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Picolinic acid (PIC) is a byproduct of tryptophan catabolism through the kynurenine pathway, with anabolic effects on bone in vivo and in vitro. Hence, PIC has been nominated as a possible candidate to treat and/or prevent osteoporosis. However, the effective dose and toxicity of PIC are not known yet. To test the effect of escalating and very high doses of oral PIC, male Sprague-Dawley rats were gavaged PIC: Group 1 (n = 3) received incremental doses of 125, 250 and 500 mg/kg/day PIC on days 1, 3 and 5. Group 2 (n = 3) received 500 mg/kg BID (8 h apart; i.e. 1000 mg/kg/day) PIC on Day 1. Group 3 (n = 3) received 125 mg/kg/day PIC for seven consecutive days. Group 4 (n = 3) received 250 mg/kg/day PIC for seven consecutive days. Groups 1, 3 and 4 rats were euthanized on Day 8. Group 5 (n = 6) received 500 mg/kg/day PIC for two consecutive days and then once a week dose (Days 9, 16 and 23) of 500 mg/kg/dose PIC, until euthanasia (Day 30). Blood and cerebrospinal fluid (CSF) were sampled at euthanasia, and tissues showing abnormalities at necropsy underwent histopathology evaluation. All rats displayed some degree of mild hypercalcemia and hyperkalemia. Rats receiving high doses (500 or 1000 mg/kg/day) of PIC died or were euthanized on humane grounds within the first week after showing clinical neurological signs, with animals later revealed to have brain necrosis and hemorrhage at histopathology. Rats receiving lower doses (125 or 250 mg/kg/day) of PIC completed treatment course without apparent clinical adverse events. In summary, very high doses of PIC (≥500 mg/kg/day) were vascular-neurotoxic. Possible future experiments must consider significantly lower doses., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Many of the behavioral symptoms that define alcohol use disorder (AUD) are thought to be mediated by amplified glutamatergic activity. As a result, previous preclinical studies have investigated glutamate receptor inhibition as a potential pharmacotherapy for AUD, particularly the metabotropic glutamate receptor 5 (mGlu5). In rodents, mGlu5 negative allosteric modulators (NAMs) have been shown to decrease alcohol self-administration. However, their effect on non-human primates has not previously been explored. To bridge this gap, the effects of mGlu5 NAM pretreatment on sweetened alcohol (8% w/v in diluted KoolAid) self-administration in female baboons were evaluated. Two different mGlu5 NAMs were tested: 1) 3-2((-Methyl-4-thiazolyl) ethynyl) pyridine (MTEP) which was administered at a dose of 2 mg/kg IM; and 2) auglurant (N-(5-fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide), a newly developed NAM, which was tested under two different routes (0.001, 0.01, 0.03, 0.1 mg/kg IM and 0.1, 0.3, 1.0 mg/kg PO). MTEP decreased both fixed ratio and progressive ratio responding for sweetened alcohol. Auglurant, administered IM, decreased alcohol self-administration at doses that did not affect self-administration of an alcohol-free sweet liquid reward (0.01 to 0.1 mg/kg). Oral administration of auglurant was not effective in decreasing alcohol self-administration. Our results extend positive findings from rodent studies on mGlu5 regulation of alcohol drinking to female baboons and further strengthen the rationale for targeting mGlu5 in clinical trials for AUD., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Dietary supplementation with the organic chromium (Cr) has been shown to positively affect the immune function of poultry. However, to our knowledge, no experiment has been done to directly compare the impacts of Cr chloride and chromium picolinate (CrPic) on the immune responses of broilers vaccinated with Avian Influenza (AI) virus vaccine. Therefore, the present experiment was conducted to investigate the effects of supplemental Cr sources (Cr chloride and CrPic) and levels on the growth performance and immune responses of broilers vaccinated with AI virus vaccine so as to provide an effective nutritional strategy for improving immune function of broilers. A total of 432 1-day (d)-old male broiler chicks were used in a 1 plus 2×4 design. Chickens were given either a diet without Cr supplementation (control) or diets supplemented with 0.4, 0.8, 1.6, or 3.2 mg Cr/kg as either Cr chloride or CrPic for 42 d. Compared to the control, dietary Cr supplementation had no effect (P>0.05) on average daily gain, average daily feed intake and gain : feed of broilers during the starter and grower phases, but increased (P<0.05) the relative weights of bursa of fabricius on d 21 and thymus, spleen, or bursa of fabricius on d 42, serum antibody titers against AI virus on d 21, 28, 35 and 42, blood T-lymphocyte transformation rate on d 28 and 42, blood T-lymphocyte percentage on d 42, and serum interleukin-2 contents on d 28. Broilers fed the diets supplemented with the inorganic Cr chloride had higher (P<0.05) weights of thymus, spleen and bursa of fabricius than those fed the diets supplemented with the CrPic on d 42. In addition, broilers fed the diets supplemented with the CrPic had higher (P<0.05) antibody titers against AI virus than those fed the diets supplemented with the inorganic Cr chloride on d 21 and 35. These results indicate that dietary Cr supplementation improved immune responses of broilers vaccinated with AI virus, and the inorganic Cr chloride was more effective than the CrPic in increasing the relative weights of lymphoid organs, however, the CrPic was more effective than the inorganic Cr chloride in enhancing the serum antibody titer against AI virus.

Currently, several immunotherapies and BACE (Beta Site APP Cleaving Enzyme) inhibitor approaches are being tested in the clinic for the treatment of Alzheimer's disease. A crucial mechanism-related safety concern is the exacerbation of microhemorrhages, which are already present in the majority of Alzheimer patients. To investigate potential safety liabilities of long-term BACE inhibitor therapy, we used aged amyloid precursor protein (APP) transgenic mice (APP23), which robustly develop cerebral amyloid angiopathy. T2*-weighted magnetic resonance imaging (MRI), a translational method applicable in preclinical and clinical studies, was used for the detection of microhemorrhages throughout the entire brain, with subsequent histological validation. Three-dimensional reconstruction based on in vivo MRI and serial Perls' stained sections demonstrated a one-to-one matching of the lesions thus allowing for their histopathological characterization. MRI detected small Perls' positive areas with a high spatial resolution. Our data demonstrate that volumetric assessment by noninvasive MRI is well suited to monitor cerebral microhemorrhages in vivo. Furthermore, 3 months treatment of aged APP23 with the potent BACE-inhibitor NB-360 did not exacerbate microhemorrhages in contrast to Aβ-antibody β1. These results substantiate the safe use of BACE inhibitors regarding microhemorrhages in long-term clinical studies for the treatment of Alzheimer's disease., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)

Hallmark features of type 2 diabetes mellitus include glucosuria and polyuria. Further, renal aquaporin 2 is pivotal to regulation of fluid excretion and urine osmolality. Accordingly, we tested the hypothesis that the db/db mouse displays increased glucosuria and fluid excretion but reduced urine osmolality in association with decreased renal aquaporin 2 level. In addition, we examined the effect of chromium picolinate (Cr(pic)3) which is purported to improve glycemic control. The db/db mice excreted more urine in association with marked glucose excretion but lower urine osmolality than db/m control group. Light microscopic examination of renal tissue revealed proliferation of tubular structures in db/db compared to the db/m mice, a feature validated with Ki67 immunostaining. Further, these tubules showed generally similar immunostaining intensity and pattern for aquaporin 2 indicating that proliferated tubules are of distal origin. On the other hand, renal aquaporin 2 protein level was significantly higher in the db/db than db/m group. Treatment of db/db mice with Cr(pic)3 reduced plasma glucose and hemoglobin A1c (~15-17%, p<0.05) and Ki67 positive cells but other parameters were similar to their untreated counterparts. Collectively, these findings suggest that proliferation of renal distal tubules and increased aquaporin 2 level likely represent an adaptive mechanism to regulate fluid excretion to prevent dehydration in the setting of marked glucosuria in the db/db mouse, features not affected by Cr(pic)3 treatment. These observations are of relevance to increasing interest in developing therapeutic agents that facilitate renal glucose elimination., (Copyright © 2011 Elsevier Inc. All rights reserved.)

In the world of athletes' nutrition, there are many ethical concerns, because there is the suspicion that in practice, large doses of supplements in athletes are not taken for nutritional purposes. It is beyond the scope of this article to highlight the possible roles of supplements or methods of supplementation in the improvement of athletic performance in elite athletes. Instead, the author briefly reviews some of the substances taken by athletes, with particular attention to their mechanisms of action and the pathways involved. Very often, the effects of many supplements are hormone-related, or supplements influence hormone secretion. Examples of possible links between "supplements or ergogenic compounds" and the endocrine/metabolic system are addressed.

Chromium picolinate, [Cr(pic)(3)], is a popular nutritional supplement found in a variety of consumer products. Despite its popularity, safety concerns over its use have arisen. The supplement has been shown to generate clastogenic damage, mitochondrial damage, oxidative damage, and mutagenic effects in cultured cells and oxidative DNA damage and lipid peroxidation in rats. Recently [Cr(pic)(3)] has been demonstrated to generate heritable genetic change and delays in progeny development in Drosophila melanogaster. Based on the damage to chromosomes of cultured cells and of animal models, similar chromosome damage appeared to be a likely source of the mutagenic effects of the supplement in Drosophila. The current three-part study examines the effects of several chromium-containing supplements and their components on hatching and eclosion rates and success of development of first generation progeny of adult Drosophila fed food containing these compounds. It further examines the effects of the compounds on longevity of virgin male and female adults. Finally, the chromosomes in the salivary glands of Drosophila late in the third instar larval stage, which were the progeny of Drosophila whose diets were supplemented with nutritional levels of [Cr(pic)(3)], are shown to contain on average over one chromosomal aberration per two identifiable chromosomal arms. No aberrations were observed in chromosomes of progeny of untreated flies. The results suggest that human consumption of the supplement should be a matter of concern and continued investigation to provide insight into the requirements of chromium-containing supplements to give rise to genotoxic effects.

Two sources of zinc [ZnSO4.H2O or ZnPicolinate (ZnPic)] supplementation were evaluated for their effects on performance, carcass weight, levels of malondialdehyde, and vitamins C, E, A in Japanese quail (Coturnix coturnix Japonica) exposed to high ambient temperature of 34 degrees C. The birds (n = 360; 10-d-old) were randomly assigned to 12 treatment groups consisting of 3 replicates of 10 birds each in a 2 x 2 x 3 factorial arrangement of treatments (temperatures, zinc sources, zinc levels). Birds were kept in wire cages in a temperature-controlled room at either 22 degrees C (thermoneutral) or 34 degrees C (heat stress) for 8 h/d (0900 to 1700 h) until the end of study, and fed a basal (control) diet or the basal diet supplemented with either 30 or 60 mg of Zn as ZnSO4 H2O or ZnPic/kg of diet. Heat exposure decreased (P = 0.001) live weight gain, feed intake, feed efficiency, and carcass weight when the basal diet was fed. A linear increase in feed intake (P = 0.01) and BW (P = 0.01), and improvement in feed efficiency (P = 0.01) and carcass weight (P < or = 0.05) were found in zinc-supplemented quail reared under heat-stress conditions. Serum vitamin C (P = 0.04), E (P = 0.05), and cholesterol (P = 0.01) concentrations increased linearly, whereas malondialdehyde concentrations decreased linearly (P = 0.02) as dietary zinc sulfate and ZnPic supplementation increased. An interaction between dietary zinc sources, temperature, and levels of supplementation (P < or = 0.05) for these parameters was detected. Serum vitamins C, E, and A concentrations were not different in supplemented birds reared at thermoneutral temperature. Supplementation with zinc improved carcass weight and antioxidant status of birds, and the effects of ZnPic were relatively greater than those of ZnSO4.H2O in heat-stressed quail. Results of the present study suggest that supplementation with ZnPic could be considered to be more protective than ZnSO4.H2O by reducing the negative effects of oxidative stress induced by heat stress in quail.

The effects of picolinic acid (PLA), a product of tryptophan catabolism, on anti- Candida activity of neutrophils were studied. Casein-induced peritoneal neutrophils of C3H/He mice partially inhibited mycelial growth of Candida albicans when cultured with C. albicans for 16 h in vitro. The growth inhibition of Candida was augmented by a combination of neutrophils and more than 4 mM picolinic acid. Especially in the presence of 200 U/ml murine interferon-gamma (IFN-gamma), 2 mM picolinic acid augmented the anti- Candida activity of neutrophils. The physiological significance of the augmenting effects of picolinic acid is discussed.

Human studies suggest that chromium picolinate (CrPic) decreases insulin levels and improves glucose disposal in obese and type 2 diabetic populations. To evaluate whether CrPic may aid in treatment of the insulin resistance syndrome, we assessed its effects in JCR:LA-corpulent rats, a model of this syndrome. Male lean and obese hyperinsulinemic rats were randomly assigned to receive oral CrPic [80 microg/(kg. d); n = 5 or 6, respectively) in water or to control conditions (water, n = 5). After 3 mo, a 120-min intraperitoneal glucose tolerance test (IPGTT) and a 30-min insulin tolerance test were performed. Obese rats administered CrPic had significantly lower fasting insulin levels (1848 +/- 102 vs. 2688 +/- 234 pmol/L; P < 0.001; mean +/- SEM) and significantly improved glucose disappearance (P < 0.001) compared with obese controls. Glucose and insulin areas under the curve for IPGTT were significantly less for obese CrPic-treated rats than in obese controls (P < 0.001). Obese CrPic-treated rats had lower plasma total cholesterol (3.57 +/- 0.28 vs. 4.11 +/- 0.47 mmol/L, P < 0.05) and higher HDL cholesterol levels (1.92 +/- 0.09 vs. 1.37 +/- 0.36 mmol/L, P < 0.01) than obese controls. CrPic did not alter plasma glucose or cholesterol levels in lean rats. Total skeletal muscle glucose transporter (Glut)-4 did not differ among groups; however, CrPic significantly enhanced membrane-associated Glut-4 in obese rats after insulin stimulation. Thus, CrPic supplementation enhances insulin sensitivity and glucose disappearance, and improves lipids in male obese hyperinsulinemic JCR:LA-corpulent rats.

This study was conducted to determine the effects of Cr (chromium picolinate, CrPic) supplementation at various levels (0, 200, 400, 800 or 1200 microg/kg of diet) on egg production, egg quality and serum concentrations of insulin, corticosterone and glucose in laying Japanese quail (Coturnix coturnix japanica) reared under conditions of heat stress (32.5 degrees C). Laying Japanese quail (n = 150; 45 d old) were divided into five groups of 30 birds. The quail were fed either a control diet containing 965 microg Cr/kg diet or the control diet supplemented with 200, 400, 800 or 1200 microg of Cr/kg diet. Increased supplemental chromium increased body weight (P = 0.05, linear), feed intake (P = 0.05, linear), egg production (P = 0.01, linear) and also improved feed efficiency (P = 0.01, linear). Increased supplemental chromium linearly increased egg weight (P = 0.01), eggshell thickness, egg specific gravity (P = 0.05) and Haugh unit (P = 0.01). Serum insulin concentration increased linearly (P = 0.01), whereas corticosterone and glucose concentration decreased linearly (P = 0.05) as dietary chromium increased. The best results were obtained with 1200 microg Cr/kg diet, and chromium supplementation at such a level can be considered to be protective management practice in a quail diet, reducing the negative effects of heat stress.

Chromium competes with iron for binding to transferrin, and high-dose chromium supplementation has been hypothesized to adversely affect iron status. This study examined the effects of chromium picolinate supplementation on hematologic indexes and selected indexes of iron status in 18 men aged 56-69 y who participated in an introductory resistive training program. The men were randomly assigned (double-blind design) to groups (n = 9) that consumed either 17.8 mumol Cr/d (924 micrograms Cr/d) as chromium picolinate or a low-chromium placebo for 12 wk while engaging in resistive training twice weekly (3 sets of 8-12 repetitions at 80% of one repetition maximum for 5 exercises). Hematocrit, hemoglobin, red blood cell (erythrocyte) count, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, red blood cell distribution width, platelet count, and mean platelet volume were within normal clinical ranges and were unchanged by either chromium picolinate supplementation or resistive training. Resistive training decreased total-iron-binding capacity from 38.4 +/- 9.3 to 27.3 +/- 5.6 mumol/L (P < 0.0001) and increased transferrin saturation from 35.7 +/- 16.3% to 45.4 +/- 16.9% (P = 0.050). Chromium picolinate supplementation did not influence these responses. Serum iron concentrations and serum ferritin concentrations were unchanged by either resistive training or chromium picolinate supplementation. These data suggest that high-dose chromium picolinate supplementation for 12 wk did not influence hematologic indexes or indexes of iron metabolism or status in older men. The decrease in total-iron-binding capacity and increase in transferrin saturation (%) with resistive training are largely opposite to changes associated with iron depletion and suggest a novel effect of resistive training on iron transport.

The blood glucose level of rats with streptozotocin (STZ)-induced diabetes has been found to be normalized by administration of vanadyl or vanadate complexes. During our investigations on the development of anti-diabetic vanadyl complexes with various types of coordination mode such as V-O, V-N and V-S, we found that a new bis(picolinato)oxovanadium (IV) complex (VPA) has a strong insulin-mimetic effects as evaluated by an in vitro experiments, in which the inhibition of free fatty acid release in isolated rat adipocytes treated with epinephrine was observed to be similar to that of insulin. VPA was also effective for normalizing the blood glucose level of STZ-induced diabetic rats when given intraperitoneally or orally. The serum glucose level was maintained in the normal range for about 30 days with body weight gain after the end of oral administration of VPA for 14 days. VPA was confirmed to be an orally active and long-term acting insulin-mimetic vanadyl complex to treat insulin-dependent diabetes mellitus (IDDM) in rats.

Twenty-four castrated male pigs were used in a 2 x 2 treatment array to determine the main effects of and interactions between dietary chromium supplementation and pituitary porcine somatotropin (ppST) administration on growth performance and serum hormone and metabolite concentrations. The treatments were 1) control (basal diet); 2) chromium (basal diet+300 micrograms/kg diet added trivalent chromium as chromium picolinate); 3) ppST (100 micrograms/(kg body wt.d); and 4) chromium+ppST. Treatments were administered when pigs weighed between 30 and 60 kg. Blood was collected when pigs weighted 45 and 60 kg. All pigs treated with ppST exhibited improvements in growth performance (P < 0.05). Pigs given chromium showed no improvements in growth rate, feed efficiency or composition of gain. Measurements at 60 kg body weight revealed that ppST increased the cholesterol:HDL cholesterol ratio (P < 0.05). Chromium lowered serum insulin and glucose concentrations relative to controls (P < 0.05) and normalized the increase in glucose and insulin resulting from ppST treatment. No ppST x chromium interactions were noted, suggesting these changes in glucose and insulin metabolism are exerted through different mechanisms. These results indicate that chromium does not affect growth performance of young growing pigs. Chromium does normalize altered hormone and metabolite concentrations resulting from ppST treatment.

Five patients with pancreatic insufficiency were evaluated for presence of impaired handling of orally administered zinc. Six hospital employees, eight alcoholic cirrhotics, and four patients with small bowel disease served as healthy or chronically ill controls. Two zinc tolerance tests (ZTT) were performed on each subject, one test using zinc sulfate and the other using zinc dipicolinate, a putative zinc binding ligand. Healthy controls demonstrated normal ZTT curves, with no significant difference between the two forms of zinc. Chronically ill controls had significantly depressed ZTT curves compared to healthy controls with both forms of zinc administered. In contrast, pancreatic insufficiency patients had significantly depressed ZTT curves with zinc sulfate but not with zinc dipicolinate, demonstrating a 40% reduction in the area under the curve with zinc sulfate compared to healthy controls. Our study shows impaired handling of orally administered zinc sulfate but not zinc dipicolinate in patients with pancreatic insufficiency and suggests normal pancreatic function may play a role in zinc metabolism in man.

The excretion of 65Zn was compared by metabolic balance studies in adult male rats fed purified diets containing 0.8 mmol Zn/kg diet, with and without 40 mmol picolinic acid per kilogram diet, after single intragastric (i.g.) and intraperitoneal (i.p.) doses of the isotope. In a third experiment picolinic acid was introduced for 3 d into the diet of rats prelabeled with 65Zn. The urinary excretion of total zinc was increased by the ingestion of picolinic acid in all three experiments. The urinary and fecal outputs of 65Zn were both consistently greater in picolinic acid-fed rats than in the corresponding control animals. This was particularly marked after i.p. injection of the tracer, and the specific activities of urine and feces from the treated rats were both increased. When picolinic acid was introduced into the diet of prelabeled rats there was a delay of 24 h in the urinary response and 48 h in the fecal response. The residual 65Zn levels were reduced in several tissues from the picolinic acid-fed rats, especially after i.p. administration of the isotope. These observations indicate that dietary picolinic acid increases the turnover of endogenous zinc in addition to enhancing the absorption and excretion of ingested metal, and this has implications for its use in cases of zinc deficiency.