The Warburg effect: a balance of flux analysis.

Cancer metabolism is characterized by increased macromolecular syntheses through coordinated increases in energy and substrate metabolism. The observation that cancer cells produce lactate in an environment of oxygen sufficiency (aerobic glycolysis) is a central theme of cancer metabolism known as the Warburg effect. Aerobic glycolysis in cancer metabolism is accompanied by increased pentose cycle and anaplerotic activities producing energy and substrates for macromolecular synthesis. How these processes are coordinated is poorly understood. Recent advances have focused on molecular regulation of cancer metabolism by oncogenes and tumor suppressor genes which regulate numerous enzymatic steps of central glucose metabolism. In the past decade, new insights in cancer metabolism have emerged through the application of stable isotopes particularly from 13C carbon tracing. Such studies have provided new evidence for system-wide changes in cancer metabolism in response to chemotherapy. Interestingly, experiments using metabolic inhibitors on individual biochemical pathways all demonstrate similar system-wide effects on cancer metabolism as in targeted therapies. Since biochemical reactions in the Warburg effect place competing demands on available precursors, high energy phosphates and reducing equivalents, the cancer metabolic system must fulfill the condition of balance of flux (homeostasis). In this review, the functions of the pentose cycle and of the tricarboxylic acid (TCA) cycle in cancer metabolism are analyzed from the balance of flux point of view. Anticancer treatments that target molecular signaling pathways or inhibit metabolism alter the invasive or proliferative behavior of the cancer cells by their effects on the balance of flux (homeostasis) of the cancer metabolic phenotype.

Food-intake dysregulation in type 2 diabetic Goto-Kakizaki rats: hypothesized role of dysfunctional brainstem thyrotropin-releasing hormone and impaired vagal output.

Thyrotropin-releasing hormone (TRH), a neuropeptide contained in neural terminals innervating brainstem vagal motor neurons, enhances vagal outflow to modify multisystemic visceral functions and food intake. Type 2 diabetes (T2D) and obesity are accompanied by impaired vagal functioning. We examined the possibility that impaired brainstem TRH action may contribute to the vagal dysregulation of food intake in Goto-Kakizaki (GK) rats, a T2D model with hyperglycemia and impaired central vagal activation by TRH. Food intake induced by intracisternal injection of TRH analog was reduced significantly by 50% in GK rats, compared to Wistar rats. Similarly, natural food intake in the dark phase or food intake after an overnight fast was reduced by 56-81% in GK rats. Fasting (48h) and refeeding (2h)-associated changes in serum ghrelin, insulin, peptide YY, pancreatic polypeptide and leptin, and the concomitant changes in orexigenic or anorexigenic peptide expression in the brainstem and hypothalamus, all apparent in Wistar rats, were absent or markedly reduced in GK rats, with hormone release stimulated by vagal activation, such as ghrelin and pancreatic polypeptide, decreased substantially. Fasting-induced Fos expression accompanying endogenous brainstem TRH action decreased by 66% and 91%, respectively, in the nucleus tractus solitarius (NTS) and the dorsal motor nucleus of the vagus (DMV) in GK rats, compared to Wistar rats. Refeeding abolished fasting-induced Fos-expression in the NTS, while that in the DMV remained in Wistar but not GK rats. These findings indicate that dysfunctional brainstem TRH-elicited vagal impairment contributes to the disturbed food intake in T2D GK rats, and may provide a pathophysiological mechanism which prevents further weight gain in T2D and obesity.

Potent hyperglycemic and hyperinsulinemic effects of thyrotropin-releasing hormone microinjected into the rostroventrolateral medulla and abnormal responses in type 2 diabetic rats.

We identified ventrolateral medullary nuclei in which thyrotropin-releasing hormone (TRH) regulates glucose metabolism by modulating autonomic activity. Immunolabeling revealed dense prepro-TRH-containing fibers innervating the rostroventrolateral medulla (RVLM) and nucleus ambiguus (Amb), which contain, respectively, pre-sympathetic motor neurons and vagal motor neurons. In anesthetized Wistar rats, microinjection of the stable TRH analog RX77368 (38-150 pmol) into the RVLM dose-dependently and site-specifically induced hyperglycemia and hyperinsulinemia. At 150 pmol, blood glucose reached a peak of 180+/-18 mg% and insulin increased 4-fold. The strongest hyperglycemic effect was induced when RX77368 was microinjected into C1 area containing adrenalin cells. Spinal cord transection at cervical-7 abolished the hyperglycemia induced by RVLM RX77368, but not the hyperinsulinemic effect. Bilateral vagotomy prevented the rise in insulin, resulting in a prolonged hyperglycemic response. The hyperglycemic and hyperinsulinemic effects of the TRH analog in the RVLM was peptide specific, since angiotensin II or a substance P analog at the same dose had weak or no effects. Microinjection of RX77368 into the Amb stimulated insulin secretion without influencing glucose levels. In conscious type 2 diabetic Goto-Kakizaki (GK) rats, intracisternal injection of RX77368 induced a remarkably amplified hyperglycemic effect with suppressed insulin response compared to Wistar rats. RX77368 microinjected into the RVLM of anesthetized GK rats induced a significantly potentiated hyperglycemic response and an impaired insulin response, compared to Wistar rats. These results indicate that the RVLM is a site at which TRH induces sympathetically-mediated hyperglycemia and vagally-mediated hyperinsulinemia, whereas the Amb is mainly a vagal activating site for TRH. Hyperinsulinemia induced by TRH in the RVLM is not secondary to the hyperglycemic response. The potentiated hyperglycemic and suppressed hyperinsulinemic responses in diabetic GK rats indicate that an unbalanced "sympathetic-over-vagal" activation by TRH in brainstem RVLM contributes to the pathophysiology of impaired glucose homeostasis in type 2 diabetes.

Phytoestrogens induce differential estrogen receptor alpha- or Beta-mediated responses in transfected breast cancer cells.

Increased intake of phytoestrogens may be associated with a lower risk of cancer in the breast and several other sites, although there is controversy surrounding this activity. One of the mechanisms proposed to explain the activity of phytoestrogens is their ability to bind and activate human estrogen receptor alpha (ERalpha) and human estrogen receptor beta (ERbeta). Nine phytoestrogens were tested for their ability to transactivate ERalpha or ERbeta at a range of doses. Mammary adenocarcinoma (MCF-7) cells were co-transfected with either ERalpha or ERbeta, and an estrogen-response element was linked to a luciferase reporter gene. Dose-dependent responses were compared with the endogenous ligand 17beta-estradiol. Purified genistein, daidzein, apigenin, and coumestrol showed differential and robust transactivation of ERalpha- and ERbeta-induced transcription, with an up to 100-fold stronger activation of ERbeta. Equol, naringenin, and kaempferol were weaker agonists. When activity was evaluated against a background of 0.5 nM 17beta-estradiol, the addition of genistein, daidzein, and resveratrol superstimulated the system, while kaempferol and quercetin were antagonists at the highest doses. This transfection assay provides an excellent model to evaluate the activation of ERalpha and ERbeta by different phytoestrogens in a breast cancer context and can be used as a screening bioassay tool to evaluate the estrogenic activity of extracts of herbs and foods.

Metabolic sensitivity of pancreatic tumour cell apoptosis to glycogen phosphorylase inhibitor treatment.

Inhibitors of glycogen breakdown regulate glucose homeostasis by limiting glucose production in diabetes. Here we demonstrate that restrained glycogen breakdown also inhibits cancer cell proliferation and induces apoptosis through limiting glucose oxidation, as well as nucleic acid and de novo fatty acid synthesis. Increasing doses (50-100 microM) of the glycogen phosphorylase inhibitor CP-320626 inhibited [1,2-(13)C(2)]glucose stable isotope substrate re-distribution among glycolysis, pentose and de novo fatty acid synthesis in MIA pancreatic adenocarcinoma cells. Limited oxidative pentose-phosphate synthesis, glucose contribution to acetyl CoA and de novo fatty acid synthesis closely correlated with decreased cell proliferation. The stable isotope-based dynamic metabolic profile of MIA cells indicated a significant dose-dependent decrease in macromolecule synthesis, which was detected at lower drug doses and before the appearance of apoptosis markers. Normal fibroblasts (CRL-1501) did not show morphological or metabolic signs of apoptosis likely due to their slow rate of growth and metabolic activity. This indicates that limiting carbon re-cycling and rapid substrate mobilisation from glycogen may be an effective and selective target site for new drug development in rapidly dividing cancer cells. In conclusion, pancreatic cancer cell growth arrest and death are closely associated with a characteristic decrease in glycogen breakdown and glucose carbon re-distribution towards RNA/DNA and fatty acids during CP-320626 treatment.

Effects of cyclo (his-pro) plus zinc on glucose metabolism in genetically diabetic obese mice.

AIMS: The specific objective of this study was to determine acute and long-term effects of cyclo (his-pro) (CHP) plus zinc and l-histidine (CZH) treatment on glucose metabolism in genetically obese (ob/ob), type 2 diabetic mice. METHODS: Acute effects of 0.3 mg of CHP plus 10 mg of zinc and 0.5 mg of l-histidine/kg body weight (BW) on fed blood glucose concentrations and 3-h average of above fasting blood glucose concentrations (TAFGCs), an index of oral glucose tolerance test, in lean and ob/ob mice were determined. To evaluate long-term effects of CZH on TAFGCs, lean and ob/ob mice were treated with drinking water containing increasing doses of CHP (0, 0.5, 1.0 or 1.5 mg/l) plus 10 mg zinc and 0.5 mg of l-histidine/l for 3 weeks. During the treatment period, fed blood glucose concentrations, BW and food and water intake were determined. At the end of the treatment, fasting blood glucose concentrations, TAFGC and fed plasma insulin concentrations were determined. RESULTS: Blood glucose concentrations significantly decreased when CZH was administered acutely via gastric gavage in food-deprived ob/ob mice. Similarly, 1.0 mg/l CHP treatment of mice with fixed amounts of 10 mg zinc and 0.5 mg l-histidine/l was optimal to decrease fed blood glucose and plasma insulin concentrations during a 3-week treatment period in ob/ob mice. TAFGC values in these mice also improved most significantly with the same combination of CHP, zinc and l-histidine used to test for fed blood glucose and plasma insulin levels. Fasting blood glucose concentrations and BW gains also decreased in ob/ob mice treated with 1.0 mg of CHP/l plus the same amount of zinc and l-histidine used in the above experiments. No effects of CZH treatment in lean mice were observed. CONCLUSIONS: CZH is effective in decreasing blood glucose concentrations in genetically obese (ob/ob), type 2 diabetic mice. These data support our working hypothesis that CZH may be an important anti-hyperglycaemic agent.

Stimulation of amylase release by Orexin is mediated by Orexin 2 receptor in AR42J cells.

INTRODUCTION AND AIMS: Orexins have been demonstrated to have mainly central physiological functions, including regulation of food and water intake, sleep, and arousal. However, little is known about their direct peripheral effects, if any. As a first step toward understanding the role of Orexin in non-neuronal tissues or cells, we initiated studies to examine expression of Orexin receptors (OXR) in an established pancreatic tumor cell line AR42J. Secondly, we wanted to determine whether Orexins, in various molecular forms, are active to stimulate any known pancreatic cell functions in AR42J cells. METHODOLOGY: Reverse transcription-PCR analysis was performed to identify the presence of specific Orexin receptor subtypes. Intracellular calcium mobilization and cAMP levels were measured following stimulation by Orexin A and B peptides, their respective C-terminal decapeptide fragments, and hypocretin-2-gly (glycine-extended Orexin B). Release of alpha-amylase was measured in conditioned media after acute stimulation with the set of Orexin peptides for 30 minutes. Cell proliferation was determined by H-thymidine incorporation after 24 hours following treatment with Orexins under serum-free condition. RESULTS: RT-PCR and sequencing results showed that Orexin receptor subtype 2 (OX2R) was the main form expressed in AR42J cells. Orexins stimulated dose-dependent increases in intracellular calcium mobilization with EC50 0.05 nM for Orexin A and 0.1 nM for Orexin B but were unable to stimulate any significant cAMP accumulation or DNA synthesis even at micromolar concentrations. Both Orexin-A and -B, but not hypocretin-2-gly, also stimulated dose-dependent increases in amylase release in the AR42J cells. Orexin-A and -B carboxyl-terminal decapeptides elicited significant but much lower calcium and amylase responses. CONCLUSION: Our data demonstrate that OX2R mediates Ca -dependent amylase release in AR42J cells, suggesting that Orexins may have secretory functions in pancreatic tumor cells.

Effects of arachidonic acid plus zinc on glucose disposal in genetically diabetic (ob/ob) mice.

AIM: The present study is designed to determine whether arachidonic acid (AA) plus zinc improves clinical signs of diabetes in genetically diabetic ob/ob mice. METHODS: In the first study, effects of acute administration of AA plus zinc on glucose disposal were determined in ob/ob and lean mice (n = 6 each). In the second study, ob/ob and lean mice were treated with increasing doses of AA plus zinc for 2 weeks (n = 5 each). Postprandial and fasting blood glucose concentrations, three-hour-area-average above fasting glucose concentration (TAFGC), water and food intake, body weight and plasma insulin concentrations were measured. RESULTS: Acute administration of AA plus zinc significantly increased glucose disposal in ob/ob mice. In the second study, postprandial and fasting blood glucose concentrations, TAFGC, and water and food intake in ob/ob mice treated with AA plus zinc for 2 weeks were significantly decreased compared with those in mice given no AA. Plasma insulin concentrations in both lean and ob/ob mice were not changed by AA treatment in drinking water. CONCLUSIONS: AA plus zinc in drinking water is effective in decreasing blood glucose levels in obese mice. These results indicate that use of these compounds should be considered as a dietary supplement to control hyperglycaemia in patients with type II diabetes.

Diet, nutrition and cancer prevention: where are we going from here?

Since the national declaration of the war on cancer three decades ago, research on carcinogenesis has yielded a tremendous knowledge base on cancer. Cancer cells are the result of multiple genetic defects resulting from exposure to environmental, dietary and infectious agents. Multistep and multistage carcinogenesis may span 20 y or more, a time that provides research and clinical opportunities to suppress this disease in its early and premalignant stages before clinical symptomatic, invasive stages. Where do we go from here? After this year's milestone of gene sequencing accomplishments, further research opportunities arise in pursuing studies on the mechanisms of the acquired capacities of cancer cells, including their limitless replicative potential, sustained angiogenesis and invasion and avoidance of apoptosis. With new DNA chip technology and functional proteomics, complex nutrient-gene interactions may now be investigated. Research on nutrient-gene interactions not only provides pathophysiologic mechanisms of cancer causation and prevention, but also improves the ability to conduct cancer surveillance, crucial in identifying at-risk populations. By combining chemoprevention approaches, from the use of single nutrients to multiple dietary constituents and functional foods, the scope of future cancer prevention strategies will be broadened. Research on eating behavior and changing dietary patterns must be included in any cancer prevention strategy. A new paradigm for diet, nutrition and cancer prevention can be developed using multidisciplinary approaches that include lifestyle and environmental changes, dietary modifications and physical activity consciousness to reduce the burden of cancer not only for high risk individuals but for the general population as well.

Liquid meal replacements and glycemic control in obese type 2 diabetes patients.

OBJECTIVE: Although weight management is an important component in the treatment of type 2 diabetes, there has been concern about the use of liquid meal replacements (MRs) in treating obese patients with type 2 diabetes because of the sugar content of the MRs. The goal of this study was to evaluate the safety and feasibility of using MRs for weight loss in obese patients with type 2 diabetes. RESEARCH METHODS AND PROCEDURES: Seventy-five subjects with type 2 diabetes, treated only with oral agents, were recruited for this 12-week clinical study. Subjects were randomized into three groups using either a MR containing lactose, fructose, and sucrose, a MR in which fructose and sucrose were replaced with oligosaccharides (sugar-free Slim-Fast), or an exchange diet plan (EDP) using the proportion of macronutrients recommended by the American Diabetes Association. RESULTS: Fifty-seven patients (41 MR and 16 EDP) finished the study. None developed serious adverse effects, including major hypoglycemic reactions. Weight losses in the MR 1 and MR 2 groups were comparable (6.4% and 6.7%, respectively) and greater than the weight loss in the EDP group (4.9%). Fasting glucose level was significantly reduced in the MR group compared with the EDP group (p = 0.012). There was a significant reduction in the MR group in total cholesterol and low-density lipoprotein cholesterol that was not seen in the EDP group. DISCUSSION: We have shown that liquid MRs are a safe and effective weight loss tool for obese subjects with type 2 diabetes, and can result in improvements in body weight, glucose, insulin, hemoglobin A1c and lipid levels.

Livistona extract inhibits angiogenesis and cancer growth.

In a screen for naturally occurring angiogenic inhibitors, we have identified an extract from the seed of the plant Livistona chinensis, which has potent anti-angiogenic and anti-tumor activity. The aqueous extract inhibits the in vitro proliferation of endothelial cells and multiple tumor cell lines including mouse fibrosarcoma and human breast and colon cancer. In mouse experiments, this extract suppresses the growth of the subcutaneous fibrosarcoma tumors. When the seed is separated into different components, the shell including the seed skin appears more potent than the inner kernel in tumor suppression. Our results suggest that the extract from the shell of Livistona chinensis may be a potential supplemental source for cancer treatment.

Insulin-leptin-visceral fat relation during weight loss.

INTRODUCTION: The relation between insulin-leptin-visceral fat axis during weight loss has not been studied previously. AIMS: To evaluate the insulin, leptin, and abdominal adiposity relation during weight loss in patients with upper body obesity. METHODOLOGY: Twenty volunteers (7 men, 13 women) with mean age 50.6+/-6.3 (SD) and upper body obesity (weight 105.4+/-12.3 kg, BMI 35.9+/-2.5 kg/m2) were recruited. Participants were enrolled in a one-arm clinical study using a calorie-deficient diet and an escalating dose regimen of sibutramine, starting with 5 mg daily and increasing in 5-mg increments to 20 mg per day. Body weight, insulin, leptin, glucose, lipids, abdominal computed tomography (CT), and total body electrical conductance (TOBEC) were measured serially at weeks 0, 4, 8, 12, and 24. RESULTS: Eighteen patients completed the 6-month study: one man and one woman discontinued because of adverse events. With diet and sibutramine, body weight was significantly and continuously reduced throughout the 6-month study. There was a 16.0% (p = 0.0001) reduction in body weight (p < 0.001) and 22.5% (p = 0.0001) decrease in total body fat mass. Abdominal CT scans showed a 28.3% (p = 0.0001) reduction in total abdominal fat, a 26.0% (p = 0.0001) reduction in subcutaneous fat (p < 0.001), and a 31.0% (p = 0.0003) reduction in visceral fat (p < 0.001). There was a 32.0% (p = 0.0008) reduction in leptin levels and 37.9% (p = 0.0001) reduction in insulin levels between baseline and week 4, but no further significant reduction in leptin and insulin levels was observed for the duration of the study. There was a significant correlation between insulin and leptin concentrations throughout the study (p = 0.0001). Leptin was presented as a function of insulin measured at the same time. Significant associations between visceral abdominal fat, subcutaneous fat, and leptin were also observed. CONCLUSION: In this study, we found that leptin and insulin were related in weight loss. The data suggest that insulin may act as a strong regulator of leptin secretion during weight loss and that circulating leptin levels can be predicted by insulin level. Using sibutramine in conjunction with hypocaloric diet reduced body weight and decreased fat mass significantly. Visceral and subcutaneous abdominal fat depots were shown to decrease. Whether sibutramine exerts any selective reduction of visceral abdominal fat as opposed to total body fat mass will require further clinical investigation.

Inverse associations between plasma lycopene and other carotenoids and prostate cancer.

Although dietary intake of tomatoes and tomato products containing lycopene has been reported to reduce the risk of prostate cancer, few studies have been done on the relationship between plasma lycopene and other carotenoids and prostate cancer. This case-control study was conducted to investigate the effects of plasma lycopene, other carotenoids, and retinol, as well as alpha- and gamma-tocopherols on the risk of prostate cancer. The study included 65 patients with prostate cancer and 132 cancer-free controls; all of them were interviewed using a standard epidemiological questionnaire at the Memorial Sloan-Kettering Cancer Center from 1993 to 1997. Plasma levels of carotenoids, retinol, and tocopherols were measured by high performance liquid chromatography. An unconditional logistic regression model was used in bivariate and multivariate analyses using Statistical Analysis System (SAS). After adjusting for age, race, years of education, daily caloric intake, pack-years of smoking, alcohol consumption, and family history of prostate cancer, significantly inverse associations with prostate cancer were observed with plasma concentrations of the following carotenoids: lycopene [odds ratio (OR), 0.17; 95% confidence interval (CI), 0.04-0.78; P for trend, 0.0052] and zeaxanthin (OR, 0.22; 95% CI, 0.06-0.83; P for trend, 0.0028) when comparing highest with lowest quartiles. Borderline associations were found for lutein (OR, 0.30; 95% CI, 0.09-1.03; P for trend, 0.0064) and beta-cryptoxanthin (OR, 0.31; 95% CI, 0.08-1.24; P for trend, 0.0666). No obvious associations were found for alpha- and beta-carotenes, retinol, and alpha- and gamma-tocopherols. Our study confirmed the inverse associations between lycopene, other carotenoids such as zeaxanthin, lutein, and beta-cryptoxanthin, and prostate cancer. This study provides justification for further research on the associations between lycopene and other antioxidants and the risk of prostate cancer.

Stimulation of intestinal mucosal afferent nerves increases superior mesenteric artery and decreases mesenteric adipose tissue blood flow.

We tested the hypothesis that stimulation of intestinal mucosal afferent nerves produces an increase in superior mesenteric artery (SMA) but a decrease in mesenteric adipose tissue (MAT) blood flow. In anesthetized rats, blood flow in the SMA (pulsed Doppler flowmetry) and MAT (hydrogen gas clearance) was measured simultaneously before and after administration of 0.9% saline, 640 microM capsaicin, or 5% dextrose into the intestinal lumen. The changes in the SMA were 3.8 +/- 3.0, 15.9 +/- 4.0, and 18.8 +/- 7.6%; and those in the MAT, 4.7 +/- 4.0, -11.5 +/- 3.4, and -0.07 +/- 3.4% of baseline, respectively. The data indicate that exposure of the intestinal lumen to an afferent nerve stimulant or nutrient induced a dichotomous pattern of blood flow changes, an increase in the SMA and a reduction in MAT. The capsaicin-sensitive afferent nerves may be instrumental in mediating these energy responses.

An analysis of nine proprietary Chinese red yeast rice dietary supplements: implications of variability in chemical profile and contents.

OBJECTIVES: Some strains of Chinese red yeast rice, when prepared by solid fermentation, produce compounds called monacolins that inhibit cholesterol production. When used as a dietary supplement to achieve and maintain healthy cholesterol levels, Chinese red yeast rice has significant potential to reduce health care costs and contribute to public health by reducing heart disease risk in individuals with moderate elevations of circulating cholesterol levels. Whereas one proprietary strain of Chinese red yeast rice has been demonstrated to lower cholesterol levels significantly in clinical trials, other strains being sold as Chinese red yeast rice dietary supplements have not undergone similar evaluation. In order to determine whether the results of a clinical trial conducted with one strain of Chinese red yeast rice could be generalized to other preparations of Chinese red yeast rice, nine different commercially available dietary supplements were purchased tested for chemical constituents. DESIGN: Monacolins were measured by high performance liquid chromatography (HPLC) that separates the various monacolins in Chinese red yeast rice. Citrinin concentration, a toxic fermentation byproduct, was measured by radioimmunoassay. RESULTS: Total monacolin content varied from 0% to 0.58% w/w and only 1 of 9 preparations had the full complement of 10 monacolin compounds. Citrinin was found at measurable concentrations in 7 of the 9 preparations. CONCLUSIONS: The findings from clinical trials demonstrating significant and clinically relevant cholesterol reduction using a defined Chinese red yeast rice preparation containing 10 different monacolins cannot be generalized to preparations that do not contain the same levels and profile of monacolins. Standardized manufacturing practices should be established for Chinese red yeast rice sold as a dietary supplement in order ensure equivalence of content of active ingredients in preparations being sold to the public and to limit the production of unwanted byproducts of fermentation such as citrinin. In common with other botanical dietary supplements, the full potential of this product will not be realized until standards for production and labeling of Chinese red yeast rice are further developed.

Synergistic antidiabetic activities of zinc, cyclo (his-pro), and arachidonic acid.

Previous studies have already shown that prostate extract (PE) has antidiabetic activity when given to animals and humans. In this study, we explore whether this antidiabetic activity is related to the high concentrations of zinc, cyclo (his-pro) (CHP), and the prostaglandin precursor, arachidonic acid (AA), in prostate tissue. When streptozotocin-induced diabetic rats were given drinking water containing 10 mg/L zinc and 100 mg/L PE for 3 weeks, fasting blood glucose levels and glucose clearance rates, but not plasma insulin levels, were significantly lower than at pretreatment. In subsequent experiments, blood glucose levels in rats given PE for 3 weeks were significantly lower than in rats given distilled water or 10 mg/L zinc alone. However, in rats given 100 mg/L CHP with zinc, blood glucose levels were also lower than in rats given PE alone. Time-course studies in diabetic rats given drinking water containing 20 mg/L Zn, 20 mg/L L-histidine, and 10 mg/L CHP showed that blood glucose levels dropped 209 +/- 53 mg/dL in 1 day and stayed low for 2 weeks. When CHP was replaced with 100 mg AA/L, blood glucose levels dropped 230 +/- 64 mg/dL in 5 days, but returned to the original values 11 days later. Growth rate improved and water consumption decreased significantly in CHP- and AA-treated diabetic rats. High intake of L-histidine and testosterone increased blood glucose concentrations in diabetic rats. To determine optimal dosages of CHP and AA, we gave rats drinking water containing 10 mg/L Zn and 0.5 mg/L L-histidine with various concentrations of CHP or AA. The most effective doses for reducing blood glucose levels were 0.32 mg CHP/kg/day and 11 mg AA/kg/day. These data suggest that the active antidiabetic ingredients in the PE are CHP, zinc, and AA or its precursors.

Green tea and its catechins inhibit breast cancer xenografts.

Investigators have shown that green tea may decrease the risk of cancer. It is widely accepted that the main active component of green tea is epigallocatechin-3-gallate (EGCG). In this study, we examined the effect of green tea on breast cancer growth and endothelial cells in in vitro assays and in animal models. Furthermore, we compared the potency of the different catechin components of green tea extract (GTE), including EGCG. Our data showed that mixed GTE and its individual catechin components were effective in inhibiting breast cancer and endothelial cell proliferation. In mouse experiments, GTE suppressed xenograft size and decreased the tumor vessel density. Our results demonstrated the value of all catechins and argued for the use of a mixed GTE as a botanical dietary supplement, rather than purified EGCG, in future clinical trials.

Acute pancreatitis secondary to pancreatic carcinoma. Study Group Participants.

Acute pancreatitis (AP) has been recognized as a presentation of patients with pancreatic carcinoma (PC). However, the natural history of patients with PC who present with AP as the first manifestation is largely unknown. The aim of this study was to determine the time between the presentation of AP and diagnosis of PC and what factors should alert the clinician to suspect underlying PC in patients with AP. Nineteen physicians completed the survey forms that encompassed 45 patients with a diagnosis of AP preceding a diagnosis of PC. Information included the patient's age, gender, race, conditions that could account for the AP, criteria for diagnosis of AP, severity of AP, criteria for diagnosis of PC, time between the diagnosis of AP and PC, pathology of the carcinoma, extension of the disease, treatment of PC, and survival after the diagnosis of PC. The study population consisted of 45 patients, 27 (60%) men and 18 (40%) women whose average age was 58 years (range, 32-89). Thirty-eight patients were Caucasian, five were black, one was Japanese, and one Arabian. The number of AP episodes before PC diagnosis ranged between one and 15 (mean + 2 SD). AP was mild in 40 (89%) and severe in five (11%). The time between the onset of AP and the diagnosis of PC averaged 34 weeks (range, 1-52). Symptoms on presentation of AP included abdominal pain 45 (100%), weight loss 15 (33%), and jaundice 3 (7%). CA 19-9 was available in 13 patients, eight of whom had levels >100 at the time AP was diagnosed. Abnormal imaging suggestive of PC was detected by ultrasonography in 17 patients, by computed tomography in 30, endoscopic retrograde cholangiopancreatography in 20, and endoscopic ultrasonography in three. Tissue diagnosis was obtained in 43 of 45 (96%) patients; by surgery in 25 patients, needle aspiration in 14, laparoscopy in one, autopsy in two, and lymph node in one. Pathology revealed adenocarcinoma in 37 patients, squamous cell carcinoma in two, undifferentiated carcinoma in two, islet cell in one, and cystadenocarcinoma in one. Surgical findings in 26 patients included 19 with a nonresectable lesion or metastasis and seven patients with resectable lesion for cure. Thirteen patients (28%) were alive 1 year after the diagnosis of PC. The patients had a mean of two (range, one to 15) episodes of AP before the diagnosis of PC, and this was associated with a delay of 34 weeks from AP to diagnosis of PC. Patients with PC who presented with AP were generally older than 50 years of age and the severity of the pancreatitis was mild. The survival rate of patients with PC who presented initially with AP was >25% at 1 year compared with 20% 1 year overall survival of patients with PC. AP seems to be an early presentation of PC and should be sought in patients with idiopathic pancreatitis.