Cancer-related hypercalcemia in oral cancer.

Cancer-related hypercalcemia (CRH) is a critical paraneoplastic disorder in advanced cancer patients. In clinical practice, patients with CRH have a poor prognosis. The medical records of 3198 oral cancer patients with CRH diagnosed at Taichung Veterans General Hospital from 1 January 2003 to 31 December 2015 were reviewed. The criteria for patient enrolment were a diagnosis of hypercalcemia or the use of antihypercalcemia medication. Patients who met any of the following criteria were excluded: use of total parenteral nutrition, incomplete serum calcium data, and unknown date of death. The total incidence of CRH was 6.95‰ per year. A total of 91 patients were enrolled; their median survival time was 28 days. The patients were divided into two groups by survival time, with a cut-off point of 30 days. Reduced serum albumin, leucocytosis, and clodronate use had a statistically significant effect on survival in the univariate analysis (all P<0.05). Forty-five patients (49.5%) had recurrence of CRH, of whom nine died within 30days. These nine patients had a shorter interval to the first episode of CRH recurrence (median 13 days) than those who survived ≥30days (median 28 days) (P<0.001). It was observed that a short interval to the first episode of CRH recurrence is a poor prognostic factor.

Mitigating ammonia nitrogen deficiency in dairy wastewaters for algae cultivation.

This study demonstrated that the limiting factor to algae growth on dairy wastewater was the ammonia nitrogen deficiency. Dairy wastewaters were mixed with a slaughterhouse wastewater that has much higher ammonia nitrogen content. The results showed the mixing wastewaters improved the nutrient profiles and biomass yield at low cost. Algae grown on mixed wastewaters contained high protein (55.98-66.91%) and oil content (19.10-20.81%) and can be exploited to produce animal feed and biofuel. Furthermore, algae grown on mixed wastewater significantly reduced nutrient contents remained in the wastewater after treatment. By mitigating limiting factor to algae growth on dairy wastewaters, the key issue of low biomass yield of algae grown on dairy wastewaters was resolved and the wastewater nutrient removal efficiency was significantly improved by this study.

Growing Chlorella sp. on meat processing wastewater for nutrient removal and biomass production.

In this work, Chlorella sp. (UM6151) was selected to treat meat processing wastewater for nutrient removal and biomass production. To balance the nutrient profile and improve biomass yield at low cost, an innovative algae cultivation model based on wastewater mixing was developed. The result showed that biomass yield (0.675-1.538 g/L) of algae grown on mixed wastewater was much higher than that on individual wastewater and artificial medium. Wastewater mixing eased the bottleneck for algae growth and contributed to the improved biomass yield. Furthermore, in mixed wastewater with sufficient nitrogen, ammonia nitrogen removal efficiencies (68.75-90.38%) and total nitrogen removal efficiencies (30.06-50.94%) were improved. Wastewater mixing also promoted the synthesis of protein in algal cells. Protein content of algae growing on mixed wastewater reached 60.87-68.65%, which is much higher than that of traditional protein source. Algae cultivation model based on wastewater mixing is an efficient and economical way to improve biomass yield.

Monoclonal antibodies as surrogate receptors in a high throughput screen for compounds that enhance insulin sensitivity.

Monoclonal antibodies (MoAbs) were made to a known insulin sensitivity enhancer (ISE) compound, CS-045. The MoAbs were characterized with respect to binding other known thiazolidinedione ISE compounds using a CS-045 labeled with b-phycoerythrin in a competitive particle concentration fluorescence immunoassay (PCFIA). By comparing the rank order of IC50 values for each compound to its respective potency as an ISE, one MoAb (13E3) was selected for further characterization. This MoAb was also used as a surrogate receptor in a high throughput screen to identify novel compounds that compete for binding to CS-045. Some of the hits were found to have efficacy in reducing blood glucose. Subsequently, another group reported that several compounds with the core thiazolidinedione structure of the ISE compounds bound with high affinity to peroxisome proliferator-activating receptors (PPAR). Therefore, we used the MoAb assay to test these and other compounds that are known to bind to PPARgamma and noted crossreactivity with some of the compounds.

Beta-agonists as antiobesity, antidiabetic and nutrient partitioning agents.

In the past decade, the antiobesity, antidiabetic and nutrient partitioning activities of beta-agonists have been extensively studied. The data generated from these compounds in experimental and farm animals have convincingly proved that body fat content and body weight can be modified to some degree by a metabolic agent without decreasing food consumption. Marginal antiobesity and antidiabetic activities in humans have been demonstrated with a few mixed beta-agonists under certain conditions, but their utility is limited by side effects. The concept of a beta 3-receptor rose from the study of these compounds and has been verified by the cloning and expression of this receptor from several species. Rat beta 3-selective agonists have so far shown no antiobesity efficacy in humans. The resolution of several issues is critical for the discovery and development of efficacious antiobesity and antidiabetic agents with minimum side effects. Ultimately, the further investigation of these beta-agonists and beta-receptors should lead to a better understanding of the relationship between energy metabolism and feeding behavior.

Antiobesity and antidiabetic beta-agonists: lessons learned and questions to be answered.

In several species of obese animals, a group of phenethanolamine beta-agonists stimulates lipolysis and thermogenesis, resulting in the loss of body fat and weight. Brown adipose tissue is considered to be the major target tissue for the antiobesity activity of these compounds. Independent of this antiobesity activity, some of these compounds are also antidiabetic and increase muscle mass. Based on the pharmacological profile of these compounds, a beta3-receptor was proposed and characterized in mouse, rat, and humans. The beta3-receptor in brown adipose tissue has been suggested to mediate the antiobesity activity of these beta-agonists. Whether this receptor is responsible for the antidiabetic activity and whether there is a linkage between the antiobesity/antidiabetic activity and the nutrient partitioning activity is not clear. Clinical trials with these mixed beta-agonists showed marginal antiobesity effects when caloric intake of subjects was restricted. Insulin sensitivity was also improved in some of the trials designed to test the antidiabetic activity of these compounds. Side effects included tachycardia and tremor. To eliminate these side effects, a second generation of compounds was selected for its agonist activity on rat beta3-receptors. Clinical trials with these compounds have shown little increase of energy expenditure even at high doses. Successful development of an antiobesity and antidiabetic drug from this class of compounds will require the elucidation of the physiological role of the human beta3-receptor and the regulatory mechanism between fuel efficiency and feeding behavior.

Dexamethasone-induced hyperglycemia in obese Avy/a (viable yellow) female mice entails preferential induction of a hepatic estrogen sulfotransferase.

Sex steroid sulfotransferases (ST) sulfurylate and thus inactivate estrogens or androgens, producing an androgenized or estrogenized state in the liver. The expression of diabetes in a number of animal models is sexually dimorphic and has been associated with steroidal states. Although the viable yellow (Avy) mutation produces an insulin-resistant obesity syndrome in mice of both sexes, only males develop chronic hyperglycemia. Hyperglycemia was rapidly induced in Avy/a females by dexamethasone (dex). This treatment completely suppressed both endogenous plasma corticosterone and hepatic corticosterone-binding globulin (CBG) mRNA within 24 h. Hyperglycemia in dex-implanted Avy/a females was accompanied by aberrant shifts in hepatic androgen/estrogen balance. This was effected by induction of estrogen sulfotransferase (EST) mRNA together with a > 10-fold increase in enzymatic activity. Similar dex-induced increases in androgen ST or phenol ST were not observed. Prior implantation of estrogen prevented development of hyperglycemia. The time-dependent spontaneous reversal of dex-induced hyperglycemia correlated with re-expression of CBG mRNA transcripts and reduced levels of EST transcripts and enzyme activity. Although dex-induced hyperglycemia was limited to Avy/a females, dex elicited hyperinsulinemia in lean a/a control mice of both sexes and exacerbated constitutive hyperinsulinemia in Avy/a males and females. In summary, dex-induced hyperglycemia in Avy/a females was associated with increased catabolism of hepatic estrogens mediated by induction of EST.

Pancreatic islet cells in preobese yellow Avy/- mice: relation to adult hyperinsulinemia and obesity.

Plasma insulin levels in yellow Avy/- mice begin to increase before the animals are overtly obese. Are the elevated insulin levels in yellow mice primary or secondary to the subsequent obesity? Elevated blood insulin levels in young preobese mice, due to synthesis and release of insulin by increased number of beta cells, would stimulate lipogenesis, resulting in excess lipid deposition and subsequent peripheral insulin resistance. Examination of this possibility was the objective of this study. The beta, alpha, and delta cells in the pancreata of 7-, 14-, and 21-day-old male yellow Avy/A and agouti A/a (BALB/c x VY)F1 hybrid mice were counted with immunohistochemical/morphometric techniques. The insulin and glucagon concentrations in pancreata from male and female mice of the same ages and genotypes were also assayed. In the 21-day-old male mice, the mean number of beta cells/pancreas was significantly greater in the yellow mice than in the agouti mice; however, insulin content and body weight were the same. This suggests that increased beta cell proliferation in yellow mice precedes any detectable genotype-specific increase in pancreatic insulin content or body weight.

Obesity, diabetes, and neoplasia in yellow A(vy)/- mice: ectopic expression of the agouti gene.

The viable yellow A(vy) mutation results in a mottled yellow mouse that is obese, slightly larger than its nonyellow sibs, and more susceptible to tumor formation in those tissues sensitized by the strain genome. The mutation exhibits variable expressivity resulting in a continuum of coat color phenotypes, from clear yellow to pseudoagouti. The mouse agouti protein is a paracrine signaling molecule that induces hair follicle melanocytes to switch from the synthesis of black pigment to yellow pigment. Molecular cloning studies indicate that the obesity and growth effects of the A(vy) mutation result from ectopic expression of the normal agouti gene product. This review seeks to summarize the current state of knowledge regarding the obesity, stimulation of somatic growth, and enhancement of tumor formation caused by the A(vy) mutation, and to interpret these pleiotropic effects in terms of the normal function of the agouti protein.

Sexually low performing male rats die earlier than their high performing peers and (-)deprenyl treatment eliminates this difference.

Out of 1600 sexually inexperienced 28-week old Wistar-Logan male rats 94 sexually inactive ('low performing', LP) and 99 highly active ('high performing', HP) rats were selected. The rats were treated from the 8th month of their life three times a week, subcutaneously, with either 0.9% NaCl or 0.25 mg/kg (-)deprenyl until they died. Their copulatory activity was tested once a week and their learning performance was measured in the shuttle box once in three months. The salt treated LP rats (n = 44) never displayed ejaculation during their life time, they were extremely dull in the shuttle box and lived 134.58 +/- 2.29 weeks. Their (-)deprenyl-treated peers (n = 48) became sexually active, their mating performance was substantially increased and lived 152.54 +/- 1.36 weeks, significantly longer than their salt-treated peers and as long as the salt-treated HP rats. The salt treated HP rats (n = 49) displayed 14.04 +/- 0.56 ejaculations during the first 36-week testing period and due to aging they produced 2.47 +/- 0.23 ejaculations between the 73-108th week of testing. Their learning performance was high. They displayed 78.45 +/- 3.01 conditioned avoidance responses (CAR) during the first 36-week testing period and this dropped to 50.67 +/- 2.99 (p < 0.01) during the 73-108th week of testing. They lived 151.24 +/- 1.36 weeks, significantly (p < 0.001) longer than their LP peers. The (-)depre-nyl-treated HP rats (n = 50) were sexually much more active than their salt-treated peers. They displayed 30.04 +/- 0.85 ejaculations during the first 36-week testing period and 7.40 +/- 0.32 ejaculations between the 73-108th week of testing. Also their learning performance was substantially increased. They produced 113.98 +/- 3.23 CARs during the first 36-week-testing period and 81.68 +/- 2.14 CARs during the 73-108th week of testing. They lived 185.30 +/- 1.96 weeks, significantly more than their salt-treated peers and out of the 50 rats 17 lived longer than the estimated technical life span (TLS).

Ciglitazone prevents and reverses dexamethasone-induced hyperglycemia in female viable yellow mice.

Hypercorticism has been observed in numerous obese and diabetic animal models. Adrenalectomy reduces adiposity, hyperglycemia, hyperinsulinemia, and insulin resistance in these animals. The effects of adrenalectomy can be reversed by glucocorticoid replacement. Male and female viable yellow mice share all phenotypic expressions caused by the viable yellow mutation except that males are hyperglycemic and most females are either normoglycemic or only mildly hyperglycemic. The mechanisms that protect female viable yellow mice from hyperglycemia are not known. Implantation of dexamethasone pellets induced hyperglycemia in female viable yellow mice but had no effect on blood glucose of male viable yellow mice and male and female normal mice. The duration of dexamethasone-induced hyperglycemia correlated to the time endogenous plasma corticosterone levels were suppressed. Plasma insulin levels rose in normal mice but only transiently in viable yellow mice. Ciglitazone prevented and reversed dexamethasone-induced hyperglycemia in female viable yellow mice. Since female viable yellow mice, similar to male viable yellow mice, are obese, hyperinsulinemic and insulin resistant, and since dexamethasone is known to cause insulin resistance, these data suggest that dexamethasone increased insulin resistance to a degree that the protective mechanism was overwhelmed and hyperglycemia was induced. Ciglitazone, a compound known to improve insulin sensitivity, may prevent and reverse dexamethasone-induced hyperglycemia by ameliorating the additional insulin resistance caused by dexamethasone. On a molecular level, since dexamethasone suppresses glucose transport, an insulin-sensitive process in many tissues, whereas ciglitazone and other thiazolidinediones facilitate glucose transport, it is possible that ciglitazone prevents and reverses dexamethasone-induced hyperglycemia by regulating the glucose transport systems in insulin-sensitive tissues.

Extension of lifespan in mice treated with Dinh lang (Policias fruticosum L.) and (-)deprenyl.

The effect of Dinh lang root extract (DLRE) and (-)deprenyl on memory function and lifespan was examined in OFA-1 male mice. Treatments of either DLRE, (-)deprenyl or their combination were carried out 3 times a week starting at 12 months of age and following to the end of life. DLRE and (-)deprenyl significantly increased the memory function as well as surviving time of aged mice. The drug-treated animals showed a lower rate of loss of body weight than saline treated ones. It suggested that DLRE and (-)deprenyl did not prolong lifespan of mice by suppressing food intake. The combined treatment of DLRE and (-)deprenyl proved to be the most effective.

Preclinical pharmacology of fluoxetine, a serotonergic drug for weight loss.

Fluoxetine selectively inhibits serotonin uptake in vitro and in vivo and thus enhances serotonergic function, leading to a decrease in food intake beginning with the first dose and a decrease in body weight or in weight gain after multiple doses of fluoxetine. Fluoxetine and other drugs that increase serotonergic function decrease food intake with characteristics that make them attractive for use in weight reduction. In rats, for instance, fluoxetine and other serotonergic drugs suppress stress-induced eating, suppress carbohydrate consumption selectively, and suppress insulin-induced hyperphagia. Fluoxetine and other serotonergic drugs do not cause amphetamine-like behavioral stimulation in animals and have no known abuse or addiction liability. In obese yellow mice and in normal mice, as in rats, fluoxetine causes a sustained decrease in food intake and body weight. The pharmacologic effects of fluoxetine in animals suggest its potential use in weight-reduction programs in obese humans.

Compound M & B 39890A [N-(3-imidazol-1-ylpropyl)- 2-(3-trifluoromethylbenezensulphonamido)-benzamide hydrochloride], a glucagon and insulin secretion inhibitor, improves insulin sensitivity in viable yellow obese-diabetic mice.

Compound M & B 39890A [N-(3-imidazol-1-ylpropyl)-2- (3-trifluoromethylbenzenesulphonamido)benzamide hydrochloride] had no effect on cellular cAMP and cGMP levels but significantly inhibited insulin and glucagon secretion from freshly isolated normal rat islets stimulated with 10 mM glucose and 20 mM arginine. Daily gavage of the compound for three days lowered the elevated blood glucose and plasma insulin levels in fed, male viable yellow obese-diabetic mice; the minimum effective dose was 25 mg/kg. However, M & B 39890A did not affect the blood glucose level of fasted diabetic mice. In addition, it had no effect on blood glucose levels of normal mice and streptozotocin-diabetic rats. M & B 39890A, fed in the diet at the concentration of 1 mg/g for 42 days, reversed the hyperglycemia of the fed diabetic mice without causing tachyphylaxis and improved the sensitivity to exogenous insulin as demonstrated by the lowering of blood glucose. When M & B 39890A was fed to young male mice destined to become diabetic, the development of hyperglycemia was prevented. Thus, M & B 39890A represents a new class of pharmacological agents that may prove to be effective for the chronic treatment of type II diabetics without the risk of hypoglycemia.

Effects of ciglitazone on endogenous plasma islet amyloid polypeptide and insulin sensitivity in obese-diabetic viable yellow mice.

The role of islet amyloid polypeptide, also known as amylin, in insulin resistance and in the etiology of diabetes has been a subject of debate. Increased plasma amylin levels have been observed in both obese and type II diabetic patients. However, data on endogenous amylin levels with relation to pharmacological interventions have not been reported. In this study, chronic treatment of obese-diabetic viable yellow mice with ciglitazone was shown to significantly alter various parameters. Blood glucose and plasma insulin, triglyceride, and amylin levels were reduced and glucose tolerance in the presence of exogenous insulin was improved. Insulin/amylin ratios which were found to be significantly elevated in diabetic mice as compared to normal controls, were decreased after ciglitazone treatment. However, observed decreases in both amylin and insulin concentrations due to ciglitazone treatment and their subsequent increases upon withdrawal of treatment were correlated, suggesting cosecretion.

Antidiabetic activity of MTP-3115 in normal and diabetic mice.

MTP-3115 is a newly-synthesized thiopyranopyrimidine compound with a structure similar to that of MTP-1403 and MTP-1307. However, the biological profile of MTP-3115 is different from that of MTP-1403 and MTP-1307 (previously reported). Similar to MTP-1403 and MTP-1307, MTP-3115 improves glucose tolerance in both normal and obese-diabetic viable yellow mice with equal potency. However, unlike MTP-1403 and MTP-1307, MTP-3115 also lowers blood glucose of fed and fasted normal and obese-diabetic viable yellow mice. Although the mechanisms of action of MTP-3115 are not elucidated, it is unlikely that its mode of action is similar to that of sulfonylureas because tolbutamide neither improves glucose tolerance nor lowers blood glucose in obese-diabetic viable yellow mice.

Oral hypoglycemic agents. Discovery and structure-activity relationships of phenacylimidazolium halides.

Blood glucose levels in viable, yellow, obese, diabetic mice are reduced following oral administration of phenacylimidazolium halides. Compounds 2 and 3 produced reductions of ca. 40% 2 h after doses of 100 mg/kg po. Since these mice do not respond to sulfonylureas, the glucose-lowering activity of phenacylimidazolium salts in this model suggests a mechanism other than that of stimulating insulin secretion. Only phenacylimidazolium halides with electron-donating groups were active; other azolium salts or variations in the phenacyl portion (alterations in the keto function; chain lengthening or extensive branching) produced inactive compounds.

Stabilization of glycogen stores and stimulation of glycogen synthesis in hepatocytes by phenacyl imidazolium compounds.

LY177507 is representative of a series of phenacyl imidazolium compounds that cause marked lowering of blood glucose levels in animal models of noninsulin-dependent diabetes mellitus. In studies conducted with isolated rat hepatocytes, LY177507 inhibited net glucose production from a variety of substrates, inhibited glycolysis from exogenous glucose and endogenous glycogen, inhibited glycogenolysis, and stimulated glycogenesis. These effects of LY177507 appear to be the consequence of activation of glycogen synthase and inactivation of glycogen phosphorylase. In vivo studies with normal fed rats demonstrated a decrease in blood glucose, an increase in hepatic glycogen stores, and an inactivation of glycogen phosphorylase. Phenacyl imidazolium compounds appear to lower blood glucose levels and affect hepatic carbohydrate metabolism by a mechanism unlike other known hypoglycemic compounds.