiol ginsenoside group, is effective in attenuating brain infarction after cerebral ischemia, but the detailed mechanism is not known. This study examined the effect of 20(S)-ginsenoside Rg3 on mitochondrial permeability transition pore (MPTP) in the rat brain. 20(S)-Ginsenoside Rg3 at 2-16 microm inhibited Ca(2+)- and H(2)O(2)-induced swelling of mitochondria isolated from rat brains. The addition of Ca(2+) generated reactive oxygen species (ROS) in isolated mitochondria. 20(S)-Ginsenoside Rg3 (2-16 microm) inhibited Ca(2+) induced generation of ROS. At the same time, 20(S)-ginsenoside Rg3 significantly improved mitochondrial energy metabolism, enhanced ATP levels and the respiratory control ratio. These results suggest that 20(S)-ginsenoside Rg3 inhibits the opening of MPTP by free radical scavenging action in the brain, and this implies that inhibition of MPTP may contribute to the neuroprotective effect of 20(S)-ginsenoside Rg3.

Phytother Res . 2009 Apr;23(4):486-91

Total ginsenosides of Radix Ginseng modulates tricarboxylic acid cycle protein expression to enhance cardiac energy metabolism in ischemic rat heart tissues.

To elucidate the underlying mechanism of cardio-protective activity of the total ginsenosides (TGS) of Radix Ginseng, proteomic analysis using two-dimensional gel electrophoresis (2-DE) and MALDI-TOF-TOF-MS techniques was employed for identifying the underlying targets of TGS on improvement of the energy metabolism of isolated rat heart tissues perfused in Langendorff system under ischemia-reperfusion injury conditions. The image analysis results revealed 11 differentially expressed proteins in the TGS-treated heart tissues; these proteins, including LDHB and ODP-2, were found to be closely related to the function of tricarboxylic acid (TCA) cycle that plays pivotal roles in cardiac energy metabolism. It is thus concluded that improvement of cardiac energy metabolism via activating proteins in TCA cycle could be the major action pathway and targets of TGS activity against rat heart tissue injury.

Molecules . 2012 Oct 29;17(11):12746-57.

Pharmacokinetic comparison of ginsenoside metabolite IH-901 from fermented and non-fermented ginseng in healthy Korean volunteers.

ETHNOPHARMACOLOGICAL RELEVANCE: IH-901 (20-O-beta-D-glucopyranosyl-20(S)-protopanaxadiol) is a novel ginseng saponin metabolite formed by human intestinal bacteria and is known to have antitumor and antimetastatic effects. However, there has been no pharmacokinetic study of IH-901 in human beings. AIM OF THE STUDY: The aim of this study was to investigate the pharmacokinetic differences of IH-901 from fermented and non-fermented ginseng. MATERIALS AND METHODS: To investigate whether the pharmacokinetics of IH-901 differ between fermented and non-fermented ginseng, an open label, randomized, single dose, fasting, two-period, cross-over, pharmacokinetic study was conducted. A total of 24 healthy Korean male volunteers participated in this study. All subjects were allocated into two equal groups and administered 3g of fermented or non-fermented Panax ginseng. Serial blood samples for pharmacokinetic analysis were collected in the 24 h after dosing. Plasma IH-901 concentration was measured by a validated high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Pharmacokinetic parameters including AUC(t), C(max), and T(max) were calculated by noncompartmental models in the BA-CALC program (KFDA, 2008, 1.0.0, Korea). RESULTS: After oral administration of fermented ginseng, 5 subjects experienced diarrhea. The means of AUC(t) and C(max) were significantly different between the two groups. In the fermented ginseng group, AUC(t) was 2083.09±91.97 ng h/mL, a 15.5-fold increase over that of IH-901 from the non-fermented group (134.50±63.10 ng h/mL), and the mean C(max) was 325.00±91.97 ng/mL in the fermented ginseng group, a 27-fold higher value than that in the non-fermented group (13.88±7.24 ng/mL). T(max) was 3.29±1.00 and 12.04±4.96 h in the fermented and non-fermented group, respectively. CONCLUSIONS: The results of this study showed that the pharmacokinetic parameters of IH-901 from fermented Panax ginseng are different from those of non-fermented ginseng, from which IH-901 is formed by intestinal

J Ethnopharmacol . 2012 Jan 31;139(2):664-7

Red ginseng supplementation more effectively alleviates psychological than physical fatigue.

Red ginseng (RG, the extract of Panax ginseng Meyer) has various biological and psychological activities and may also alleviate fatigue-related disorders. The present study was undertaken to evaluate what kind of fatigue red ginseng alleviate. Animals were orally administered with 50, 100, 200, 400 mg/kg of RG for 7 days. Before experiments were performed. Physiological stress (swimming, rotarod, and wire test) are behavioral parameters used to represent physical fatigue. Restraint stress and electric field test to a certain degree, induce psychological fatigue in animals. Plasma concentration of lactate and corticosterone (CORT) were also measured after these behavioral assays. RG supplementation (100 mg/kg) increased movement duration and rearing frequency of restrainted mice in comparison with control. 100 and 200 mg/kg of RG increased swimming time in cold water (8±4) while at 100 mg/kg, RG increased electric field crossing over frequencies. 50, 100 and 200 mg/kg RG prolonged running time on the rotarod and at 100 mg/kg, it increased balancing time on the wire. RG at those doses also reduced falling frequencies. RG supplementation decreased plasma CORT levels, which was increased by stress. Lactate levels were not significantly altered. These results suggest that RG supplementation can alleviate more the damages induced by psychological than physical fatigue.

J Ginseng Res . 2011 Sep;35(3):331-8

Phaseolus vulgaris extract affects glycometabolic and appetite control in healthy human subjects.

Extracts of Phaseolus vulgaris (beans) are known to reduce glycaemia and food intake in rodents and humans. The present study evaluated the effects of a new, standardised and purified P. vulgaris extract (PVE), when employed as a supplement in a mixed balanced meal (60 % carbohydrates, 25 % lipids and 15 % protein), on glycometabolic and appetite control. To this end, a randomised, double-blind, placebo-controlled study was performed in twelve volunteers. Plasma glucose, insulin, C-peptide, ghrelin and satiety sensation ratings were assessed at baseline and during 3 h after meal consumption associated with PVE (100 mg) or placebo. Compared with placebo, PVE consumption resulted in lower increments in glucose (+15·4 (sem 5·4) v. 26·1 (SEM 7·3) %, P= 0·04 at 30 min), insulin (+981 (SEM 115) v. 1325 (SEM 240) %, P= 0·04 between 45 and 120 min) and C-peptide (+350 (SEM 27) v. 439 (SEM 30) %, P= 0·04 between 30 and 90 min). In the first 2 h, plasma ghrelin decreased similarly in both groups but did not rebound as in placebo thereafter (P= 0·04). Correspondingly, satiety sensation in the third hour was significantly reduced in the placebo but not in the PVE condition. PVE induced a lower desire to eat than placebo (P= 0·02) over the 3 h. In conclusion, PVE supplementation reduced postprandial glucose, insulin and C-peptide excursions, suppressed ghrelin secretion and affected satiety sensations, inducing a lower desire to eat. These results support that further studies are needed to prove the concept of employing PVE as a supplement in mixed balanced meals in obese, glucose-intolerant and diabetic subjects.

Br J Nutr . 2013 May 28;109(10):1789-95

Metabolic and hormonal changes after laparoscopic Roux-en-Y gastric bypass and sleeve gastrectomy: a randomized, prospective trial.

BACKGROUND: The mechanisms of amelioration of glycemic control early after laparoscopic Roux-en-Y gastric bypass (LRYGB) or laparoscopic sleeve gastrectomy (LSG) are not fully understood. METHODS: In this prospective, randomized 1-year trial, outcomes of LRYGB and LSG patients were compared, focusing on possibly responsible mechanisms. Twelve patients were randomized to LRYGB and 11 to LSG. These non-diabetic patients were investigated before and 1 week, 3 months, and 12 months after surgery. A standard test meal was given after an overnight fast, and blood samples were collected before, during, and after food intake for hormone profiles (cholecystokinin (CCK), ghrelin, glucagon-like peptide 1 (GLP-1), peptide YY (PYY)). RESULTS: In both groups, body weight and BMI decreased markedly and comparably leading to an identical improvement of abnormal glycemic control (HOMA index). Post-surgery, patients had markedly increased postprandial plasma GLP-1 and PYY levels (p < 0.05) with ensuing improvement in glucose homeostasis. At 12 months, LRYGB ghrelin levels approached preoperative values. The postprandial, physiologic fluctuation returned, however, while LSG ghrelin levels were still markedly attenuated. One year postoperatively, CCK concentrations after test meals increased less in the LRYGB group than they did in the LSG group, with the latter showing significantly higher maximal CCK concentrations (p < 0.012 vs. LRYGB). CONCLUSIONS: Bypassing the foregut is not the only mechanism responsible for improved glucose homeostasis. The balance between foregut (ghrelin, CCK) and hindgut (GLP-1, PYY) hormones is a key to understanding the underlying mechanisms.

Obes Surg . 2012 May;22(5):740-8

Multiple cycles of repeated treatments with a Phaseolus vulgaris dry extract reduce food intake and body weight in obese rats.

Previous lines of experimental evidence have suggested that Phaseolus vulgaris extracts reduce food intake, body weight, lipid accumulation, hedonic properties of food, carbohydrate absorption and metabolism, and glycaemia in rats. The present study was designed to assess the effect of multiple cycles of repeated treatments with a standardised P. vulgaris dry extract on daily food intake and body weight in genetically obese Zucker fa/fa rats (Expt 1). Additionally, the study tested the effect of acute treatment with P. vulgaris dry extract on postprandial glycaemia in Zucker fa/fa rats (Expt 2). In Expt 1, P. vulgaris dry extract was administered daily, at doses of 50 and 500 mg/kg, in three 5 d treatment periods followed by three 20 d off-treatment periods. Administration of P. vulgaris dry extract resulted in dose-dependent decreases in daily food intake and body weight in each treatment phase. Reductions in food intake were of comparable magnitude in each treatment phase. In Expt 2, food-deprived rats were acutely treated with 50 and 500 mg P. vulgaris dry extract per kg immediately before access to a fixed amount of a starch-enriched chow. Treatment with P. vulgaris dry extract resulted in a dose-dependent suppression of glycaemia. These results extend previous data on the anorectic and hypoglycaemic effects of the P. vulgaris dry extract to a validated animal model of obesity. Together with data published previously in the literature, these results strengthen the hypothesis that potentially effective, novel pharmacotherapies for obesity and related disorders may originate from extracts and derivatives of P. vulgaris.

Br J Nutr. 2011 Sep;106(5):762-8

Effects of a brown beans evening meal on metabolic risk markers and appetite regulating hormones at a subsequent standardized breakfast: a randomized cross-over study.

BACKGROUND: Dietary prevention strategies are increasingly recognized as essential to combat the current epidemic of obesity and related metabolic disorders. The purpose of the present study was to evaluate the potential prebiotic effects of indigestible carbohydrates in Swedish brown beans (Phaseolus vulgaris var. nanus) in relation to cardiometabolic risk markers and appetite regulating hormones. METHODS: Brown beans, or white wheat bread (WWB, reference product) were provided as evening meals to 16 healthy young adults in a randomised crossover design. Glucose, insulin, appetite regulatory hormones, GLP-1, GLP-2, appetite sensations, and markers of inflammation were measured at a following standardised breakfast, that is at 11 to 14 h post the evening meals. Additionally, colonic fermentation activity was estimated from measurement of plasma short chain fatty acids (SCFA, including also branched chain fatty acids) and breath hydrogen (H2) excretion. RESULTS: An evening meal of brown beans, in comparison with WWB, lowered blood glucose (-15%, p<0.01)- and insulin (-16%, p<0.05) responses, increased satiety hormones (PYY 51%, p<0.001), suppressed hunger hormones (ghrelin -14%, p<0.05), and hunger sensations (-15%, p = 0.05), increased GLP-2 concentrations (8.4%, p<0.05) and suppressed inflammatory markers (IL-6 -35%, and IL-18 -8.3%, p<0.05) at a subsequent standardised breakfast. Breath H2 (141%, p<0.01), propionate (16%, p<0.05), and isobutyrate (18%, P<0.001) were significantly increased after brown beans compared to after WWB, indicating a higher colonic fermentative activity after brown beans. CONCLUSIONS: An evening meal with brown beans beneficially affected important measures of cardiometabolic risk and appetite regulatory hormones, within a time frame of 11-14 h, in comparison to a WWB evening meal. Concentrations of plasma SCFA and H2 were increased, indicating involvement of colonic fermentation. Indigestible colonic substrates from brown beans may provide a preventive tool in relation to obesity and the metabolic syndrome.

PLoS One . 2013;8(4):e59985

Potential efficacy of preparations derived from Phaseolus vulgaris in the control of appetite, energy intake, and carbohydrate metabolism.

Preclinical data on extracts of and preparations derived from beans of Phaseolus vulgaris are reviewed as potential remedies for use in controlling food consumption, body weight, lipid accumulation, and glycemia. A growing body of evidence suggests that acute and chronic administration of P. vulgaris derivatives reduces food intake (including highly palatable foods), body weight, lipid deposit, and glycemia in rats exposed to multiple experimental procedures. Two possible lectin-mediated mechanisms of action have been proposed: (a) inhibition of α-amylase, resulting in a reduced carbohydrate metabolism and absorption; (b) phytohemoagglutinin-induced modulation of the activity of cholecystokinin and glucagon-like peptides, resulting in a reduced appetite. Preliminary clinical data, as well as reports focusing on the use of several traditional medicines, apparently extend these findings to humans. Should these initial clinical data be confirmed by future surveys, P. vulgaris derivatives might constitute novel remedies for the treatment of obesity and metabolic syndrome. Future studies are also expected to identify active structures leading to the development of new pharmaceutical agents

Diabetes Metab Syndr Obes . 2009 Sep 7;2:145-53

Reducing effect of a Phaseolus vulgaris dry extract on food intake, body weight, and glycemia in rats.

Extracts of kidney beans (Phaseolus vulgaris ) are known to reduce food intake and glycemia in rodents and humans. This study evaluated the effect of a novel extract of P. vulgaris on food (regular food pellets, starch-enriched diet, and chocolate-flavored beverage) intake, body weight, and glycemia in rats. The effect of the combination of the colecistokinin (CCK) receptor antagonist, lorglumide, and P. vulgaris dry extract on food intake was also investigated. Administration of doses of P. vulgaris dry extract devoid of any behavioral toxicity dose-dependently decreased food intake (irrespective of the diet), body weight gain, and glycemia. Pretreatment with lorglumide blocked the reducing effect of P. vulgaris dry extract on food intake. The capacity of this P. vulgaris dry extract to reduce food intake, body weight, and glycemia in rats may be due to (a) inhibition of alpha-amylase, (b) stimulation of CCK release from the intestinal brush border cells, and/or (c) interference with the central mechanism(s) regulating appetite, food intake, and food palatability.

J Agric Food Chem. 2009 Oct 14;57(19):9316-23

Lipid accumulation in obese Zucker rats is reduced by inclusion of raw kidney bean (Phaseolus vulgaris) in the diet.

The effects of inclusion of different levels of raw kidney bean (Phaseolus vulgaris) of high lectin content (27 g/kg meal) in a high-quality (lactalbumin) control diet were tested in nutritional trials on the growth and metabolism of obese Zucker (fafa) rats and their lean littermates in comparison with pair-fed controls. All diets contained 100 g total protein/kg and either 50 g lipids/kg (low fat) or 150 g lipids/kg (moderate fat). The growth of both obese and lean rats on bean diets was retarded by the daily bean intake in a dose-dependent manner. However, most of this was because bean-fed rats contained less body fat than the controls after 10 d. Thus, after feeding low-fat diets containing up to 130 g kidney bean/kg (lectin intake < or = 0.2 g/kg body weight (BW) per d) in both 10 d and 70 d trials, the bodies of obese rats contained less fat but not protein than their pair-fed controls. Moreover, by increasing the lipid content of the diet to 150 g/kg, the level of bean inclusion could be increased to 280 g/kg (lectin intake > or = 0.4 g/kg BW per d) without loss of body protein and skeletal muscle. Although these rats contained more body fat than those which were fed on low-fat diets, their weight reduction could be accounted for exclusively by reduced lipid content. In contrast, significant body protein loss occurred when the same diet of high lectin content was fed to lean littermates. Plasma insulin levels were significantly depressed in the obese Zucker rats on bean diets but the pancreas was not significantly enlarged nor its insulin content changed in 10 d trials. However, significant pancreatic growth occurred on long-term (70 d) bean feeding compared with pair-fed controls. The results suggest that, in addition to animal nutrition, it may also be possible to use the bean lectin as a dietary adjunct or therapeutic agent to stimulate gut function and ameliorate obesity if a safe and effective dose-range can be established for human subjects.

Br J Nutr. 1998 Feb;79(2):213-21

Reducing effect of a Phaseolus vulgaris dry extract on operant self-administration of a chocolate-flavoured beverage in rats.

Extracts from or derivatives of Phaseolus vulgaris beans reduce body weight and food intake, including highly palatable foods and fluids, in multiple rodent models of overeating and obesity. The present study was designed to assess whether a standardised P. vulgaris dry extract was effective in reducing also the operant self-administration of a chocolate-flavoured beverage. To this end, rats were initially trained to lever-press for a chocolate-flavoured beverage under a fixed ratio 10 schedule of reinforcement in daily 60 min sessions. Once lever-responding reached stable levels, the effect of a P. vulgaris dry extract on the number of lever-responses for the chocolate-flavoured beverage was determined. Pretreatment with 50, 200 and 500 mg (intragastric) P. vulgaris dry extract per kg produced an approximate 15, 35 and 40 % reduction, respectively, in lever-responding for the chocolate-flavoured beverage. These results indicate the capacity of a P. vulgaris preparation to reduce the reinforcing properties of a highly palatable fluid in rats.

Br J Nutr . 2010 Sep;104(5):624-8

Reducing effect of a combination of Phaseolus vulgaris and Cynara scolymus extracts on operant self-administration of a chocolate-flavoured beverage in rats.

Treatment with a rational combination of standardized extracts of Phaseolus vulgaris and Cynara scolymus reduced food intake and glycemia in rats. The present study was designed to assess the effect of this extract combination and of each single extract in an experimental model of food craving, made up of rats displaying exaggerated seeking and taking behaviors for a chocolate-flavoured beverage. After training to lever-respond for the chocolate-flavoured beverage, rats were treated with vehicle, Phaseolus vulgaris extract alone (200 mg/kg), Cynara scolymus extract alone (400 mg/kg), or combination of Phaseolus vulgaris (200 mg/kg) and Cynara scolymus (400 mg/kg) extracts. The Phaseolus vulgaris extract and the extract combination exerted similar and substantial decrements in the number of lever-responses and amount of self-administered chocolate-flavoured beverage; conversely, the Cynara scolymus extract was totally ineffective. These results suggest that (i) the capacity of the extract combination to reduce the self-administration of the chocolate-flavoured beverage entirely relied on the Phaseolus vulgaris extract, (ii) Phaseolus vulgaris extract may interfere with the mechanisms regulating food-related addictive-like behaviors, and (iii) combinations of Phaseolus vulgaris and Cynara scolymus extracts may possess a broad spectrum of activities, from treatment of metabolic syndrome to overweight, obesity, and possibly food-related addictive disorders.

Phytother Res . 2013 Jun;27(6):944-7

Reducing effect of an extract of Phaseolus vulgaris on food intake in mice—focus on highly palatable foods.

Different lines of experimental evidence indicate that treatment with extracts from and derivatives of Phaseolus vulgaris reduces intake of food, including highly palatable foods and beverages, in rats. The present study was designed to extend to mice these lines of evidence. To this end, CD1 mice were treated acutely with a standardized extract of P. vulgaris and then exposed to unlimited access to regular food pellets (Experiment 1) or 1-hour limited access to three different palatable foods/beverages, such as butter cookies (Experiment 2), a condensed-milk beverage (Experiment 3), and a chocolate-flavored beverage (Experiment 4). Treatment with P. vulgaris extract resulted in a significant reduction in the intake of regular food pellets, that was still evident 24h later, as well as of the three palatable nourishments. Together, these results (a) extend to mice several previous findings on the capacity of P. vulgaris extracts to suppress food intake in rats, (b) suggest that P. vulgaris extracts may interfere with the central mechanisms regulating appetite, food intake, palatability, and/or the rewarding and hedonic properties of food, and (c) P. vulgaris extracts may represent a potentially effective therapy for overeating, obesity, and food

Fitoterapia . 2013 Mar;85:14-9

Curcumin attenuates inflammatory response in IL-1beta-induced human synovial fibroblasts and collagen-induced arthritis in mouse model.

Curcumin, a major component of turmeric, has been shown to exhibit anti-oxidant and anti-inflammatory activities. The present study was performed to determine whether curcumin is efficacious against both collagen-induced arthritis (CIA) in mice and IL-1beta-induced activation in fibroblast-like synoviocytes (FLSs). DBA/1 mice were immunized with bovine type II collagen (CII) and treated with curcumin every other day for 2weeks after the initial immunization. For arthritis, we evaluated the incidence of disease and used an arthritis index based on paw thickness. In vitro proliferation of CII- or concanavalin A-induced splenic T cells was examined using IFN-gamma production. Pro-inflammatory cytokines TNF-alpha and IL-1beta were examined in the mouse ankle joint and serum IgG1 and IgG2a isotypes were analyzed. The expression levels of prostaglandin E(2) (PGE(2)), cyclooxygenase-2 (COX-2), and matrix metalloproteinases (MMPs) in human FLSs were also determined. The results showed that compared with untreated CIA mice, curcumin-treated mice downregulated clinical arthritis score, the proliferation of splenic T cells, expression levels of TNF-alpha and IL-1beta in the ankle joint, and expression levels of IgG2a in serum. Additionally, by altering nuclear factor (NF)-kappaB transcription activity in FLSs, curcumin inhibited PGE(2) production, COX-2 expression, and MMP secretion. These results suggest that curcumin can effectively suppress inflammatory response by inhibiting pro-inflammatory mediators and regulating humoral and cellular immune responses.

Int Immunopharmacol. 2010 May;10(5):605-10

Influence of a specific ginger combination on gastropathy conditions in patients with osteoarthritis of the knee or hip.

BACKGROUND: Nonsteroid anti-inflammatory drugs represent an important osteoarthritis (OA) therapy component, but also a leading cause of gastropathy: one of the most frequent and serious OA therapy complications. The aim of the present study was to study the influence of GI health in an OA population receiving either ginger or diclofenac. METHODS: Forty-three (43) patients with confirmed OA (knee and hip) were included in a randomized controlled study. A ginger group of 21 patients (17 women, 4 men) was given a specific ginger combination daily (340 mg EV.EXT 35 Zingiber officinalis extract) for 4 weeks. A diclofenac group (positive control) of 22 patients (18 women, 4 men) received 100 mg diclofenac daily for the same period. Both groups also received 1000 mg glucosamine daily. Gastrointestinal pain and dyspepsia were evaluated according to the severity of dyspepsia assessment (SODA) form. Patients also underwent esophagogastroduodenoscopy (EGDS) including biopsy before and after the treatment. Serum gastrin-17 levels, and stomach mucosa prostaglandins (PG) E1, E2, F2α, and 6-keto PGF1α (PGI2) levels were measured. Arthritic pain was evaluated using the visual analogue scale (VAS) on standing and moving. RESULTS: The ginger group showed a slight but significantly lowered SODA pain and no change of SODA dyspepsia. EGDS showed significantly increased levels of PGE1, PGE2, and PGF2α in the stomach mucosa. This rise in gastric mucosa PG levels correlated with an increase in serum gastrin-17. On the other hand, the diclofenac group showed increased SODA pain and dyspepsia values with a corresponding significant decrease of stomach mucosa prostaglandins and general negative stomach mucosa degeneration. Both groups showed a relevant and significantly lowered VAS pain both on standing and moving. CONCLUSIONS: The ginger combination is as effective as diclofenac but safer in treating OA, being without effect on the stomach mucosa. The increased mucosal PGs synthesis in the ginger group supports an increased mucosa-protective potential. VAS; visual analogue scale, 0-100 mm.

J Altern Complement Med . 2012 Jun;18(6):583-8

Effect of turmeric oil and turmeric oleoresin on cytogenetic damage in patients suffering from oral submucous fibrosis.

In vitro studies on the effect of alcoholic extracts of turmeric (TE), turmeric oil (TO) and turmeric oleoresin (TOR), on the incidence of micronuclei (Mn) in lymphocytes from normal healthy subjects showed that the test compounds did not cause any increase in the number of Mn as compared with those found in untreated controls. Further it was observed that all three compounds offered protection against benzo[a]pyrene induced increase in Mn in circulating lymphocytes. In subsequent studies, patients suffering from submucous fibrosis were given a total oral dose of TO (600 mg TO mixed with 3 g TE/day). TOR (600 mg + 3 g TE/day) and 3 g TE/day as a control for 3 months. It was observed that all three treatment modalities decreased the number of micronucleated cells both in exfoliated oral mucosal cells and in circulating lymphocytes. TOR was found to be more effective in reducing the number of Mn in oral mucosal cells (P < 0.001), but in circulating lymphocytes the decrease in Mn was comparable in all three groups.

Cancer Lett. 1997 Jun 24;116(2):265-9

Curcumin in cancer chemoprevention: molecular targets, pharmacokinetics, bioavailability, and clinical trials.

Curcumin (diferuloylmethane), a derivative of turmeric is one of the most commonly used and highly researched phytochemicals. Abundant sources provide interesting insights into the multiple mechanisms by which curcumin may mediate chemotherapy and chemopreventive effects on cancer. The pleiotropic role of this dietary compound includes the inhibition of several cell signaling pathways at multiple levels, such as transcription factors (NF-κB and AP-1), enzymes (COX-2, MMPs), cell cycle arrest (cyclin D1), proliferation (EGFR and Akt), survival pathways (β-catenin and adhesion molecules), and TNF. Curcumin up-regulates caspase family proteins and down-regulates anti-apoptotic genes (Bcl-2 and Bcl-X(L)). In addition, cDNA microarrays analysis adds a new dimension for molecular responses of cancer cells to curcumin at the genomic level. Although, curcumin’s poor absorption and low systemic bioavailability limits the access of adequate concentrations for pharmacological effects in certain tissues, active levels in the gastrointestinal tract have been found in animal and human pharmacokinetic studies. Currently, sufficient data has been shown to advocate phase II and phase III clinical trials of curcumin for a variety of cancer conditions including multiple myeloma, pancreatic, and colon cancer.

Arch Pharm (Weinheim). 2010 Sep;343(9):489-99

Antibacterial activity of turmeric oil: a byproduct from curcumin manufacture.

Curcumin, the yellow color pigment of turmeric, is produced industrially from turmeric oleoresin. The mother liquor after isolation of curcumin from oleoresin contains approximately 40% oil. The oil was extracted from the mother liquor using hexane at 60 degrees C, and the hexane extract was separated into three fractions using silica gel column chromatography. These fractions were tested for antibacterial activity by pour plate method against Bacillus cereus, Bacillus coagulans, Bacillus subtilis, Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. Fraction II eluted with 5% ethyl acetate in hexane was found to be most active fraction. The turmeric oil, fraction I, and fraction II were analyzed by GC and GC-MS. ar-Turmerone, turmerone, and curlone were found to be the major compounds present in these fractions along with other oxygenated compounds.

J Agric Food Chem . 1999 Oct;47(10):4297-300

Chemical composition of turmeric oil—a byproduct from turmeric oleoresin industry and its inhibitory activity against different fungi.

Curcumin, the yellow coloring pigment of turmeric is produced industrially from turmeric oleoresin. The mother liquor after isolation of curcumin from oleoresin known as curcumin removed turmeric oleoresin (CRTO) was extracted three times with n-hexane at room temperature for 30 min to obtain turmeric oil. The turmeric oil was subjected to fractional distillation under vacuum to get two fractions. These fractions were tested for antifugal activity against Aspergillus flavus, A. parasiticus, Fusarium moniliforme and Penicillium digitatum by spore germination method. Fraction II was found to be more active. The chemical constituents of turmeric oil, fraction I and fraction II were determined by GC and identified by GC-MS. Aromatic turmerone, turmerone and curlone were major compounds present in fraction II along with other oxygenated compounds.

Z Naturforsch C . 2001 Jan-Feb;56(1-2):40-4

Ginger and its health claims: molecular aspects.

Recent research has rejuvenated centuries-old traditional herbs to cure various ailments by using modern tools like diet-based therapy and other regimens. Ginger is one of the classic examples of an herb used for not only culinary preparations but also for unique therapeutic significance owing to its antioxidant, antimicrobial, and anti-inflammatory potential. The pungent fractions of ginger, namely gingerols, shogaols, paradols, and volatile constituents like sesquiterpenes and monoterpenes, are mainly attributed to the health-enhancing perspectives of ginger. This review elucidates the health claims of ginger and the molecular aspects and targets, with special reference to anticancer perspectives, immunonutrition, antioxidant potential, and cardiovascular cure. The molecular targets involved in chemoprevention like the inhibition of NF-kB activation via impairing nuclear translocation, suppresses cIAP1 expression, increases caspase-3/7 activation, arrests cell cycle in G2 + M phases, up-regulates Cytochrome-c, Apaf-1, activates PI3K/Akt/I kappaB kinases IKK, suppresses cell proliferation, and inducts apoptosis and chromatin condensation. Similarly, facts are presented regarding the anti-inflammatory response of ginger components and molecular targets including inhibition of prostaglandin and leukotriene biosynthesis and suppression of 5-lipoxygenase. Furthermore, inhibition of phosphorylation of three mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinases 1 and 2 (ERK1/2), and c-Jun N-terminal kinase (JNK) are also discussed. The role of ginger in reducing the extent of cardiovascular disorders, diabetes mellitus, and digestive problems has also been described in detail. Although, current review articles summarized the literature pertaining to ginger and its
components. However, authors are still of the view that further research should be immediately carried out for meticulousness.

Crit Rev Food Sci Nutr. 2011 May;51(5):383-93

Molecular inflammation: underpinnings of aging and age-related diseases.

Recent scientific studies have advanced the notion of chronic inflammation as a major risk factor underlying aging and age-related diseases. In this review, low-grade, unresolved, molecular inflammation is described as an underlying mechanism of aging and age-related diseases, which may serve as a bridge between normal aging and age-related pathological processes. Accumulated data strongly suggest that continuous (chronic) upregulation of pro-inflammatory mediators (e.g., TNF-alpha, IL-1beta, IL-6, COX-2, iNOS) are induced during the aging process due to an age-related redox imbalance that activates many pro-inflammatory signaling pathways, including the NF-kappaB signaling pathway. These pro-inflammatory molecular events are discussed in relation to their role as basic mechanisms underlying aging and age-related diseases. Further, the anti-inflammatory actions of aging-retarding caloric restriction and exercise are reviewed. Thus, the purpose of this review is to describe the molecular roles of age-related physiological functional declines and the accompanying chronic diseases associated with aging. This new view on the role of molecular inflammation as a mechanism of aging and age-related pathogenesis can provide insights into potential interventions that may affect the aging process and reduce age-related diseases, thereby promoting healthy longevity.

Ageing Res Rev . 2009 Jan;8(1):18-30

Curcumin inhibits proliferation, invasion, angiogenesis and metastasis of different cancers through interaction with multiple cell signaling proteins.

Because most cancers are caused by dysregulation of as many as 500 different genes, agents that target multiple gene products are needed for prevention and treatment of cancer. Curcumin, a yellow coloring agent in turmeric, has been shown to interact with a wide variety of proteins and modify their expression and activity. These include inflammatory cytokines and enzymes, transcription factors, and gene products linked with cell survival, proliferation, invasion, and angiogenesis. Curcumin has been found to inhibit the proliferation of various tumor cells in culture, prevents carcinogen-induced cancers in rodents, and inhibits the growth of human tumors in xenotransplant or orthotransplant animal models either alone or in combination with chemotherapeutic agents or radiation. Several phase I and phase II clinical trials indicate that curcumin is quite safe and may exhibit therapeutic efficacy. These aspects of curcumin are discussed further in detail in this review.

Cancer Lett. 2008 Oct 8;269(2):199-225

Update on the chemopreventive effects of ginger and its phytochemicals.

The rhizomes of Zingiber officinale Roscoe (Zingiberaceae), commonly known as ginger, is one of the most widely used spice and condiment. It is also an integral part of many traditional medicines and has been extensively used in Chinese, Ayurvedic, Tibb-Unani, Srilankan, Arabic, and African traditional medicines, since antiquity, for many unrelated human ailments including common colds, fever, sore throats, vomiting, motion sickness, gastrointestinal complications, indigestion, constipation, arthritis, rheumatism, sprains, muscular aches, pains, cramps, hypertension, dementia, fever, infectious diseases, and helminthiasis. The putative active compounds are nonvolatile pungent principles, namely gingerols, shogaols, paradols, and zingerone. These compounds are some of the extensively studied phytochemicals and account for the antioxidant, anti-inflammatory, antiemetic, and gastroprotective activities. A number of preclinical investigations with a wide variety of assay systems and carcinogens have shown that ginger and its compounds possess chemopreventive and antineoplastic effects. A number of mechanisms have been observed to be involved in the chemopreventive effects of ginger. The cancer preventive activities of ginger are supposed to be mainly due to free radical scavenging, antioxidant pathways, alteration of gene expressions, and induction of apoptosis, all of which contribute towards decrease in tumor initiation, promotion, and progression. This review provides concise information from preclinical studies with both cell culture models and relevant animal studies by focusing on the mechanisms responsible for the chemopreventive action. The conclusion describes directions for future research to establish its activity and utility as a human cancer preventive and therapeutic drug. The above-mentioned mechanisms of ginger seem to be promising for cancer prevention; however, further clinical studies are warranted to assess the efficacy and safety of ginger.

Crit Rev Food Sci Nutr. 2011 Jul;51(6):499-523

Pre-diabetes, metabolic syndrome, and cardiovascular risk.

Pre-diabetes represents an elevation of plasma glucose above the normal range but below that of clinical diabetes. Pre-diabetes can be identified as either impaired fasting glucose (IFG) or impaired glucose tolerance (IGT). The latter is detected by oral glucose tolerance testing. Both IFG and IGT are risk factors for type 2 diabetes, and risk is even greater when IFG and IGT occur together. Pre-diabetes commonly associates with the metabolic syndrome. Both in turn are closely associated with obesity. The mechanisms whereby obesity predisposes to pre-diabetes and metabolic syndrome are incompletely understood but likely have a common metabolic soil. Insulin resistance is a common factor; systemic inflammation engendered by obesity may be another. Pre-diabetes has only a minor impact on microvascular disease; glucose-lowering drugs can delay conversion to diabetes, but whether in the long run the drug approach will delay development of microvascular disease is in dispute. To date, the drug approach to prevention of microvascular disease starting with pre-diabetes has not been evaluated. Pre-diabetes carries some predictive power for macrovascular disease, but most of this association appears to be mediated through the metabolic syndrome. The preferred clinical approach to cardiovascular prevention is to treat all the metabolic risk factors. For both pre-diabetes and metabolic syndrome, the desirable approach is lifestyle intervention, especially weight reduction and physical activity. When drug therapy is contemplated and when the metabolic syndrome is present, the primary consideration is prevention of cardiovascular disease. The major targets are elevations of cholesterol and blood pressure.

J Am Coll Cardiol. 2012 Feb 14;59(7):635-43

Gluconeogenic substrates and hepatic gluconeogenic enzymes in streptozotocin-diabetic rats: effect of mulberry (Morus indica L.) leaves.

Mulberry (Morus indica L.) leaves, the sole food of the silk worm, were evaluated for antidiabetic effects in streptozotocin (STZ)-diabetic rats. Treatment with dried mulberry leaf powder at 25% of the diet for a period of 8 weeks was found to be remarkably beneficial to STZ-diabetic rats as evidenced by controlled hyperglycemia and glycosuria. In addition, mulberry leaves countered (reversed) the alterations in gluconeogenic substrates in STZ-diabetic rats as indicated by significant reduction in serum pyruvic and lactic acid levels, a significant increase in proteins and a significant decrease in free amino acid, urea, and creatinine levels in blood, and a decreased urinary excretion of urea and creatinine. Anomalies in the activities of hepatic gluconeogenic enzymes associated with impaired glucose homeostasis in STZ-diabetic rats were ameliorated by feeding the mulberry leaf-supplemented diet, indicating that control over hyperglycemia and associated complications in the diabetic state by mulberry leaves is by way of regulation of gluconeogenesis. With respect to all the parameters, mulberry leaves were more effective than the oral hypoglycemic drug glibenclamide

J Med Food. 2007 Mar;10(1):41-8.

Effect of mulberry (Morus indica L.) therapy on plasma and erythrocyte membrane lipids in patients with type 2 diabetes.

BACKGROUND: Mulberry (Morus indica L.) is non-toxic natural therapeutic agent shown to possess hypoglycemic, hypotensive, and diuretic properties. METHODS: The hypoglycemic effect of the mulberry leaves was evaluated by comparing the anti-diabetic activity of the standard drug, glibenclamide. A total of 24 type 2 diabetic patents were divided randomly into two treatment groups: the mulberry agent and glibenclamide, for 30 days. Serum and erythrocyte membrane lipid profiles of the patients were analyzed before and after the treatments. RESULTS: Patients with mulberry therapy significantly improved their glycemic control vs. glibenclamide treatment. The results from pre- and post-treatment analysis of blood plasma and urine samples showed that the mulberry therapy significantly decreased the concentration of serum total cholesterol (12%, p<0.01), triglycerides (16%, p<0.01), plasma free fatty acids (12%, p<0.01), LDL-cholesterol (23%, p<0.01), VLDL-cholesterol (17%, p<0.01), plasma peroxides (25%, p<0.01), urinary peroxides (55%, p<0.01), while increasing HDL-cholesterol (18%, p<0.01). Although the patients with glibenclamide treatment showed marginal improvement in glycemic control, the changes in the lipid profile were not statistically significant except for triglycerides (10%, p<0.05), plasma peroxides (15%, p<0.05), and urinary peroxides (19%, p<0.05). Both treatments displayed no apparent effect on the concentrations of the glycosylated hemoglobin (Hb A(1)c) in diabetic patients. However, the fasting blood glucose concentrations of diabetic patients were significantly reduced by the mulberry therapy. CONCLUSIONS: Mulberry therapy exhibits potential hypoglycemic and hypolipidemic effects in diabetic patients.

Clin Chim Acta. 2001 Dec;314(1-2):47-53

Repeated ingestion of the leaf extract from Morus alba reduces insulin resistance in KK-Ay mice.

The objective of this study was to test the hypothesis that repeated ingestion of diet containing the leaf extract from a Morus alba (LEM) maintains the postprandial hypoglycemic response and suppresses the progression of insulin resistance in high-sucrose diet-fed KK-Ay mice with spontaneous type 2 diabetes mellitus (DM). This hypothesis is based on our previous studies where LEM competitively inhibited intestinal disaccharidases and suppressed the elevation of postprandial plasma glucose and insulin levels. Ten KK-Ay mice in each group were raised on 0%, 3%, or 6% LEM powder-containing high-sucrose diets for 8 weeks. Blood samples were collected to measure fasting plasma glucose and insulin levels at weeks 2, 4, and 7 after the start of feeding. Urinary glucose excretion was monitored as a parameter of insulin resistance in 3-day intervals. Fasting plasma glucose level and urinary glucose excretion were significantly lower in both 3% and 6% LEM groups compared with the control group throughout the experiment. The plasma insulin of the 6% LEM group was significantly lower compared with the 3% LEM and control groups. Maintenance of low blood glucose and insulin delayed the onset time of urinary glucose excretion and were reflected by the ratio of additional LEM to sucrose in the diet. We observed the suppressive effects on the progression of hyperglycemia and hyperinsulinemia in the repeated ingestion of the LEM-containing diet. Namely, repeated ingestion of the LEM-containing diet reduces insulin resistance and may delay the appearance of DM, especially type 2 DM. Therefore, daily intake of LEM may be suitable for the prevention of obesity and DM.

Nutr Res. 2011 Nov;31(11):848-54

Sorghum extract exerts an anti-diabetic effect by improving insulin sensitivity via PPAR-g in mice fed a high-fat diet.

This study investigated the hypothesis that a sorghum extract exerts anti-diabetic effects through a mechanism that improves insulin sensitivity via peroxisome proliferator-activated receptor gamma (PPAR-g) from adipose tissue. Seven C57BL/6 mice were fed an AIN-93M diet with fat consisting of 10% of total energy intake (LF) for 14 weeks, and 21 mice were fed a high-fat AIN diet with 60% of calories derived from fat (HF). From week 8, the HF diet-fed mice were orally administered either saline (HF group), 0.5% (0.5% SE group), or 1% sorghum extract (1% SE group) for 6 weeks (n = 7/group). Perirenal fat content was significantly lower in the 0.5% SE and 1% SE groups than that in the HF mice. Levels of total and low-density lipoprotein cholesterol, triglycerides, glucose, and the area under the curve for glucose were significantly lower in mice administered 0.5% SE and 1% SE than those in HF mice. Serum insulin level was significantly lower in mice administered 1% SE than that in HF mice or those given 0.5% SE. PPAR-g expression was significantly higher, whereas the expression of tumor necrosis factor-a was significantly lower in mice given 1% SE compared to those in the HF mice. Adiponectin expression was also significantly higher in mice given 0.5% SE and 1% SE than that in the HF mice. These results suggest that the hypoglycemic effect of SE may be related with the regulation of PPAR-g-mediated metabolism in this mouse model.

Nutr Res Pract. 2012 Aug;6(4):322-7

Anti-diabetic effect of sorghum extract on hepatic gluconeogenesis of streptozotocin-induced diabetic rats.

BACKGROUND: It has been suggested that Sorghum, a rich source of phytochemicals, has a hypoglycemic effect, but the mechanism is unknown. We investigated the effects of oral administration of sorghum extract (SE) on hepatic gluconeogenesis and the glucose uptake of muscle in streptozotocin-induced diabetic rats for six weeks. METHODS: Male Wistar rats were divided in five groups (n=5 per group): normal control (NC), rats with STZ-induced diabetic mellitus (DM), diabetic rats administrated 0.4 g/kg body weight of SE (DM-SE 0.4) and 0.6 g/kg body weight of SE (DM-SE 0.6), and diabetic rats administrated 0.7 mg/kg body weight of glibenclamide (DM-G). RESULTS: Administration of SE and G reduced the concentration of triglycerides, total and LDL-cholesterol and glucose, and the area under the curve of glucose during intraperitoneal glucose tolerance tests down to the levels observed in non-diabetic rats. In addition, administration of 0.4 and 0.6 g/kg SE and 0.7 mg/kg glibenclamide (G) significantly reduced the expression of phosphoenolpyruvate carboxykinase and the phosphor-p38/p38 ratio, while increased phosphor adenosine monophosphate activated protein kinase (AMPK)/AMPK ratio, but the glucose transporter 4 translocation and the phosphor-Akt/Akt ratio was significantly increased only by administration of G. CONCLUSIONS: These results indicate that the hypoglycemic effect of SE was related to hepatic gluconeogenesis but not the glucose uptake of skeletal muscle, and the effect was similar to that of anti-diabetic medication.

Nutr Metab (Lond). 2012 Nov 27;9(1):106

Inhibition of aromatase and α-amylase by flavonoids and proanthocyanidins from Sorghum bicolor bran extracts.

We compared the ability of simple flavonoids and proanthocyanidins in Sorghum bicolor bran extracts to inhibit enzymes in vitro. In particular, aromatase is a target for breast cancer therapy, and inhibition of α-amylase can reduce the glycemic effect of dietary starches. Proanthocyanidin-rich sumac sorghum bran extract inhibited α-amylase at a lower concentration (50% inhibitory concentration [IC₅₀]=1.4 µg/mL) than did proanthocyanidin-free black sorghum bran extract (IC₅₀=11.4 µg/mL). Sumac sorghum bran extract inhibited aromatase activity more strongly than black sorghum bran extract (IC₅₀=12.1 µg/mL vs. 18.8 µg/mL, respectively). Bovine serum albumin (BSA), which binds proanthocyanidins, reduced inhibition by sumac but not black sorghum bran extract. When separated on Sephadex LH-20, sumac sorghum proanthocyanidins inhibited both enzymes but showed reduced inhibition with BSA. Flavonoids from either cultivar had higher IC₅₀ values than proanthocyanidins, and BSA had little effect on their inhibition. Proanthocyanidins and simple flavonoids in LH-20 fractions both inhibited aromatase with mixed kinetics and affected K(m) and V(max). The results show that potential health benefits of sorghum bran may include actions of monomeric flavanoids as well as proanthocyanidins.

J Med Food. 2011 Jul-Aug;14(7-8):799-807

Phloridzin reduces blood glucose levels and improves lipids metabolism in streptozotocin-induced diabetic rats.

Phloridzin is the specific and competitive inhibition of sodium/glucose cotransporters in the intestine (SGLT1) and kidney (SGLT2). This property which could be useful in the management of postprandial hyperglycemia in diabetes and related disorders. Phloridzin is one of the dihydrochalcones typically contained in apples and in apple-derived products. The effect of phloridzin orally doses 5, 10, 20 and 40 mg/kg body weight on diabetes was tested in a streptozotocin-induced rat model of diabetes type 1. From beneficial effect of this compound is significant reduction of blood glucose levels and improve dyslipidemia in diabetic rats. As a well-known consequence of becoming diabetic, urine volume and water intake were significantly increased. Administration of phloridzin reduced urine volume and water intake in a dose-dependent manner. Phloretin decreases of food consumption, as well as a marked lowering in the weight. In conclusion, this compound could be proposed as an antihyperglycemic and antihyperlipidemic agent in diabetes and potential therapeutic in obesity.

Mol Biol Rep. 2012 May;39(5):5299-306

Dietary phloridzin reduces blood glucose levels and reverses Sglt1 expression in the small intestine in streptozotocin-induced diabetic mice.

Phloridzin is a dihydrochalcone typically contained in apples. In this study, it is shown that a diet containing 0.5% phloridzin significantly reduced the blood glucose levels in streptozotocin (STZ)-induced diabetic mice after 14 days. We detected phloridzin in the plasma of STZ-induced diabetic mice fed the phloridzin diet for 14 days, although its concentration was much lower than that of the phloridzin metabolites. A quantitative RT-PCR analysis showed a reversal of STZ induction of the sodium/glucose cotransporter gene Sglt1 and the drug-metabolizing enzyme genes Cyp2b10 and Ephx1 in the small intestine of mice fed a 0.5% phloridzin diet. These mice also showed a reversal of the STZ-mediated renal induction of the glucose-regulated facilitated glucose transporter gene Glut2. Dietary phloridzin improved the abnormal elevations in blood glucose levels and the overexpression of Sglt1, Cyp2b10, and Ephx1 in the small intestine of STZ-induced diabetic mice.

J Agric Food Chem. 2009 Jun 10;57(11):4651-6

Effect of phlorizin on SGLT2 expression in the kidney of diabetic rats.

BACKGROUND: The purpose of our study was to determine whether increased SGLT2 expression in the kidney of diabetic rats was associated with the development of hypertension and to investigate the effect of phlorizin (P) on blood pressure and SGLT2 expression in diabetic rats. METHODS: The animals were divided into two groups: Control (C) and streptozotocin-induced diabetic (D) rats were used to evaluate SGLT2 activity in brush border membrane vesicles (BBMV) using a rapid filtration technique. Others animals were divided into two groups: Normal (NSD) or high salt diet (4%)(HSD), and subdivided in four groups: C, C+P, D, D+P. Systolic blood pressure (SBP) was recorded for 30 days by the use of a telemetric system and at day 30 urine samples (24 h) were collected to evaluate renal function and SGLT2 expression in the renal cortex. RESULTS: At day 30, diabetic animals with NSD or HSD exhibited hyperglycemia, lower body weight, glycosuria, diuresis, decrease natriuresis, increased SBP values and SGLT2 expression. In diabetic rats, phlorizin treatment decreased hyperglycemia and prevented development of hypertension, decreased SGLT2 activity in BBMV but did not modify SGLT2 expression. CONCLUSIONS: In conclusion, SGLT2 inhibition prevented the development of hypertension in diabetic rats as well as hyperglycemia, suggesting a hypertensive mechanism associated with SGLT2 activity and the likelihood that increased SGLT2 expression may be associated with progression of diabetic renal complications.

J Nephrol. 2010 Sep-Oct;23(5):541-6

Life span extension by caloric restriction: an aspect of energy metabolism.

Caloric restriction (CR) may retard aging processes and extend life span in organisms by altering energy-metabolic pathways. In CR rodents, glucose influx into tissues is not reduced, as compared with control animals fed ad libitum (AL), although plasma concentrations of glucose and insulin are lower. Gene expression profiles in rodents have suggested that CR promotes gluconeogenesis and fatty acid biosynthesis in skeletal muscle. In the liver, CR promotes gluconeogenesis but decreases fatty acid synthesis and glycolysis. In lower organisms such as yeasts and nematodes, incomplete blocks in steps of insulin/insulin-like growth factor-1 (IGF-1) signal pathway extend life span. The life-prolonging effect of CR in yeasts requires NPT1 and SIR2 genes, both of which relate to sensing energy status and silencing genes. These findings stress the substantial role of energy metabolism on CR. Future studies on metabolic adaptation and gene silencing with regard to lower caloric intake will be warranted to understand the mechanisms of the anti-aging and life-prolonging effects of CR.

Microsc Res Tech. 2002 Nov 15;59(4):325-30

Induction of epigenetic alterations by dietary and other environmental factors.

Dietary and other environmental factors induce epigenetic alterations which may have important consequences for cancer development. This chapter summarizes current knowledge of the impact of dietary, lifestyle, and environmental determinants of cancer risk and proposes that effects of these exposures might be mediated, at least in part, via epigenetic mechanisms. Evidence is presented to support the hypothesis that all recognized epigenetic marks (including DNA methylation, histone modification, and microRNA (miRNA) expression) are influenced by environmental exposures, including diet, tobacco, alcohol, physical activity, stress, environmental carcinogens, genetic factors, and infectious agents which play important roles in the etiology of cancer. Some of these epigenetic modifications change the expression of tumor suppressor genes and oncogenes and, therefore, may be causal for tumorigenesis. Further work is required to understand the mechanisms through which specific environmental factors produce epigenetic changes and to identify those changes which are likely to be causal in the pathogenesis of cancer and those which are secondary, or bystander, effects. Given the plasticity of epigenetic marks in response to cancer-related exposures, such epigenetic marks are attractive candidates for the development of surrogate endpoints which could be used in dietary or lifestyle intervention studies for cancer prevention. Future research should focus on identifying epigenetic marks which are (i) validated as biomarkers for the cancer under study; (ii) readily measured in easily accessible tissues, for example, blood, buccal cells, or stool; and (iii) altered in response to dietary or lifestyle interventions for which there is convincing evidence for a relationship with cancer risk.

Adv Genet . 2010;71:3-39

Long-term calorie restriction is highly effective in reducing the risk for atherosclerosis in humans.

Little is known regarding the long-term effects of caloric restriction (CR) on the risk for atherosclerosis. We evaluated the effect of CR on risk factors for atherosclerosis in individuals who are restricting food intake to slow aging. We studied 18 individuals who had been on CR for an average of 6 years and 18 age-matched healthy individuals on typical American diets. We measured serum lipids and lipoproteins, fasting plasma glucose and insulin, blood pressure (BP), high-sensitivity C-reactive protein (CRP), platelet-derived growth factor AB (PDGF-AB), body composition, and carotid artery intima-media thickness (IMT). The CR group were leaner than the comparison group (body mass index, 19.6 +/- 1.9 vs. 25.9 +/- 3.2 kg/m(2); percent body fat, 8.7 +/- 7% vs. 24 +/- 8%). Serum total cholesterol (Tchol), low-density lipoprotein cholesterol, ratio of Tchol to high-density lipoprotein cholesterol (HDL-C), triglycerides, fasting glucose, fasting insulin, CRP, PDFG-AB, and systolic and diastolic BP were all markedly lower, whereas HDL-C was higher, in the CR than in the American diet group. Medical records indicated that the CR group had serum lipid-lipoprotein and BP levels in the usual range for individuals on typical American diets, and similar to those of the comparison group, before they began CR. Carotid artery IMT was approximately 40% less in the CR group than in the comparison group. Based on a range of risk factors, it appears that long-term CR has a powerful protective effect against atherosclerosis. This interpretation is supported by the finding of a low carotid artery IMT.

Proc Natl Acad Sci U S A . 2004 Apr 27;101(17):6659-63

Calorie restriction in humans inhibits the PI3K/AKT pathway and induces a younger transcription profile.

Caloric restriction (CR) and down-regulation of the insulin/IGF pathway are the most robust interventions known to increase longevity in lower organisms. However, little is known about the molecular adaptations induced by CR in humans. Here, we report that long-term CR in humans inhibits the IGF-1/insulin pathway in skeletal muscle, a key metabolic tissue. We also demonstrate that CR induces dramatic changes of the skeletal muscle transcriptional profile that resemble those of younger individuals. Finally, in both rats and humans, CR evoked similar responses in the transcriptional profiles of skeletal muscle. This common signature consisted of three key pathways typically associated with longevity: IGF-1/insulin signaling, mitochondrial biogenesis, and inflammation. Furthermore, our data identify promising pathways for therapeutic targets to combat age-related diseases and promote health in humans.

Aging Cell. 2013 Aug;12(4):645-51

Epigenetics: mechanisms and implications for diabetic complications.

Epigenetic modifications regulate critical functions that underlie chromosome metabolism. Understanding the molecular changes to chromatin structure and the functional relationship with altered signaling pathways is now considered to represent an important conceptual challenge to explain diabetes and the phenomenon of metabolic or hyperglycemic memory. Although it remains unknown as to the specific molecular mechanisms whereby hyperglycemic memory leads to the development of diabetic vascular complications, emerging evidence now indicates that critical gene-activating epigenetic changes may confer future cell memories. Chemical modification of the H3 histone tail of lysine 4 and 9 has recently been identified with gene expression conferred by hyperglycemia. The persistence of these key epigenetic determinants in models of glycemic variability and the development of diabetic complications has been associated with these primary findings. Transient hyperglycemia promotes gene-activating epigenetic changes and signaling events critical in the development and progression of vascular complications. As for the role of specific epigenomic changes, it is postulated that further understanding enzymes involved in writing and erasing chemical changes could transform our understanding of the pathways implicated in diabetic vascular injury providing new therapeutic strategies.

Circ Res. 2010 Dec 10;107(12):1403-13

Insulin, IGF-1 and longevity.

It has been demonstrated in invertebrate species that the evolutionarily conserved insulin and insulin-like growth factor (IGF) signaling (IIS) pathway plays a major role in the control of longevity. In the roundworm Caenorhabditis elegans, single mutations that diminish insulin/IGF-1 signaling can increase lifespan more than twofold and cause the animal to remain active and youthful much longer than normal. Likewise, substantial increases in lifespan are associated with mutations that reduce insulin/IGF-1 signaling in the fruit fly Drosophila melanogaster. In invertebrates, multiple insulin-like ligands exist that bind to a common single insulin/IGF-1 like receptor. In contrast, in mammals, different receptors exist that bind insulin, IGF-1 and IGF-2 with different affinities. In several mouse models, mutations that are associated with decreased GH/IGF-1 signaling or decreased insulin signaling have been associated with enhanced lifespan. However, the increased complexity of the mammalian insulin/IGF-1 system has made it difficult to separate the roles of insulin, GH and IGF-1 in mammalian longevity. Likewise, the relevance of reduced insulin and IGF-1 signaling in human longevity remains controversial. However, studies on the genetic and metabolic characteristics that are associated with healthy longevity and old age survival suggest that the conserved ancient IIS pathway may also play a role in human longevity.

Aging Dis. 2010 Oct;1(2):147-57

Decisions on life and death: FOXO Forkhead transcription factors are in command when PKB/Akt is off duty.

Forkhead transcription factors of the FOXO family are important downstream targets of protein kinase B (PKB)/Akt, a kinase shown to play a decisive role in cell proliferation and cell survival. Direct phosphorylation by PKB/Akt inhibits transcriptional activation by FOXO factors, causing their displacement from the nucleus into the cytoplasm. Work from recent years has shown that this family of transcription factors regulates the expression of a number of genes that are crucial for the proliferative status of a cell, as well as a number of genes involved in programmed cell death. As such, these transcription factors appear to play an essential role in many of the effects of PKB/Akt on cell proliferation and survival. Indeed, in cells of the hematopoietic system, mere activation of a FOXO factor is sufficient to activate a variety of proapoptotic genes and to trigger apoptosis. In contrast, in most other cell types, activation of FOXO blocks cellular proliferation and drives cells into a quiescent state. In such cell types, FOXO factors also provide the protective mechanisms that are required to adapt to the altered metabolic state of quiescent cells. Thus, as PKB/Akt signaling is switched off, FOXO factors take over to determine the fate of a cell, long-term survival in a quiescent state, or programmed cell death. This review summarizes our current understanding of the mechanisms by which PKB/Akt and FOXO factors regulate these decisions.

J Leukoc Biol . 2003 Jun;73(6):689-701

Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction.

Caloric restriction (CR) extends the life span and health span of a variety of species and slows the progression of age-related hearing loss (AHL), a common age-related disorder associated with oxidative stress. Here, we report that CR reduces oxidative DNA damage in multiple tissues and prevents AHL in wild-type mice but fails to modify these phenotypes in mice lacking the mitochondrial deacetylase Sirt3, a member of the sirtuin family. In response to CR, Sirt3 directly deacetylates and activates mitochondrial isocitrate dehydrogenase 2 (Idh2), leading to increased NADPH levels and an increased ratio of reduced-to-oxidized glutathione in mitochondria. In cultured cells, overexpression of Sirt3 and/or Idh2 increases NADPH levels and protects from oxidative stress-induced cell death. Therefore, our findings identify Sirt3 as an essential player in enhancing the mitochondrial glutathione antioxidant defense system during CR and suggest that Sirt3-dependent mitochondrial adaptations may be a central mechanism of aging retardation in mammals.

Cell. 2010 Nov 24;143(5):802-12

Glucose restriction can extend normal cell lifespan and impair precancerous cell growth through epigenetic control of hTERT and p16 expression.

Cancer cells metabolize glucose at elevated rates and have a higher sensitivity to glucose reduction. However, the precise molecular mechanisms leading to different responses to glucose restriction between normal and cancer cells are not fully understood. We analyzed normal WI-38 and immortalized WI-38/S fetal lung fibroblasts and found that glucose restriction resulted in growth inhibition and apoptosis in WI-38/S cells, whereas it induced lifespan extension in WI-38 cells. Moreover, in WI-38/S cells glucose restriction decreased expression of hTERT (human telomerase reverse transcriptase) and increased expression of p16(INK4a). Opposite effects were found in the gene expression of hTERT and p16 in WI-38 cells in response to glucose restriction. The altered gene expression was partly due to glucose restriction-induced DNA methylation changes and chromatin remodeling of the hTERT and p16 promoters in normal and immortalized WI-38 cells. Furthermore, glucose restriction resulted in altered hTERT and p16 expression in response to epigenetic regulators in WI-38 rather than WI-38/S cells, suggesting that energy stress-induced differential epigenetic regulation may lead to different cellular fates in normal and precancerous cells. Collectively, these results provide new insights into the epigenetic mechanisms of a nutrient control strategy that may contribute to cancer therapy as well as antiaging approaches.

FASEB J. 2010 May;24(5):1442-53.

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